AU741921B2 - Farnesyl transferase inhibitors - Google Patents
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- AU741921B2 AU741921B2 AU56694/98A AU5669498A AU741921B2 AU 741921 B2 AU741921 B2 AU 741921B2 AU 56694/98 A AU56694/98 A AU 56694/98A AU 5669498 A AU5669498 A AU 5669498A AU 741921 B2 AU741921 B2 AU 741921B2
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/72—4,7-Endo-alkylene-iso-indoles
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- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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Description
FARNESYL TRANSFERASE INHIBITORS The present invention relates to novel benzoperhydroisoindole derivatives, to their preparation, to the pharmaceutical compositions which contain them and to their use in the preparation of medicaments.
The protein farnesyl transferase is an enzyme which catalyses the transfer of the farnesyl group from famesyl pyrophosphate (FPP) to the terminal cysteine residue of the tetrapeptide sequence CAAX of a certain number of proteins and in particular of the p21Ras protein, which expresses the ras oncogene.
The ras N- or K-ras) oncogene is known to play a key role in cell signalling pathways and cell division processes. The mutation of the ras oncogene or.
its overexpression is often associated with human cancer: the mutated p21Ras protein is found in many human cancers and in particular in more than 50% of cancers of the colon and 90% of cancers of the pancreas (Kohl et al., Science, 260, 1834-1837, 15 1993).
The inhibition of farnesyl transferase and consequently of the famesylation of the p21Ras protein blocks the ability of the mutated p21Ras protein to induce cell proliferation and to transform normal cells into cancerous cells.
Moreover, it has been demonstrated that farnesyl transferase inhibitors are 20 also active with respect to tumoral cell lines which do not express mutated or S• overexpressed ras but which exhibit the mutation of an oncogene or the overexpression of an oncoprotein, the signalling pathway of which uses the farnesylation of a protein, such as a normal ras (Nagasu et al., Cancer Research 5310-5314, 1995; Sepp-Lorenzino et al., Cancer Research 55, 5302-5309, 1995).
The inhibitors of famesyl transferase are inhibitors of cell proliferation and consequently antitumour and antileukaemic agents.
It has now been discovered, and this is also the subject of this invention, that the novel products of general formula presented hereinbelow possess, entirely surprisingly and unexpectedly, an inhibitory activity for farnesyl transferase and proveto be notable antitumour and antileukaemic agents.
In particular, it has been discovered, according to the invention, that the biological activity of the compounds according to the invention is very markedly improved, contrary to all expectations, by the presence of specific groups (represented by Ar hereinbelow) substituted at the 9 position of the benzoperhydroisoindole skeleton.
In particular, the corresponding compounds exhibit activities which are much higher than those obtained to date with compounds with similar structures but not exhibiting these Ar substituents.
The present invention relates to the novel compounds of general formula I Ar R3 (I) 9 9. 9 which: 15 e9.e Noz y v.
Ar represents a phenyl radical substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and the following radicals: alkyl containing 1 to 4 carbon atoms, such as methyl, alkenyl containing 2 to 4 carbon atoms, hydroxyl, mercapto, alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, cyano or trifluoromethyl, or alkoxy containing 1 to 4 carbon atoms, such as methoxy, the alkyl portion of which is optionally perhalogenated, such as trifluoromethoxy, or a phenyl radical condensed with a 4- to 7-membered heterocycle containing one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms, it being possible for the bicyclic system thus formed to be in particular chosen from 2,3-dihydro-1,4-benzo-dioxin-6-yl or 2,3-dihydrobenzofuran-5-yl or
S"
2,3-dihydrobenzopyran-6-yl radicals or an aromatic or non-aromatic polycyclic radical, such as 1- or 2-naphthyl or or 1,2,3,4-tetra-hydronaphth-6-yl a 5- to 12-membered aromatic or non-aromatic heterocyclic radical incorporating one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms, bonded to the condensed ring via a carbon-carbon bond, the said radical being substituted, if appropriate, by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and the following radicals: alkyl, alkenyl containing 2 to 4 carbon atoms, hydroxyl, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, cyano or trifluoromethyl, preferably Ar represents a 2,3-dihydro-1,4-benzodioxin-6-yl or 2,3-dihydrobenzofuran-5-yl radical or a phenyl radical substituted at the 4 position, preferably by a methyl, trifluoromethyl or methoxy radical; in particular, the 2,3-dihydro-1,4-benzodioxin-6-yl radical; very advantageously, Ar represents a phenyl radical substituted at the 4 position by a methyl radical, with, for all of these radicals, alkyl containing 1 to 4 carbon atoms, R represents a radical of general formula
-(CH
2 2 )n-Z in which X, represents a single bond or an oxygen or sulphur atom, m represents an integer equal to 0 or 1, n represents an integer equal to 0, 1 or 2, one or more methylene radicals can be substituted by a carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, amino, alkylamino or dialkylamino radical with, for all of these radicals, alkyl containing 1 to 4 carbon 30 atoms,
RA,
AIN
Z represents a carboxyl radical, a COOR 6 radical, in which R 6 represents a straight or branched alkyl radical containing 1 to 3 carbon atoms, such as the methyl, or a radical of formula CON(R 7
)(R
8 in which
R
7 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms and R, represents a hydrogen atom, a hydroxyl radical, an arylsulphonyl radical, such as phenyl-sulphonyl, optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms, 15 a 5- to 7-membered heterocycle incorporating one or more o heteroatoms chosen from nitrogen, oxygen or sulphur atoms, it being possible for the said heterocycle to be bonded via a heteroatom, an amino radical optionally substituted by one or two radicals, which are identical or different, chosen from the following radicals: 20 alkyl containing 1 to 4 carbon atoms, So- aryl, such as phenyl, optionally substituted by one or more radicals, which are identical or different, chosen from alkyl or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms, 5- to 7-membered heterocyclyl containing one or more heteroatoms chosen from nitrogen, oxygen and sulphur atoms, arylcarbonyl, such as benzoyl, optionally substituted by one or more radicals, which are identical or different, chosen from alkyl or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms, an alkyloxy radical containing 1 to 6 straight- or branched-chain carbon atoms optionally substituted by a phenyl radical, a straight or branched alkyl radical containing 1 to 6 carbon atoms, such as methyl, optionally substituted by an amino, alkylamino, dialkylamino, hydroxyl, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylthio, alkyloxycarbonyl, carboxyl or cyano radical, an optionally substituted mono- or polycyclic aromatic radical having from 5 to 12 ring members which may or may not incorporate one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms, it being possible for the said aromatic radical to be in particular the 2- or 3- or 4-pyridyl radical, preferably 3-pyridyl or 4-pyridyl, or the N-oxide of pyridine, or it also being possible for the said aromatic radical to be a phenyl radical optionally substituted by one or more halogen atoms or by one or more hydroxyl, amino or trifluoromethyl 15 groups or by one or more alkyl or alkenyl, alkoxy, alkylthio, alkylamino, alkylcarbonyl or C 2 to C 4 alkoxycarbonyl, carbamoyl, alkyl-carbamoyl or dialkylcarbamoyl, the alkyl part of which contains 1 to 8 carbon atoms, or formyl radicals, or alternatively a 1- or 2-naphthyl radical, or 20 preferably, R represents a carboxyl radical or a -COOMe radical or alternatively a
-CON(R
7
)(R
8 radical in which, when R 7 represents a hydrogen atom, R 8 represents a methyl radical substituted by the 3-pyridyl radical; very advantageously, R represents a carboxyl radical; very particularly advantageously, R represents a -CON(R 7
)(R
8 radical in which, when R 7 represents a hydrogen atom, R, represents a methyl radical substituted by the 3-pyridyl radical; Z represents a PO(OR 9 2 radical in which R 9 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms, or 3.0 an -NH-CO-T radical in which T represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms optionally substituted by an amino, carboxyl, alkyloxycarbonyl, hydroxyl; alkyloxy, mercapto or alkylthio radical, or alternatively a -CH2- radical having an anion, such as trifluoromethanesulphonate, as counterion, with, for all of the radicals possessing an alkyl group provided in the definition of Z, alkyl containing 1 to 4 carbon atoms, R, and R 2 which are identical or different, represent a hydrogen atom, a halogen atom or an alkyl radical, an alkyloxy radical, such as methoxy, each optionally substituted by a dialkylamino radical, each alkyl part of which contains 1 10 to 4 carbon atoms or forms, with the nitrogen atom, a saturated heterocycle containing 5 or 6 ring members, an alkylthio radical or an alkyloxycarbonyl radical, or alternatively Ssituated at the ortho position with respect to one another, R, and R 2 form a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms chosen from nitrogen and S 15 oxygen, optionally substituted by a halogen atom or by an alkyl or alkyloxy radical, preferably, one of the R, or R 2 symbols represents a hydrogen atom and the other of the symbols represents a methoxy radical, more advantageously attached at the ortho position of the phenyl ring, with, for all of the radicals possessing an alkyl group provided in the definition of R, and R 2 alkyl containing 1 to 4 carbon atoms,
R
3 and R 4 which are identical or different, represent a hydrogen or halogen atom or an alkyl, hydroxyl, alkyloxy, alkylcarbonyloxy, mercapto, alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino or dialkylamino, alkyloxycarbonylamino, carboxyl, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, formyl, alkylcarbonyl, cyano or trifluoromethyl radical, preferably, either R 3 and R 4 each represent a hydrogen atom or alternatively one of the R 3 or R 4 symbols represents a hydrogen atom and the other of the R 3 or R 4 symbols represents a methoxy radical, more advantageously at the 5 position of the benzoperhydroisoindole nucleus; very advantageously, R 3 and R 4 each represent a hydrogen atom; with, for all of the radicals possessing an alkyl group provided in the definition of R 3 and R 4 alkyl containing 1 to 4 carbon atoms,
R
5 represents a hydrogen atom or an alkyl radical or an alkylthio radical, with, for the definition ofRs, alkyl containing 1 to 4 carbon atoms; preferably, R 5 represents a hydrogen atom or a methyl radical; very advantageously, R 5 represents a hydrogen atom; X represents an oxygen or sulphur atom or one of the following groups: -NHmethylene, alken-1,1-diyl, such as vinyldiyl, or cycloalkan-1,1-diyl containing 3 to 6 carbon atoms, Spreferably, X represents a methylene or vinyldiyl group, S: in a particularly advantageous way, X represents the vinyldiyl group, 15 and Y represents an oxygen or sulphur atom, preferably, Y represents an oxygen atom, in the racemic form or their optical isomers, as well as the salts of the product of general formula 20 In the preceding and succeeding definitions, the "alkyl containing 1 to 8 carbon atoms" radicals or portions defines the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl radicals and the corresponding iso isomers, the "alkyl containing 1 to 6 carbon atoms" radicals or portions defines the methyl, ethyl, propyl, butyl, pentyl and hexyl radicals and the corresponding iso, sec and tert isomers, the "alkyl containing 1 to 4 carbon atoms" radicals or portions defines the methyl, ethyl, propyl and butyl radicals and the corresponding iso, sec and tert isomers, "alkenyls containing 2 to 4 carbon atoms" defines the vinyl, allyl, propen-2- 9**
S.
*0
S
S
*SS*
5555.
yl, buten-1-yl, buten-2-yl and buten-3-yl radicals and the corresponding iso isomers, "alkoxy containing 1 to 4 carbon atoms" defines the methoxy, ethoxy, propoxy and butoxy radicals and the corresponding iso, sec and tert isomers,
"C
2 to C 4 alkoxycarbonyl" defines the methoxy-carbonyl, ethoxycarbonyl and propoxycarbonyl radicals and the corresponding iso, sec and tert isomers.
Preferably, the compounds according to the invention exhibit a general formula in which: Ar represents a 2,3-dihydro-1,4-benzodioxin-6-yl or 2,3-dihydrobenzofuran-5-yl radical or a phenyl radical substituted at the 4 position, preferably by a methyl, trifluoromethyl or methoxy radical, R represents a carboxyl radical or a -COOMe radical or alternatively a
-CON(R
7 radical in which, when R 7 represents a hydrogen atom, R 8 represents a methyl radical substituted by the 3-pyridyl radical, one of the R, or R 2 symbols represents a hydrogen atom and the other of the symbols represents a methoxy radical, more advantageously attached at the ortho position of the phenyl ring, either R 3 and R 4 each represent a hydrogen atom or one of the R 3 or R 4 symbols represents a hydrogen atom and the other of the R 3 or R 4 symbols represents a methoxy radical, more advantageously at the 5 position of the benzoperhydroisoindole nucleus,
R
5 represents a hydrogen atom or a methyl radical, X represents a methylene or vinyldiyl group, Y represents an oxygen atom; in the racemic form or their optical isomers, as well as their salts.
According to the invention, the compounds of general formula are preferably provided in the dextrorotatory form.
As it is possible for the technical effect of the compounds presented here, that is to say the biological activity, to be related to the specific nature of the Ar substituents defined as above, the compounds according to the invention are in particular the compounds of general formula in which R, R 2 R R 4
R
5 X and Y are defined R/ Ll f Li)i as above and which can be characterized in that Ar represents a phenyl radical substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and the following radicals: alkyl containing 1 to 4 carbon atoms, such as methyl, alkenyl containing 2 to 4 carbon atoms, hydroxyl, mercapto, alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, cyano or trifluoromethyl, or alkoxy containing 1 to 4 carbon atoms, such as methoxy, the alkyl portion of which is optionally perhalogenated, such as trifluoromethoxy, or a phenyl radical condensed with a 4- to 7-membered heterocycle containing one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms, it being possible for the bicyclic system thus formed to be in particular chosen from 2,3-dihydro-1,4benzodioxin-6-yl or 2,3-dihydrobenzofuran-5-yl or 2,3-dihydrobenzopyran-6-yl Sradicals or 15 an aromatic or non-aromatic polycyclic radical, such as 1- or 2-naphthyl or or 1,2,3,4-tetrahydronaphth-6-yl a 5- to 12-membered aromatic or non-aromatic heterocyclic radical incorporating one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms, bonded to the condensed ring via a carbon-carbon bond, the said radical being substituted, if S 20 appropriate, by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and the following radicals: alkyl, alkenyl containing 2 to 4 carbon atoms, hydroxyl, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, cyano or trifluoromethyl, preferably Ar represents a 2,3-dihydro- 1,4-benzo-dioxin-6-yl or 2,3-dihydrobenzofuran-5-yl radical or a phenyl radical substituted at the 4 position, preferably by a methyl, trifluoromethyl or methoxy radical; in particular, the 2,3-dihydro-l,4-benzodioxin-6-yl radical; very advantageously, Ar represents a phenyl radical substituted at the 4 position by a methyl radical.
1 The compounds of general formula I in which: Ar represents a phenyl radical substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl, alkenyl containing 2 to 4 carbon atoms, hydroxyl, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkyl-carbamoyl, cyano or trifluoromethyl radicals, or a polycyclic aromatic radical, such as 1- or 2-napthyl or 5-indanyl, or a 5- to 12-membered heterocyclic aromatic radical incorporating one or more heteroatoms chosen from oxygen, nitrogen and sulphur 15 atoms, bonded to the condensed ring via a carbon-carbon bond, the said radical being substituted, if appropriate, by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and the following radicals: alkyl, alkenyl containing 2 to 4 carbon :atoms, hydroxyl, alkoxy containing 1 to 4 carbon atoms, mercapto, S 20 alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, cyano or trifluoromethyl, with, for all of these radicals, alkyl containing 1 to 4 carbon atoms, R represents a radical of general formula
-(CH
2 )m-Xi-(CH 2 )n-Z in which X, represents a single bond or an oxygen or sulphur atom, m represents an integer equal to 0 or 1, -0 LU
C
)V7TO^ n represents an integer equal to 0, 1 or 2, the methylene radicals can be substituted by a carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, amino, alkylamino or dialkylamino radical with, for all of these radicals, alkyl containing 1 to 4 carbon atoms, 4 0 0 0t 4 0 0 0 00* 0 0* S. Z represents a carboxyl radical, a COOR 6 radical, in which R 6 represents a straight or branched alkyl radical containing 1 to 3 carbon atoms, or a radical of formula CON(R 7
)(R
8 in which
R
7 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms and
R
8 represents a hydrogen atom, a hydroxyl radical, an amino, alkylamino or dialkylamino radical with alkyl containing from 1 to 4 carbon atoms, an alkyloxy radical containing 1 to 6 straight- or branched-chain carbon atoms optionally substituted by a phenyl radical, a straight or branched alkyl radical containing 1 to 6 carbon atoms, and preferably a methylene group, optionally substituted by an amino, alkylamino, dialkylamino, hydroxyl, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylthio, alkyloxycarbonyl, carboxyl or cyano radical, a mono- or polycyclic aromatic radical having from 5 to 12 ring members which may or may not incorporate one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms and, if appropriate, substituted, which can be a phenyl radical substituted by one or more halogen atoms or by a hydroxyl,
RA
Fzr -12amino or trifluoromethyl group or by an alkyl or alkenyl, alkoxy, alkylthio, alkylamino, alkylcarbonyl or C 2 to C 4 alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, containing 1 to 8 carbon atoms, or formyl radical, or alternatively a 1-naphthyl or 2-naphthyl radical or, Z represents a PO(OR 9 2 radical in which R 9 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms, or an -NH-CO-T radical in which T represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms optionally substituted by an amino, carboxyl, alkyloxycarbonyl, hydroxyl, alkyloxy, a -CH 2 N radical *mercapto or alkylthio radical, or alternativelywith, for all of the radicals possessing an alkyl group provided in the definition of Z, alkyl containing 1 to 4 carbon atoms, and R2, which are identical or different, represent a hydrogen atom, a 15 halogen atom or an alkyl radical, an alkyloxy radical optionally substituted by a dialkylamino radical, each alkyl part of which contains 1 to 4 carbon atoms or forms, with the nitrogen atom, a saturated heterocycle containing 5 or 6 ring members, an alkylthio radical or an alkyloxy-carbonyl radical, or alternatively situated at the ortho position with respect to one another, R, and R2 form a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms chosen from nitrogen and oxygen, optionally substituted by a halogen atom or by an alkyl or alkyloxy radical, with, for all of the radicals possessing an alkyl group provided in the definition of R, and R2, alkyl containing 1 to 4 carbon atoms, R3 and R4, Which are identical or different, represent a halogen atom or an alkyl, hydroxyl, alkyloxy, alkylcarbonyloxy, mercapto, alkylthio, alkylsulphonyl or
C
o mercapto or alkylthio radical, or alternativelywith, for all of the radicals possessing an alkyl group provided in the definition of Z, alkyl containing 1 to 4 carbon atoms, 15 R and R 2 which are identical or different, represent a hydrogen atom, a 15 halogen atom or an alkyl radical, an alkyloxy radical optionally substituted by a dialkylamino radical, each alkyl part of which contains 1 to 4 carbon atoms or forms, with the nitrogen atom, a saturated heterocycle containing 5 or 6 ring members, an alkylthio radical or an alkyloxy-carbonyl radical, or alternatively situated at the ortho position with respect to one another, R and R 2 form a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms chosen from nitrogen and oxygen, optionally substituted by a halogen atom or by an alkyl or alkyloxy radical, with, for all of the radicals possessing an alkyl group provided in the definition of R and R 2 alkyl containing 1 to 4 carbon atoms,
R
3 and R 4 which are identical or different, represent a halogen atom or an alkyl, hydroxyl, alkyloxy, alkylcarbonyloxy, mercapto, alkylthio, alkylsulphonyl or 0 -13alkylsulphinyl, amino, alkylamino or dialkylamino, alkylcarbonyloxyamino, carboxyl, alkyl-oxycarbonyl, carbamoyl, alkylcarbamoyl or dialkyl-carbamoyl, formyl, alkylcarbonyl, cyano or trifluoromethyl radical, with, for all of the radicals possessing an alkyl group provided in the definition of R 3 and R 4 alkyl containing 1 to 4 carbon atoms,
R
5 represents a hydrogen atom, X represents an oxygen or sulphur atom or one of the following groups: -NHmethylene, alken-1,l-diyl, such as vinyldiyl, or cycloalkan-1,1-diyl containing 3 to 6 carbon atoms, and Y represents an oxygen or sulphur atom, in the racemic form, as well as the optical isomers of the product of general formula are of very particular interest.
Mention will very particularly be made, as preferred compounds according to the present invention, of those represented in the general formula I in 15 which R represents a radical S*
-(CH
2 )m-Xi-(CH 2 )n-CONH-CH 2 -Ar' with m, n and X, being as defined above and Ar' preferably representing therein a phenyl optionally substituted by one or more radicals chosen from alkoxys containing 1 to 4 carbon atoms, trifluoromethyl, 1- or 2-naphthyl, 2- or 3-furyl, 2- or 20 3-thienyl, 2- or 3-pyrrolyl, 2- or 3-indolyl, 2- or 3- or 4-quinolyl, 1- or 3- or I 4-isoquinolyl, 2- or 3-benzofuryl, 2- or 3-benzothienyl, 2- or 4- or 5-pyrimidyl, 2- or 3-pyrazinyl, 2- or.4-quinazolyl, 1-phthalazinyl, 2- or 3- or 4-naphthyridinyl, 2- or 4-imidazolyl, 2- or 4-thiazolyl or 2- or 3- or 4-pyridyl, indanyl, chromanyl or thiochromanyl radical.
Mention may more particularly be made, as non-limiting illustration of the claimed compounds, of the following compounds: methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxy-phenyl)propenoyl]-9]-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-(2-methoxyphenyl)-propenoyl-9-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylic acid -14- (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl]-9-(4methylphenyl)-2,3 ,3-a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[(2methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl]-9-(4methylsulphanylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 acarboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2-[(2methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 acarboxylate acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl]-9-(3methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -methoxyphenyl)-2-[(2- :2 15 methoxyphenyl)acetyl]-2,3,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 a-carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-(3,4-dimethylphenyl)-4,9-ethano-2-[(2methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahlydro- 1H-benzo [flisoindole-3 acarboxylate (3 aRS ,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[(2methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-3 a-N-benzylcarbamoyl-4,9-ethano-2- methoxyphenyl)propenoyl]-9-(4-methylphenyl)2, 3,3 a,4, 9, 9a-hexahydro-l1Hbenzo[fjisoindole (3aRS,4SR,9SR,9aRS)-3a-carbamoyl-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl] -9-(4-methylphenyl)2 ,3,3 a,4, 9, 9a-hexahydro-l1Hbenzo[flisoindole benzyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxy-phenyl)propenoyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [fjisoindole-3 a-hydroxamate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2--(2-methoxyphenyl)-propenoyl]-9-(4methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [tlisoindole-3-a-hydroxamic acid in the racemic form, as well as of their optical isomers.
Mention may also be made, according to the invention, of any compound of general formula individually selected from: methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxy-phenyl)propenoyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-(2-methoxyphenyl)-propenoyl-9-(4methylphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-,3a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)..acetyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo isoindole-3 a-carboxylic acid (3aIRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[(2methoxyphenyl)acetyl]-2 3a, 4,9,9 a-hexahydro-1H-benzo(flisoindole-3a-carboxylic acid m::15 (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-.[(2-methoxyphenyl)acetyl]-9-(4methylsulphanylphenyl)-2 3a,4 9a-hexahydro-1IH-benzo [fl isoindole-3 acarboxylic acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2-[(2-methoxyphenyl)acetyl]- .dot*. 2,3,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid 6 0 020 (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [(2-methoxyphenyl)-acetyl]-9-(3methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[fiisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -methoxyphenyl)-2-[(2-methoxyphenyl)acetyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid methyl (3 aRS ,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[(2methoxyphenyl)acetyl]-2 3a, 4,9,9 a-hexahydro-1H-benzo[fiisoindole-3acarboxylate (3 aRS,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-'4,9-ethano-2-[(2-methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole.-3 a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-3 a-N-benzylcarbamoyl-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-
JI
benzo[flisoindole (3 aRS,4SR,9SR,9aRS)-3 a-carbamoyl-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole benzyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-hydroxamate (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] methylphenyl)-3 ,3 a,4,9,9a-hexahydro- IH-benzo [f]isoindole-3 a-hydroxamic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N-(3pyridylmethyl)-carboxamide (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(4- 15methylphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-N-(4pyridylmethyl)-carboxamide methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] methylphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1 H-benizo [flisoindole-3 a-hydroxamate (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] ~methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-N',N'-dimethylcarbohydrazide 20 (3aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-N'-phenylcarbohydrazide (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3 ,3a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N' pentamethylene-carbohydrazide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(methoxyphenyl)propenoyl]-9-(4- -methylphenyl)-3 a-phenylsulphonylaminocarbonyl-2,3 ,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole (3aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] m.nethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N-(N-oxo-3 0 C -17pyridyl)methylcarboxamide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxypheny)propenoy1]-9-(4methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [fjjisoindole-3 a-N'- (4-methoxyphenyl)- carbohydrazide (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2 ,3 ,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N'-methyl-N'phenylcarbohydrazide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-N'-(2-methylphenyl)carbohydrazide methyl (3 aRS,4SR,9SR,9aRS)-9-(2,3 -dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2- [2-(2-methoxyphenyl)-propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 acarboxylate (3 aRS ,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2- 15 methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 acarboxylic acid (3 aRS,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N-(3pyridylmethyl)carboxamide 20 (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N-(2thienylmethyl)carboxamide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl] ,4,5 trimethylphenyl)-2 3a, 4,9, 9a-hexahydro-1H-benzo[flisoindole-3a-carboxylic acid (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[fjisoindole-3 a-carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4trifluoromethylphenyl)-2 ,3,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 acarboxylate (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)-propenoyl]-9-(4trifluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [fjisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(4trifluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 a-N-(4pyridylmethyl)carboxamide (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl] trifluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3 a-N'benzoylcarbohydrazide (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(4trifluoromethylphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N'-phenylo carbohydrazide methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(2naphthyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[fjisoindole-3 a-carboxylate 15(3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(2- *1 naphthyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[f] isoindole-3a-carboxylic acid methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(5- ~methyl-2-thienyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylate (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(5,-methylse.,2-thienyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid 20 methyl (3 aRS,4SR,9SR,9aRS)-9-(4-bromophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 acarboxylate (3 aRS ,4SR,9SR,9aRS)-9-(4-bromophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 acarboxylic acid (3 aRS ,4SR,9SR,9aRS)-9-(3 ,4-dichlorophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 acarboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4chlorophenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylate -19- (3 aRS,4SR,9SR,9aRS)-9-(4-chlorophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 acarboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4methoxy-3-methylphenyl)-2 3a,4, 9, 9a-hexahydro-1H-benzo[flisoindole-3acarboxylic acid methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(3indolyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)-2- [(2-methoxyphenyl)acetyl]-2 ,3 ,3a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a- :carboxylic acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(3 15thienyl)-2,3 ,3a,4,9,9a-hexahydro- 1 H-benzo[flisoinldole-3a-carboxylate methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-ethylphenyl)-2-[2-(2- ~methoxyphenlyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 acarboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-ethylphenyl)-2-[2-(2- 20 methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 acarboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 acarboxylate methyl (3 aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5 -yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 acarboxylate acid (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N-(3 pyridylmnethyl)- carboxamide methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [fjisoindole-3 acarboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2-[2-(2methoxyphenyl)propenoyl2 3a, 4,9,9 a-hexahydro-1H-benzo[flisoindole-3,acarboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-(4-chloro-3 -fluorophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl-2,3, 3a, 4,9, 9a-hexahydro-1H-benzo~flisoindole-3acarboxylate (3 aRS ,4SR,9SR,9aRS)-9-(4-chloro-3-fluorophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 acarboxylic acid C C methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(3 methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 a-carboxylate 15 (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(3 methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid methyl (3aRS ,4SR,9SR,9aRS)-9-( 1,3 -benzodioxol-5-yl)-4,9-ethano-2- methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 acarboxylate 20 methyl (3aRS,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 acarboxylate (3 aRS,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxy-phenyl)-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3acarboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2- [2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 a-N-(3pyridylmethyl)carboxamide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3a,4,9,9a-hexahydro- 1 H-benzo [f]isoindole-3 a-N'phenylcarbohydrazide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- I H-benzo[flisoindole-3a-hydroxamic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3 pyridyl)carbohydrazide (3 aRS,48R,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-12-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-N-(3 thienylmethyl)carboxamide 15 and aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyl] -2,3 ,3 a,4,9,9 a-hexahydro- 1 H-benzo flisoindole-3 acarbonylamino}phenylacetic acids (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4trifluoromethoxyphenyl)-2,3 ,3a,4 9a-hexahydro-1H-benzo[flisoindole-3a- :20 carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-(3-bromophenyl)-4,9-ethano-2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 acarboxylate (3 aRS,4SR,9SR,9aRS)-9 -bromophenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahyclro- 1H-benzo [flisoindole-3 a-carboxylic acid methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-fluoro-phenyl)-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3 acarboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-fluorophenyl)-2-12-(2-methoxy- P phenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-fluorophenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N-(3pyridylmethyl)carboxamide methyl (3 aRS,4SR,9SR,9aRS)-9-(3 -chlorophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole,-3acarboxylate (3 aRS ,4SR,9SR,9aRS)-9-(3 -chlorophenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-9-(3-chlorophenyl)-4,9-ethano-2-t2-(2-methoxyphenyl)propenoyll-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-N-(3 pyridylmethyl)carboxamide methyl (3 aRS,4SR,9SR,9aRS)-9-(3-N,N-dimethylaminophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9,9a-hexahydro-l1H-benzo[flisoindole-3a- ~:carboxylate (3 aRS,4SR,9SR,9aRS)-9-(3-N,N-dimethylaminophenyl)-4,9-ethano-2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9,9a-hexahydro- 1H-benzoflisoindole-3 acarboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-(3-aminophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3,3 a,4,9,9,9a-hexahydro-l1H-benzo[flisoindole-3 acarboxylate hydrochloride.
methyl (3 aRS,4SR,9SR,9aRS)-9-(4-N,N-dimethylaminophenyl)'-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9,9a-hexahydro-l1H-benzo[flisoindole-3 acarboxylate (3 aRS,4SR,9SR,9aRS)-9-(4-cyanophenyl)-4,9-ethano-2-fI2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid methyl (3 aRS ,4SR,9SR,9aRS)-9-(3 -cyanophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3,3 a,4,9,9,9a-hexahydro- 1H-benzo [flisoindole-3 acarboxylate (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(3 -hydroxy-4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [f]isoindole-3acarboxylic acid methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-5 -methoxy-2-[2-(2methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2 ,3,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate (3aRS ,4SR,9SR,9aRS)-4,9- ethano-5 -methoxy-2-[2-(2-methoxyphenyl)propenoyl]-9- (4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-2-propenoyl] -4-methyl- 9-(4-methoxyphenyl)-2,3 ,3a,4,9,9a-hexahydro-IH-benzo [flisoindole-3 a-carboxy lic acid in the racemic form or their optical isomers, as well as their salts.
In that which precedes and that which follows, the expression "optical isomer"~ or optically active form defines the pure form of the said optical isomer or :~:optionally the "enriched" mixture of the optical isomers, that is to say comprising 15 predominantly the said optical isomer or the said form.
More preferably, mention may also be made, according to the invention, of any compound of general formula individually selected from: (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(4methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid 20 (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)-propenoyl]-9-(4- ~methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [tlisoindole-3 a-N-(3 pyridylmethyl)carboxamide (3 aRS ,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- lH-benzo [f]isoindole-3 a-N-(3pyridylmethyl)carboxamide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] trifluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofurai-5-yl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1 1-benzo[flisoindole-3 a-N-(3 pyridylmethyl)carboxamide (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo~fisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-5-methoxy-2-[2-(2-methoxyphenyl)propenoyl] -9- (4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-2-propenoyl]-4-methyl- 9-(4-methoxyphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid in the racemic form or their optical isomers, as well as their salts.
Mention may be made, as very particularly advantageous optical isomer of the compounds of general formula according to the invention, of any compound chosen individually from: dextrorotatory enantiomer of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3a-carboxylic acid dextrorotatory enantiomer of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxy- ~phenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-N-(3 -pyridylmethyl)carboxamide laevorotatory enantiomer of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo~f]isoindole-3 a-N-(3 -pyridylmethyl)carboxamide dextrorotatory enantiomer of (3 aRS ,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4benzodioxin-6-yl)-4,9.-ethano-2-[2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9ahexahydro- 1H-benz o[flisoindole-3a-N-(3-pyridyhmethyl)carboxamide laevorotatory enantiomer of (3 aRS ,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4-benzodioxmn- 6-yl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3a,4,9,9a-hexahydro- 1Hbenzo [flisoindole-3 a-N-(3 -pyridylmethyl)carboxamnide dextrorotatary enantiomer of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-tri-fluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylic acid dextrorotatary enantiomer of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-lHbenzo[f]isoindole-3a-carboxylic acid dextrorotatary enantiomer of (3aRS,4SR,9SR,9aRS)-4,9-ethano-5-methoxy-2-[2-(2methoxyphenyl)-2-propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzo[fjisoindole-3a-carboxylic acid dextrorotatary enantiomer of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)-2-propenoyl]-4-methyl-9-(4-methoxyphenyl)-2,3,3a,4,9,9ahexahydro-1H-benzo[f]isoindole-3a-carboxylic acid or their salts.
Mention may in particular be made of dextrorotatory enantiomer of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]- 9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro- H-benzo[f]isoindole-3a-carboxylic acid or its salts.
The Applicant Company additionally provides hereinbelow, without implied limitation of the present invention, various operating protocols as well as reaction intermediates liable to be of use in the preparation of the compounds of general formula Of course, it is within the capability of a person skilled in the art to be inspired by these protocols and/or intermediates in developing analogous processes for the purpose of leading to these same compounds.
According to the invention, the claimed novel products of general formula in which: Y represents an oxygen or sulphur atom and X represents one of the following groups: methylene, alkene-1,1-diyl, such as vinyldiyl, or cycloalkane-1,1-diyl containing 3 to 6 carbon atoms, can be obtained by reaction of an acid of general formula (II): (II) X HO- XR2 Y RI in which: RI and R 2 are defined according to the general formula I and X [lacuna] defined as above and Y represents an oxygen or sulphur atom, of its methyl ester or of a derivative of this acid, such as a halide or the anhydride, with a product of general formula (III): 9 9* 09 9 9 9 9* 9 9 9 9* 9 9 in which: Ar, R, R 3
R
4 and R 5 are defined according to the general formula I and G, represents a hydrogen atom (which can be obtained from a product of general formula (III) in which G, represents a protective group for an amino functional group, such as a benzyl, benzyloxycarbonyl, tert-butoxycarbonyl or vinyloxycarbonyl radical, by hydrogenolysis in the presence of a catalyst, such as palladium-on-charcoal, when G, represents a benzyl or benzyloxycarbonyl radical, or by hydrolysis in acidic medium, when G, represents a tert-butoxycarbonyl, 15 vinyloxycarbonyl or benzyloxycarbonyl radical).
In that which follows, the definition for which G, represents a benzyl radical is given only by way of illustration and it is obvious to a person skilled in the art to adapt the various protocols to the other protective groups for an amino functional group, such as a benzyl, benzyloxycarbonyl, tert-butoxycarbonyl or vinyloxycarbonyl radical.
Generally, the reaction of the product of general formula in the acid form, with the product of general formula (III) is carried out in an organic solvent, such as a halogenated aliphatic hydrocarbon, such as dichloromethane, in the presence of a coupling agent, such as l-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 1,3-dicyclo-hexylcarbodiimide or 3~TR 4 ri/ P -27benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, and optionally of an activating agent, such as hydroxy-benzotriazole, at a temperature of between 0 C and the reflux temperature of the reaction mixture.
The reaction of the product of general formula in the form of the methyl ester, with a product of general formula (III) is generally carried out in an organic solvent, such as dioxane or a halogenated aliphatic hydrocarbon, such as dichloromethane, at a temperature of between 0 0 C and the reflux temperature of the reaction mixture.
The reaction of the product of general formula in the halide form, with the product of general formula (III) is generally carried out in an organic solvent, such as a halogenated aliphatic hydrocarbon, such as dichloromethane, in the presence of a base (tertiary aliphatic amine) at a temperature of between O'C and the C: reflux temperature of the reaction mixture.
The reaction of the product of general formula in the anhydride 15 form, with the product of general formula (III) is generally carried out in an organic solvent, such as a halogenated aliphatic hydrocarbon, such as dichloromethane, in the S" presence of a base (tertiary aliphatic amine, pyridine or 4-dimethylaminopyridine) at a temperature of between 0 C and 50 0
C.
In addition, on conclusion of the reaction of II with III, it is optionally 20 possible, when R represents or contains a -COOR 6 or -PO(OR 9 2 radical with R 6 and
R
9 representing an alkyl radical, to saponify the product obtained, in order to obtain a product of general formula in which R represents or contains a carboxyl radical or to convert, by means of a nucleophilic agent, the product obtained, in order to obtain a product of general formula in which R represents or contains a -P0 3
H
2 radical.
The saponification of a product of general formula in which R represents or contains an ester of general formula -COOR 6 into a product of general formula in which R represents or contains a carboxyl radical is generally carried out by means of an inorganic base, such as sodium hydroxide or potassium hydroxide r or sodium carbonate, in an organic solvent, such as an alcohol, for example methanol or ethanol, or such as an ether, for example dioxane, at a temperature of between and the reflux temperature of the solvent.
The conversion of a product of general formula in which R represents or contains a PO(OR 9 2 radical into a product of general formula in which R represents or contains a PO 3
H
2 radical is generally carried out by reaction with a nucleophilic agent, such as a trialkylsilyl (trimethylsilyl) halide (iodide), or with a sodium or lithium halide (sodium iodide) in the presence of a trialkylhalosilane (trimethylchlorosilane, trimethylbromosilane), the reaction being carried out in a solvent, such as carbon tetrachloride or acetonitrile, at a temperature of between 0 and 50°C, or by heating with an alkali metal halide (sodium iodide), followed by hydrolysis.
•The present invention also relates to the products of general formula 15 in which: A4 Ar, R, R 3
R
4 and R 5 are defined according to the general formula I and G, represents a hydrogen atom or a protective group for an amino functional group, such as benzyl.
According to the invention, the novel products of general formula (I) in which: Y represents an oxygen or sulphur atom and X represents an oxygen atom can be obtained by the reaction of a haloformate or of a halothioformate of general formula (IV): 41)41 KI?- o -29- /o (IV) Hal 0O R2 Y RI in which: Y represents an oxygen or sulphur atom, R, and R2 are defined as above and Hal represents a halogen atom, with a product of general formula (III).
The reaction of the halide of general formula (IV) with the product of general formula (III) is generally carried out in organic or aqueous/organic medium, such as a dioxane/water mixture, in the presence of an inorganic base (sodium hydroxide) or organic base (triethylamine) at a temperature of between 0 and 10 In the same way as above, when R represents or contains a -COOR 6 or
-PO(OR
9 2 radical, it is possible to saponify the product obtained, in order to obtain a product of general formula in which R represents or contains a carboxyl radical, or to convert, by means of a nucleophilic agent, the product obtained into a product .o of general formula in which R represents or contains a -P0 3
H
2 radical.
15 According to the invention, the novel products of general formula (I) in which: S- Y represents an oxygen or sulphur atom and X represents an NH group can be obtained by reaction of an isocyanate or of an isothiocyanate of general formula Y=C=N (V R1 in which: Y represents an oxygen or sulphur atom and R, and R 2 are defined according to the general formula I with a product of general formula (III) as defined above.
The reaction of the product of general formula with the product of general formula (III) is generally carried out in an inert organic solvent, such as tetrahydrofuran or toluene, in the presence of an activating agent, such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine, at a temperature of between 0 and 0
C.
The reaction of V with II is optionally followed, when R represents or contains a -COOR 6 or -PO(OR 9 2 radical in which R 6 or R 9 represent an alkyl radical, by the saponification of the product obtained, in order to obtain a product of general formula in which R represents or contains a carboxyl radical, or by the conversion, by means of a nucleophilic agent, of the product obtained, in order to obtain a product of general formula in which R represents or contains a -P0 3
H
2 radical. The optional conversion of the -COOR 6 and PO(OR 9 2 radicals respectively 15 by carboxyl and P0 3
H
2 radicals is carried out under the conditions described above.
According to the invention, the novel products of general formula (I) in which: R represents a radical of general formula
-(CH
2 )m-Xi-(CH 2 n
-Z
with m and n defined as above and Z representing a -COOR 6 radical with R 6 representing a straight or branched alkyl radical containing 1 to 3 carbon atoms, can be obtained by esterification of a product of general formula in which Z represents a carboxyl radical.
The esterification is generally carried out by means of an alcohol of general formula R 6 -OH in which R 6 is defined as above, the reaction being carried out in acidic medium, or by means of an alkyl halide of general formula R 6 -Hal in which Hal represents a halogen (iodine) atom, the reaction being carried out in alkaline medium (alkali metal or alkaline-earth metal carbonate, such as caesium carbonate), the reaction being carried out in an organic solvent, such as dimethylformamide, at a temperature of between 0 and According to the invention, the novel products of general formula (I) in which: R represents a radical of general formula
-(CH
2 )-Xl-(CH 2 )n-Z in which: m and n are defined as above and Z represents a -CON(R 7
)(R
8 radical in which:
R
7 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms and Sa 0 R 8 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to Is 6 .e 6 carbon atoms optionally substituted by an amino, alkylamino containing 1 to 4 6800a carbon atoms, dialkylamino, each alkyl part of which contains 1 to 4 carbon atoms, i 15 alkoxy containing 1 to 4 carbon atoms, alkylthio containing 1 to 4 carbon atoms, So 0 alkyloxycarbonyl, the alkyl part of which contains 1 to 4 carbon atoms, carboxyl, "see: cyano, phenyl optionally substituted by one or more identical or different radicals 0 chosen from alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl
S
radicals, 1- or 2-naphthyl, 2- or 3-furyl, 2- or 3-thienyl, 4- or 5-imidazolyl or 4- or 20 5-thiazolyl, or 3- or 4-pyridyl radical, or an indanyl or chromanyl radical S or alternatively
R
7 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms and
R
8 represents a hydroxyl, amino, alkyloxy containing 1 to 6 straight- or branchedchain carbon atoms optionally substituted by a phenyl radical, alkylamino or dialkylamino, the alkyl parts of which contain 1 to 4 carbon atoms, radical, or else preferably in which
R
7 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms and
R
8 represents a hydrogen atom, a hydroxyl radical, an arylsulphonyl radical, such as phenyl-sulphonyl, optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms, a 5- to 7-membered heterocycle incorporating one or more heteroatoms chosen from nitrogen, oxygen or sulphur atoms, it being possible for the said heterocycle to be bonded via a heteroatom, an amino radical optionally substituted by one or two radicals, which are identical or different, chosen from the following radicals: alkyl containing 1 to 4 carbon atoms, aryl, such as phenyl, optionally substituted by one or more radicals, which are identical or different, chosen from alkyl or 15 alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms, 5- to 7-membered heterocyclyl containing one or more heteroatoms chosen from nitrogen, oxygen and sulphur atoms, arylcarbonyl, such as benzoyl, optionally substituted by one or 20 more radicals, which are identical or different,.chosen from alkyl 3 or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms, an alkyloxy radical containing 1 to 6 straight- or branched-chain carbon atoms optionally substituted by a phenyl radical, a straight or branched alkyl radical containing 1 to 6 carbon atoms, such as methyl, optionally substituted by an amino, alkylamino, dialkylamino, hydroxyl, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylthio, alkyloxycarbonyl, carboxyl or cyano radical, an optionally substituted mono- or polycyclic aromatic radical having from 5 to 12 ring members which may or may not incorporate -33one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms, it being possible for the said aromatic radical to be in particular the 2- or 3- or 4-pyridyl radical, preferably 3-pyridyl or 4-pyridyl, or the N-oxide ofpyridine, or it also being possible for the said aromatic radical to be a phenyl radical optionally substituted by one or more halogen atoms or by one or more hydroxyl, amino or trifluoromethyl groups or by one or more alkyl or alkenyl, alkoxy, alkylthio, alkylamino, alkylcarbonyl or C 2 to C 4 alkoxycarbonyl, carbamoyl, alkyl-carbamoyl or dialkylcarbamoyl, the alkyl part of which contains 1 to 8 carbon atoms, or formyl radicals, or alternatively a 1- or 2-naphthyl radical, preferably, R 7 represents a hydrogen atom and R 8 represents a methyl radical substituted by the 3-pyridyl radical, can be obtained by reaction of a product of general formula: 15 HN(R 7 )(Rs) in which R 7 and R 8 are defined as above with a product of general formula in which Z represents a carboxyl radical.
It is particularly advantageous: either first to react oxalyl chloride with a compound of general 20 formula in which R represents a carboxyl radical, in solution in dichloromethane, in order to form the acid chloride as an intermediate, and then to react the compound of general formula HN(R 7 optionally in the presence of a base, such as triethylamine, or directly to react the compound of general formula HN(R 7
)(R
8 with a compound of general formula in which R represents a carboxyl radical, in an organic solvent, such as an alcohol (ethanol) or a halogenated solvent, such as dichloromethane, in the presence of a coupling agent, such as N,N'-carbonyldiimidazole, 1,1-dicyclohexylcarbodiimide, 1-ethyl-3-[3- (dimethylamino)propyl]carbodiimide or benzotriazol-1yloxytris(dimethylamino)phosphonium hexafluorophosphate, at a temperature of between 0 and When at least one of the R 7 and R 8 symbols is substituted by an amino radical, it is particularly advantageous to protect it by a protective group, such as a tert-butoxycarbonyl, benzyloxycarbonyl or benzyl radical, prior to the coupling of the amine of general formula HN(R 7
)(R
8 to the appropriate acid and then to replace the protective group by a hydrogen atom, for example by hydrogenolysis by means of hydrogen in the presence of a catalyst, such as palladium-on-charcoal, when it represents a benzyl or benzyloxycarbonyl radical, or by hydrolysis in acidic medium, when it represents a tert-butoxycarbonyl or benzyloxycarbonyl radical.
When at least one of the R 7 and R 8 symbols is substituted by a carboxyl radical, it is particularly advantageous to protect it by a protective group, such as an alkyl radical optionally substituted by a phenyl radical, such as the benzyl Sradical, prior to the coupling of the amine of general formula HN(R 7
)(R
8 to the appropriate acid and then to replace the protective group by a hydrogen atom, for 15 example by hydrogenolysis by means of hydrogen in the presence of a catalyst, such as palladium-on-charcoal, or by saponification under the conditions described above.
When, in the product of general formula R 7 represents a hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms and R 8 represents an alkyloxy radical substituted by a phenyl radical, the replacement of the alkyloxy radical, 20 substituted by a phenyl radical, by a hydroxyl radical, carried out: either by hydrogenolysis in the presence of a catalyst, such as palladium-on-charcoal, or by treatment with aluminium chloride in the presence of anisole in an organic solvent, such as nitromethane, at a temperature of between -20 °C and room temperature, when the alkyl radical substituted by a phenyl radical is a benzyl radical, makes it possible to obtain a product of general formula in which R 7 represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms and R, represents a hydroxyl radical.
According to the invention, the novel products of general formula (I) \s .to'j in which: R represents a radical of general formula:
-NHCO-T
in which T represents a hydrogen atom or an alkyl radical (1 to 6 carbon atoms) optionally substituted by an amino, carboxyl, alkyloxycarbonyl, hydroxyl, alkyloxy, mercapto or alkylthio radical, can be obtained by reaction of an acid of general formula:
T-CO-OH
in which T is defined as above with a product of general formula VI: R Ar R3
H
R5
RS
in which: Ar, R 2 R R 4
R
5 X and Y are defined according to the general formula I.
The reaction of the acid of general formula T-CO-OH, in the acid form, with a product of general formula (VI) is generally carried out in an organic 15 solvent, such as a halogenated aliphatic hydrocarbon, such as dichloromethane, in the presence of a coupling agent, such as 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride, 1,1-dicyclohexylcarbodiimide or benzotriazol-1oxytris(dimethylamino)phosphonium hexafluorophosphate, optionally in the presence of an activating agent, such as hydroxybenzotriazole, at a temperature of between 0 and 50 0
C.
The reaction of the acid of general formula T-CO-OH, in the halide form, when T is other than a hydrogen atom, with the product of general formula (VI) is generally carried out in an organic solvent, such as a halogenated aliphatic hydrocarbon, such as dichloromethane, in the presence of a base (tertiary aliphatic amine) at a temperature of between 0 and 50 0
C.
*A
~-~TI
C;
The reaction of the acid of general formula T-CO-OH, in the anhydride form, with the product of general formula (VI) is generally carried out in an organic solvent, such as a halogenated aliphatic hydrocarbon, such as dichloromethane, in the presence of a base (tertiary aliphatic amine, pyridine or 4-dimethylaminopyridine) at a temperature of between 0 and The reaction of a compound T-CO-OH with a compound VI can optionally be followed by replacement of the protected ester functional groups or amine functional groups carried by T by carboxyl or amino radicals respectively, under the conditions described above.
When T is substituted by an amino radical, it is particularly advantageous to protect it by a protective group, such as a benzyloxycarbonyl or tertbutoxycarbonyl radical, prior to the coupling of the acid of general formula S' T-CO-OH to the appropriate amine and then to replace the protective group by a hydrogen atom, for example by hydrogenolysis by means of hydrogen in the 15 presence of a catalyst, such as palladium-on-charcoal, or by hydrolysis in acidic medium.
When T is substituted by a carboxyl radical, it is particularly advantageous to protect it by a protective group, such as a methyl, ethyl or benzyl radical, prior to the coupling of the acid of general formula T-CO-OH to the 20 appropriate amine and then to replace the protective group by a hydrogen atom, for example by hydrogenolysis by means of hydrogen in the presence of a catalyst, such as palladium-on-charcoal, or by saponification under the conditions described above.
According to the invention, the novel products of general formula (I) in which: R represents a radical of general formula
CH
2
-N+
can be obtained by reaction of an excess of pyridine and of a strong acid or of a derivative of this acid with a product of general formula: 7 f \J R2 SY R1
CH
2
-OH
R
in which Ar, RI, R 2
R
3
R
4
R
5 X and Y are defined according to the general formula
I.
The strong acid is preferably trifluoromethanesulphonic acid, optionally in the presence of trifluoromethanesulphonic anhydride.
According to the invention, the novel products of general formula (I) in which Y represents a sulphur atom can be obtained by thionation of a product of i: general formula in which Y represents an oxygen atom.
The thionation is generally carried out under the usual conditions by means of phosphorus pentasulphide, the reaction being carried out in an organic 10 solvent, such as tetrahydrofuran, at a temperature of between 0 and 50 0
C.
According to the invention, the products of general formula in which one of the R, or R 2 symbols represents an alkylcarbonyloxy radical can be obtained by acylation of a product of general formula in which one of the R, or R 2 symbols represents a hydroxyl radical by means of an aliphatic acid or of a derivative of this acid, such as a halide orthe anhydride, under the usual esterification conditions.
As regards the intermediates described above, operating protocols and compounds useful in obtaining them are also provided hereinbelow.
Conventionally, the products of general formula (III) in which R represents a carboxyl radical or a radical of general formula COOR 6 can be obtained by the action of trifluoromethanesulphonic acid on a product of general formula
(VIII):
i-o I 'K -38- -GI (VIII) Rs 5
COOR
6 R3 R4 in which: Ar, R 3
R
4 and R, are defined as above, G, represents a benzyl radical,
R
6 represents an alkyl radical containing 1 to 3 carbon atoms followed by replacement of the G, group by a hydrogen atom either by hydrogenolysis under the conditions described above, then, optionally, depending on the situation, by replacement of the hydrogen atom by a tert-butoxycarbonyl radical, by reaction with tert-butoxycarbonyl anhydride in an organic solvent, or by a benzyloxycarbonyl radical, by reaction by benzyloxycarbonyl chloride in an organic solvent or by reaction with an alkyl chloroformate, such as vinyl chloroformate or ethyl chloroformate or 2-chloroethyl chloroformate or 2,2,2trichloroethyl chloroformate, in an organic solvent, such as dichloromethane, at a temperature of between 0 C and room temperature, followed by acid hydrolysis of the intermediate carbamate formed, generally using a 1 to 6M aqueous hydrochloric acid solution, optionally in an organic solvent, such as an alcohol, for example methanol or ethanol, or an ether, for example tetrahydrofuran or dioxane.
The intramolecular cyclization of Friedal-Crafts type of the product of general formula (VIII) to the product of general formula (III) can generally be carried out by the action of an excess, from 3 to 15 molar equivalents, of a strong acid, such as trifluoromethanesulphonic acid, optionally in the presence of -39trifluoromethanesulphonic anhydride as a catalytic amount or optionally added as successive additions, the reaction being carried out in an organic solvent, such as dichloromethane, at a temperature of between 0°C and the reflux temperature, for a few minutes to several days. It is also possible to carry out the intramolecular cyclization of Friedel-Crafts type by the action of a Lewis acid, such as aluminium chloride or titanium tetrachloride or boron trifluoride, optionally in the form of a complex with diethyl ether, in an organic solvent, such as dichloromethane or nitromethane or nitrobenzene.
This reaction can optionally be followed by saponification of the product obtained and optionally followed, depending on the situation, by replacement of the benzyl radical by a hydrogen atom.
The product of general formula (VIII) can be obtained, for its part, conventionally by reaction of an organomagnesium derivative of general formula Ar- Mg-X, in which Ar is defined as above and X represents a halogen atom, or of an 15 organolithium derivative of general formula Ar-Li, in which Ar is defined as above, with a product of general formula (IX): *0
COOR
I G (D) R. COOR 6
R
3 in which R 3
R
4
R
6 and G are defined as above, under the usual conditions.
The reaction of an arylmagnesium derivative, obtained conventionally and optionally in the presence of anhydrous cerium(nI) chloride under the conditions described by Imamoto (Tetrahedron Lett., 1985, p. 4763), with the ketone derivative of general formula (IX) is generally carried out in an organic solvent, such as diethyl ether or tetrahydrofuran, the reaction being carried out at a temperature of between -o i( wc h rY an pionlyi h rsneonyru eimlI hoieudrtecniin b mao(Ttahdo Lt. 18, .463,wihte eon eivtv 0°C and the reflux temperature of the reaction mixture from a few minutes to 24 hours. However, it has been found to be particularly advantageous to carry out the reaction in toluene, optionally as a mixture with diethyl ether or tetrahydrofuran.
The reaction of an aryllithium derivative, obtained conventionally, with the ketone derivative of general formula (IX) is generally carried out in an organic solvent, such as diethyl ether or tetrahydrofuran, the reaction being carried out at a temperature of between -78' and -20°C for a few minutes to 4 hours.
However, it has been found to be particularly advantageous to carry out the reaction in toluene, optionally as a mixture with diethyl ether or tetrahydrofuran.
Advantageously, a preparation process has been developed, in the context of the present invention, which makes it possible to obtain the compounds of general formula (III) from compounds of general formula (IX) via the formation of a stable and characterizable intermediate of general formula (XV) characterized by the presence of an arylethylene functional group at the 7 position.
15 More specifically, the compounds of general formula (III)
V
H
-Gi (III)
R
in which R 3
R
4 Rs, Ar and R are as defined in general formula I and G1 represents a benzyl radical, can be obtained from compounds of general formula (IX):
S(IX)
-Gi(IX) in which R 3
R
4
R
5
R
6 and G, are as defined above, via the formation of an intermediate of general formula (XV) Ar
H
N-G (XV)
R
5 s'
COOR
6 R3 R4 in which R 3
R
4
R
5
R
6 Ar and G, are as defined above.
5 The operating protocol developed successively involves: either the condensation, at the 7 position, of a ketone derivative of general formula (IX) with hydrazine, to result in a hydrazone, followed by reaction o with iodine to result, according to the Barton reaction Chem. Soc., 1962, p. 470), in an iodoethylene derivative; followed by a palladium coupling reaction with an 10 arylboronic acid, the Suzuki reaction (Tetrahedron Lett., 1979, p. 3437), of general formula Ar-B(OH) 2 or optionally with the trimeric anhydride of arylboronic acid, in which Ar is defined as above, or with an arylstannane, the Stille reaction (Angew.
Chem. Int. Ed. Engl., 1986, p. 508), of general formula Ar-SnMe 3 in which Ar is defined as above, in order to result in this arylethylene intermediate of general formula the conversion of which by intramolecular cyclization of Friedel- Crafts type results in the expected product (III), or the reaction of a ketone derivative of general formula (IX) with trifluoromethanesulphonic anhydride, in order to result in an enol triflate at the 7 position (Org. Synth., 1990, p. 116); followed by a palladium coupling reaction with an arylboronic acid, the Suzuki reaction (Tetrahedron Lett., 1979, p. 3437), of general formula Ar-B(OH) 2 in which Ar is defined as above, or with an arylstannane, the Stille reaction (Angew. Chem. Int. Ed. Engl., 1986, p. 508), of general formula Ar-SnMe 3 in which Ar is defined as above, in order to result in this arylethylene R/ -42intermediate of general formula the conversion of which by intramolecular cyclization ofFriedel-Crafts type results in the expected product (III).
The ketone derivative of general formula (IX) is generally treated with an excess ofhydrazine hydrate, from 3 to 20 molar equivalents, at reflux in a solvent, such as ethanol, from a few minutes to a few hours. The hydrazone thus obtained is then stirred with an excess of iodine, in the presence of an aliphatic tertiary amine, such as triethylamine, at a temperature in the region of 20°C for a few hours in order to result in an iodoethylene derivative.
The ketone derivative of general formula (IX) is generally treated: either with trifluoromethanesulphonic anhydride in the presence of an organic base, such as 2,6-di-tert-butyl-4-methylpyridine, in an organic solvent, such as dichloromethane, at a temperature in the region of room temperature for a few hours, according to Stang (Synthesis, 1980, p. 283), or with a bis(trifluoromethylsulphonyl)amide, such as N,N-bis(trifluoromethylsulphonyl)aniline, according to MacMurry (Tetrahedron Lett., 1983, p. 979), or 2-[N,N-bis(trifluoromethylsulphonyl)amino]pyridine, according to Comins (Tetrahedron Lett., 1992, p. 979), in the presence of a base, such as lithium diisopropylamide, in an organic solvent, such as dichloromethane or 1,2-dimethoxyethane, 20 in order to result in an enol triflate.
The coupling between the iodoethylene derivative or the enol triflate obtained above and an arylboronic acid obtained conventionally and optionally isolated in the trimeric anhydride form is generally carried out by stirring in a twophase system composed of an organic solvent, preferably a mixture of toluene and methanol, and of a basic aqueous solution, preferably a 2N sodium carbonate solution, in the presence of a catalytic amount of palladium(0) derivative, preferably tetrakis(triphenylphosphine)palladium, at a temperature in the region of the reflux temperature for a few hours, in order to result in the arylethylene compound of general formula (XV).
The coupling between the iodoethylene derivative or the enol triflate -43obtained above with an arylstannane obtained conventionally is generally carried out by stirring in a polar aprotic organic solvent, preferably dimethylformamide or N-methylpyrrolidone, in the presence of a catalytic amount of palladium(0) derivative, preferably tetrakis(triphenylphosphine)palladium, at a temperature of between 500 and 100 0 C for a few hours, in order to result in the arylethylene compound of general formula (XV).
The intramolecular cyclization of Friedel-Crafts type of the compound of general formula (XV) to the product of general formula (III) is generally carried out under the conditions described above for the intramolecular cyclization of the products of general formula (VIII).
Advantageously, a second preparation process has additionally been developed, in the context of the present invention, which makes it possible to obtain the compounds of general formula (III) as defined above from the compounds of general formula (IX) via the formation of the intermediate of general formula (XV), 15 which can optionally be isolated. This second process is very particularly advantageous when the aryl radical Ar represents a phenyl nucleus substituted, at the para or meta-para or meta-para-meta' positions, by electron-donating groups or a heterocyclic radical which is naturally rich in electrons or a heterocyclic radical suitably substituted by electron-donating groups. This second process consists in 20 directly reacting, according to tandem intermolecular and then intramolecular cyclization reactions of Friedel-Crafts type, an aromatic or heterocyclic hydrocarbon Ar-H with a compound of general formula (IX) in an organic solvent in the presence of an excess of strong acid, such as trifluoromethanesulphonic acid, or optionally of a Lewis acid, such as aluminium chloride.
The procedure developed consists in condensing the product of general formula (IX) with an excess of trifluoromethanesulphonic acid (from 5 to molar equivalents) in an organic solvent, such as dichloromethane, at a temperature in the region of room temperature, for a few hours to several days. According to the number of molar equivalents in the concentration of trifluoromethanesulphonic acid, as well as the nature of the Ar radical and of the substituents which it carries, this reaction results either directly in the compounds of general formula (III) or in the compounds of general formula (XV) as intermediates, which are then cyclized as described above to compounds of general formula (III).
In addition, the compounds of general formula or (III) can be obtained by functionalization of the substituents of the aromatic ring Ar of the corresponding compounds of general formula or (III), by application or adaptation of the known methods for standard functionalizations, such as, and without implied limitation: functional substitution reactions (for example the replacement of a halogen atom by a cyano group by a palladium coupling), dealkylation reactions (for example by BBr 3 or alkylation reactions (in particular alkylation/ cyclization reactions by the action of BBr 2 Another subject of the present invention also relates to these compounds of general formula (XV):
H
Ar
(XV)
COOR
6 R3 •R4 in which R 3
R
4 R, and Ar are as defined in general formula I, G, represents a benzyl radical and R 6 represents an alkyl radical containing 1 to 3 carbon atoms, in the racemic form, and to their optical isomers.
The product of general formula in the racemic form or its optical isomers, in which R 3
R
4 Rs, R 6 and Ar are as defined in general formula I and G, represents a benzyl radical can be obtained by reaction of an N-trialkylsilylmethyl-N- (alkoxy-methyl)amine carrying a protective group for the amine functional group, such as a benzyl radical, for example N-trimethylsilylmethyl-N-(nbutoxymethyl)benzylamine, which can be prepared under the conditions described in Chem. Pharm. Bull., 276 (1985), with a cyclohexenone derivative of general formula:
O
(X)
COOR
6
R
R3 R4 .0 5 in which R 3
R
4
R
5 and R 6 are defined as above, in the racemic form or its optical isomers.
0** The reaction is generally carried out in an organic solvent, such as a halogenated aliphatic hydrocarbon, for example dichloromethane, in the presence of 0 a strong acid, such as trifluoroacetic acid, at a temperature of between 0°C and the 10 reflux temperature of the reaction mixture.
0: The products of general formula can be obtained by esterification 0'00* of 3-oxo-6-phenylcyclohex-1-ene-1-carboxylic acids, in which R 3
R
4 and R 5 are 000*'* defined as above, by means of an aliphatic alcohol containing 1 to 3 carbon atoms, in 0.
0* the presence of an inorganic base, such as hydrochloric acid or sulphuric acid, at a temperature of between 06C and the reflux temperature of the reaction mixture, or by means of an alkyl halide (iodide), in the presence of an organic base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, or an inorganic base, such as caesium carbonate, the reaction being carried out in a solvent chosen from tetrahydrofuran, dimethylformamide, acetone or dioxane.
3-Oxo-6-phenylcyclohex-1-ene-1-carboxylic acids, in which R 3
R
4 and R 5 are defined as above, can be obtained from 3-oxo-6-phenylcyclohexane-l-ol- 1-carboxylic acids, in which R 3
R
4 and R 5 are defined as above, either by thermal dehydration, by heating at a temperature in the region of 190 C (according to J. Org.
-46- Chem., 1971, p. 3707) or by heating in refluxing toluene in the presence of p-toluenesulphonic acid, or by reacting with an inorganic base, such as sodium hydroxide, at a temperature of between 0 and 3-Oxo-6-phenylcyclohexane-l-ol-l-carboxylic acids, in which R 3
R
4 and R, are defined as above, can be obtained by reaction ofphenylpyruvic acids, or optionally of the corresponding esters, more particularly in the case where R, does not represent a hydrogen atom, the phenyl nucleus of which is optionally substituted by substituents defined by R 3 and R 4 with methyl vinyl ketone, the reaction generally being carried out in aqueous/alcoholic medium, such as a methanol/water mixture, in the presence of an inorganic base, such as sodium hydroxide (according to J. Org. Chem., 1971, 3707).
Phenylpyruvic acids, the phenyl nucleus of which is optionally a a substituted by substituents defined by R 3 and R 4 can be obtained, more particularly in the case where R 5 represents a hydrogen atom, either by hydrolysis of the 15 corresponding a-acetamidocinnamic acids, by heating in hydrochloric acid, according to Org. Synth., 1943, p. 519, or by hydrolysis of the corresponding benzalhydantoins, by heating in 20% sodium hydroxide solution, according to Org. Synth. Coll. Vol. V, S 627.
Sa-Acetamidocinnamic acids, the phenyl nucleus of which is optionally 20 substituted by substituents defined by R 3 and R 4 can be obtained, from the corresponding benzaldehydes according to Org. Synth., 1939, p. 1, by reaction with N-acetylglycine in refluxing acetic anhydride in the presence of sodium acetate. The intermediate azlactones thus obtained are then hydrolysed to a-acetamidocinnamic acids by heating at reflux in aqueous acetone.
Benzalhydantoins, the phenyl nucleus of which is optionally substituted by substituents defined by R 3 and R 4 can be obtained by heating the corresponding benzaldehydes, according to Org. Synth. Coll. Vol. V, p. 267, with hydantoin in the presence of an organic base, such as piperidine, at a temperature in the region of 130 0
C.
Phenylpyruvates, the phenyl nucleus of which is optionally substituted by substituents defined by R 3 and R 4 can be obtained, more particularly in the case where R 5 does not represent a hydrogen atom but an alkyl or alkylthio radical, from 2-phenylalkanoic acids, the phenyl nucleus of which is optionally substituted by substituents defined by R 3 and R 4 by reaction of the corresponding dianion, generally obtained by reaction of an organic base, such as n-butyllithium, with the acid, with ethyl oxalate at a temperature in the region of-70°C, followed by decarboxylation, the reaction being carried out under the conditions described in Tetrahedron Lett., 1981, 2439-42.
The products of general formula (III) R3
H
R
I
(CH2)m-Xl(CH2)n-Z in which: 9 m is equal to 0, Xi represents a bond, n is equal to 0 and Z represents a -COOR or -CON(R)(Rg) radical can be obtained from a product of general formula (VIII), in which R represents a carboxyl radical, by esterification and amidation under the conditions described above, followed by cyclization by the action of trifluoromethanesulphonic acid under the conditions described above.
The products of general formula (III) in which R represents a radical
(CH
2 )m-X,(CH 2 )n-Z in which: m is equal to 1, X, represents a bond, 9.
:Zrpesnsa-OR 6 o CNR)( 8 aia n is equal to 0 and Z represents a -COOR6 -CON(R 7
)(R
8 or PO(OR 9 2 radical can be obtained from a product of general formula: Ar R3 H R4 G (XI) CH2-G2 in which Ar, R 3
R
4 and R are defined as above, G, represents a protective group for the amine functional group (benzyl, benzyloxycarbonyl or tert-butoxycarbonyl and
G
2 represents a leaving group, such as a trifluoromethylsulphonyloxy radical.
More particularly, in order to obtain a product of general formula (III) S. in which R represents a radical
(CH
2
)-X,(CH
2 10 in which: m is equal to 1, X, represents a bond, S n is equal to 0 and Z represents a carboxyl, -COOR 6 in which R 6 repressents an alkyl radical, or S 15 -CON(R 7
)(R
8 radical, it is particularly advantageous to use the corresponding nitrile as an intermediate, which nitrile can be obtained by reaction of an alkali metal cyanide with the product of general formula the reaction being carried out in a polar organic solvent, such as dimethyl sulphoxide, at a temperature of between 0 and 50 C, which nitrile is hydrolysed to the corresponding acid, which can then be esterified or amidated under the usual conditions.
More particularly, in order to obtain a product of general formula (III) in which R represents a radical
(CH
2 )m-X,(CH 2 )n-Z in which: -49m is equal to 1, X, represents a bond, n is equal to 0 and Z represents a -PO(OR) 2 radical, it is particularly advantageous to react a trialkyl phosphite with a product of general formula (XI) and then, optionally, to convert the phosphonate obtained to the corresponding phosphonic acid.
The products of general formula (III) R3
H
R4 (III)
R
10 in which: R represents a (CH 2 )m-Xi-(CH 2 )n-Z radical with m equal to 1, X, representing an oxygen or sulphur atom, n equal to 1 or 2 and Z representing a carboxyl, -COOR 6 in which R 6 represents an alkyl radical, or -CON(R 7
)(R
8 radical and G, represents a protective group for the amine functional group 15 can be obtained by reaction of an ester or of an amide of general formula: H-X,-(CH2)-Z in which n and Z are defined as above with a product of general formula the reaction being carried out in an anhydrous organic solvent, such as dioxane, in the presence of an alkali metal hydride, such as sodium hydride, optionally followed, depending on the situation, by saponification of the product of general formula (III) thus obtained.
The products of general formula (III) in which: m is equal to 1, X, represents a bond, n is equal to 1, with it being possible for the methylene group to be
R"
substituted by a carboxyl or alkoxycarbonyl or carbamoyl or alkylcarbamoyl or dialkylcarbamoyl radical, G, represents a protective group for the amine functional group and Z represents a carboxyl, -COOR 6 in which R 6 represents an alkyl radical, or
-CON(R
7
)(R
8 radical, can be obtained by reaction of a malonic acid, anionized beforehand, or of a malonic acid derivative, preferably a diester, with a product of general formula the reaction being carried out in an anhydrous organic solvent, such as dioxane, in the presence of an alkali metal hydride, such as sodium hydride, at a temperature of between 0°C and the reflux temperature of the reaction mixture, followed, depending on the situation, by saponification, esterification, amidation or decarboxylation of the product of general formula (III) thus obtained.
The products of general formula (III) in which: o SR represents an -NH-CO-T radical in which T is defined as above 15 can be obtained by amidation of a product of general formula (III) in which: oo**
R
3 is defined as above, G represents a protective group of the amine functional group and o- R represents an amino radical by means of an acid of general formula T-CO-OH in which T is defined as above, S* 20 under the conditions described above for the amidation of a product of general formula (VI).
The products of general formula (III) in which R represents an amino radical or the products of general formula (VI) can be obtained according to the methods which make it possible to convert a carboxyl radical to an amino radical without affecting the remainder of the molecule.
The carboxyl functional group of a product of general formula (III) or is generally converted to the amino radical via an isocyanate which can be obtained by pyrolysis of the acid azide, which can itself be obtained by reaction of an alkali metal azide with the corresponding acid halide. The intermediate isocyanate thus obtained is conventionally condensed with benzyl alcohol and then the benzyl carbamate obtained is converted to the amino radical, either by hydrogenolysis or by acid hydrolysis under the conditions described above.
The products of general formula (III) in which R represents a -CH 2 radical can be obtained by reaction of pyridine and of a strong acid or of a derivative of this acid with a product of general formula (XII): 4
H
R4 -G (XII) T CH2-OH
R
in which Ar, R 3
R
4 and R 5 are defined as above and G, represents a protective group for the amine functional group.
The products of general formula (VII) or of general formula (XII) can be obtained respectively by reduction of a product of general formula or of a product of general formula (III) in which R represents a radical of general formula
-COOR
6 in which R 6 preferably represents an alkyl radical containing 1 to 3 carbon atoms.
The reduction is generally carried out by means of a lithium aluminium hydride, the reaction being carried out in an organic solvent, such as an ether, for example tetrahydrofuran, at a temperature of between 0 and According to the invention, the products of general formula in which Ar, RI, R 2
R
3
R
4
R
5 X and Y are defined as above and R represents a
COOR
6 radical in which R 6 is defined as above, can also be obtained from a product of general formula (IX) in which R 3
R
4
R
5 and R 6 are defined as above and G, -52represents a hydrogen atom.
According to the invention, the product of general formula (IX)
O
H
-G (IX) Rs 5
COOR
6
R
3 R4 in which G, represents a hydrogen atom, is obtained from the product of general formula in which G, represents a protective group for the amino functional group, under the conditions described above for the preparation of a product of ii I general formula (III) in which G, represents a hydrogen atom.
The product of general formula (IX) in which G, represents a hydrogen atom is converted to the product of general formula:
O
H
or R2 Y RI
SR
5
COOR
6 R3 R4 in which RI, R 2 R R 4
R
5 R6, X and Y are defined as above, the reaction being carried out, depending on the meanings of X and Y, in the following way: the products of general formula (XIII), in which Y represents an oxygen or Ssulphur atom and X represents a methylene, vinyldiyl, alkene-1,1-diyl or cycloalkane-1,1 -diyl group, can be obtained by reaction of an acid of general formula (II) or of its chloride or of its anhydride with a product of general formula (IX) in
/\R
fiu-0\ which G, represents a hydrogen atom, the reaction being carried out under the conditions described above for the reaction of a product of general formula (II) with a product of general formula (III) in which G, represents a hydrogen atom, the products of general formula (XIII), in which Y represents an oxygen or sulphur atom and X represents an oxygen atom, can be obtained by reaction of a haloformate or of a halothioformate of general formula (IV) with a product of general formula (IX) in which G, represents a hydrogen atom, the reaction being carried out under the conditions described above for the reaction of a product of general formula (IV) with a product of general formula (III) in which G, represents a hydrogen atom, the products of general formula (XIII), in which Y represents an oxygen or sulphur atom and X represents an NH group, can be obtained by reaction of an isocyanate or of an isothiocyanate of general formula with a product of general formula (IX) in which G, represents a hydrogen atom, the reaction being carried out under the conditions described above for the reaction of a product of general formula 15 with a product of general formula (III) in which G, represents a hydrogen atom.
The product of general formula (XIII) is converted to the product of general formula: Ar H I (xv) Y Ri Rs5""' COOR 6 R3 R4 in which Ar, R 2
R
3
R
4
R
6 X and Y are defined as above, by reaction of a metallic derivative of general formula Ar-Mg-X or Ar-Li, in which X represents a halogen atom, with a product of general formula (XIII), the reaction being carried out under the conditions described above for the reaction of an organomagnesium or organolithium derivative of general formula Ar-Mg-X or Ar-Li with a product of general formula (IX).
-o
C"
-54- The product of general formula (XIV) is converted to the product of general formula in which Ar, R 1
R
2
R
3
R
4
R
5
R
6 X and Y are defined as above, by the action of trifluoromethanesulphonic acid or of a Lewis acid on the product of general formula (XIV), the reaction being carried out under the conditions described above for the action of trifluoromethanesulphonic acid or of a Lewis acid on a product of general formula (VIII).
The reaction of an aromatic hydrocarbon or of an aromatic heterocycle Ar-H, as defined above, in the presence of trifluoromethanesulphonic acid or of a Lewis acid, with a product of general formula (XIII), in which Ri, R 2
R
3
R
4
R
5
R
6 X and Y are defined as above, results in a product of general formula in which Ar is defined as above and R represents a COOR 6 radical in which R 6 represents an alkyl radical containing 1 to 3 carbon atoms.
.According to the invention, the products of general formula in S. which: 15 Ar, R 1
R
2
R
3
R
4 Rs, X and Y are defined as above and R represents a radical
CH
2 )m-Xi-(CH 2 )n-Z in which m, n, X, and Z are defined as above can also be prepared from a product of general formula (VII) under the conditions oee-: 20 described above for the preparation of the products of general formula (III) from a product of general formula after replacement of the hydroxyl radical of the product of general formula (VII) by a leaving group, such as a trifluoromethanesulphonyloxy radical.
The reaction mixtures obtained by the various processes described above are treated according to conventional physical methods (evaporation, extraction, distillation, chromatography, crystallization, for example) or conventional chemical methods (formation of salts, for example).
The compounds of formula can optionally be converted into addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent, such as an alcohol, a ketone, an ether or a chlorinated solvent. These salts also form part of the invention.
The optical isomers of the products of general formula can be obtained according to the usual separation methods from the corresponding racemic product. It is particularly advantageous to carry out the separation by high performance liquid phase chromatography using a chiral stationary phase of modified Pirkle type, elution being carried out with a suitable solvent.
Use may preferably be made, as chiral stationary phase, of a phase in which the chiral selector, which is preferably 3,5-dinitrophenylalanine, is kept at a distance from the silica by an aminoalkyl arm containing 3 to 14 carbon atoms attached to the amine functional groups of an aminopropyl silica, the free silanol functional groups of which are blocked by trialkylsilyl radicals.
This chiral phase may be defined by the following structure: -O-Si(R') 3 0 S- (CH 2 3 NHCO-(CH2)n-NHCO- NH-G 3 -0 O-Si(R")3 H2 O-Si(R") 3
C
6 in which the R' symbols, which are identical or different, and the R" symbols, which are identical or different, represent alkyl radicals containing 1 to 10 carbon atoms, G 3 15 represents an electron-withdrawing group and n represents an integer between 3 and 13 inclusive, the porosity of which is in the region of 100 A.
'i The chiral phase can be prepared by reaction of an aminopropyl silica with the anhydride of an aminoalkanoic acid containing 4 to 14 carbon atoms, the amine functional group of which is protected by a protective group, such as the tertbutoxycarbonyl radical, followed by blocking a part of the silanol functional groups by Si(R') 3 radicals as defined above, then, after removal of the protective groups for the amine functional group, by amidation by means of an amino acid of general formula: m -56- HO-CO-H-NH-G3
CH
2
C
6
H
in which G 3 is defined as above, and finally blocking of the residual silanol functional groups by Si(R") 3 radicals as defined above.
Generally, the reaction of the anhydride of a protected aminoalkanoic acid with the aminopropyl silica is carried out in an anhydrous organic solvent, such as dimethylformamide, at a temperature in the region of Blocking of the silanol functional groups by -Si(R' 3 groups as defined above is carried out by reaction of a halotrialkylsilane with the aminopropyl silica, which has been grafted by aminoalkanoyl residues, in an organic solvent, such as .9 S. 10 methylene chloride, in the presence of a basic agent, such as pyridine.
Removal of the protective groups from the aminoalkanoyl residues is S. generally carried out, when the protective group is a tert-butoxycarbonyl radical, by 9 the action of trifluoroacetic acid in an organic solvent, such as methylene chloride.
Amidation by means of phenylalanine in which the amine functional 15 group is protected is carried out in the presence of a coupling agent, such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, in an anhydrous organic solvent, S* such as dimethylformamide.
i. Blocking the residual silanol functional groups by -Si(R") 3 radicals as defined above is generally carried out by means of trialkylsilylimidazole in an organic solvent, such as methylene chloride.
The aminopropyl silica can be prepared by reaction of aminopropyltriethoxysilane with a silica in which the porosity is in the region of 100 A in the presence ofimidazole in an anhydrous organic solvent, such as an aromatic hydrocarbon, for example toluene.
As shown in the examples below, the novel products of general formula which inhibit faresyl transferase and the farnesylation of the Ras R -57protein, exhibit notable antitumour and antileukaemic properties.
Another subject of the present invention is any pharmaceutical composition containing at least one product of general formula in combination with one or more pharmaceutically acceptable diluents or adjuvants, whether inert or biologically active.
The novel products of general formula can be provided in the form of non-toxic and pharmaceutically acceptable salts. These non-toxic salts comprise salts with inorganic acids (hydrochloric, sulphuric, hydrobromic, phosphoric, nitric acids) or with organic acids (acetic, propionic, succinic, maleic, hydroxymaleic, benzoic, fumaric, methanesulphonic, trifluoroacetic or oxalic acids) or with inorganic bases.
(sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide) or organic bases (tertiary amines, such as triethylamine, piperidine, benzylamine), Io O depending on the nature of the compounds of general formula The present invention also relates to the use of the compounds of 15 general formula according to the invention in the preparation of pharmaceutical compositions useful in inhibiting famesyl transferase and more particularly in inhibiting famesylation of the ras oncogene.
In particular, the present invention relates to the use of the compounds of general formula according to the invention in the preparation of pharmaceutical 20 compositions useful in the treatment of diseases related to cell proliferations by inhibition of famesyl transferase and in particular in the treatment of diseases related Sto cell proliferations overexpressing any one of the H-Ras, N-Ras or K-Ras oncoproteins or exhibiting a mutation of any one of the corresponding ras oncogenes.
The invention relates in particular to the use of the compounds of general formula according to the invention in the preparation of pharmaceutical compositions useful in the treatment of diseases related to cell proliferations, malignant or benign, of cells of various tissues and/or organs, comprising muscle, bone or connective tissues, the skin, the brain, the lungs, the sexual organs, the lymphatic or renal systems, mammary or blood cells, the liver, the digestive system, RA I f^\3 the colon, the pancreas and the thyroid or adrenal glands, and including the following pathologies: psoriasis, restenosis, solid tumours, Kaposi's sarcoma, carcinomas, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumour, Hodgkin's disease, melanomas, teratocarcinomas, gliomas, multiple myelomas, chronic lymphocytic leukaemias, acute or chronic granulocytic lymphomas, and cancers, such as cancers of the pancreas, colon, lung, ovary, breast, brain, prostate, liver, stomach, bladder or testicles.
The invention very particularly relates to the use of the compounds of general formula according to the invention, preferably the compound described in Example 3, in the preparation of pharmaceutical compositions useful in the treatment of cancers, such as cancers of the pancreas, colon, lung, ovary, breast, brain, prostate, liver, stomach, bladder or testicles, and more advantageously cancer of the colon and S: pancreas, in particular of the colon.
15 The compounds according to the invention can also be useful in the preparation of medicaments in the treatment and/or the prevention of pathological conditions related to cell signalling pathways, associated with famesyl transferase, or to their consequences or symptoms.
The compounds according to the present invention can 20 advantageously be used in in the preparation of medicaments in the treatment and/or Sthe prevention of diseases associated with cell signalling pathways related to Ras.
Thus, the compounds according to the invention can be used in the preparation of medicaments in the treatment and/or the prevention of the rejection of grafts (such as allografts) (O'Donnel et al. 1995, Kidney International, vol. 48, suppl. 52, pp. 29-33).
The compounds according to the invention can also be useful in the preparation of medicaments for inhibiting angiogenesis and acting on tumour growth Rak et al., Cancer Research, 55, 4575-4580, 1995), it being possible for these antiangiogenic properties also to be useful in the treatment of certain forms of blindness relating to retinal vascularization.
The compounds according to the invention can also be useful in the preparation of -59medicaments in the treatment and/or the prevention of diseases related to (pro- or anti-)apoptotic dysfunctioning comprising in particular the abovementioned cancers; of delta hepatitis and associated viruses Glenn et al., Science, 256, 1331-1333, 1992), as well as, and in a non-limiting way, the Herpes, Pox, Epstein-Barr and Sindbis viruses and adenoviruses); of inflammatory and/or autoimmune diseases, such as, by way of illustration, polyarthritides, polyarticular rheumatisms, intestinal inflammations, pulmonary oedemas, myocardial infarctions, fibroses, the various forms of lupus erythematosus, such as Kaposi's sarcoma, immunoglomerulonephritides or autoimmune diabetes; cardiovascular diseases (arteriosclerosis or other arterial lesions) or restenosis following angioplasty or vascular surgery; bone diseases, of regulation of bone metabolism, for example Paget's disease, S hypercalcaemia, bony metastases or osteoporosis; diseases associated with a high level of cholesterol, such as hypercholesterolaemia, hyperlipidaemia, hyperpoproteinaemia, nephrotic hyperlipidaemia or artherosclerosis (Massey et al., Lancet, 347, 102-103, 1996); neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, neurological disorders associated with viral diseases, 20 such as AIDS, retinites, or spinocerebellar atrophies or degenerations); and in the prevention and/or the treatment of the following diseases: in particular AIDS and also polycystic kidney Schaffner et al., American Journal of Pathology, 142, 1051-1060, 1993), neurofibromatoses, pulmonary fibroses, arthrites, psoriasis, glomerulonephritides, hypertrophic scar formations or endotoxin shocks; as well as myeliodysplastic syndromes, aplastic anaemia, ischaemic lesions associated with infarctions, lesions associated with strokes and, arrhythmias, atheroscleroses, liver diseases due to toxins or alcohol, haematological diseases, including in particular chronic or aplastic anaemia, degenerative diseases of the muscle-skeleton system, including in particular osteoporosis and arthritis, cystic fibroses, multiple scleroses, liver diseases or pain related to cancer.
*A^
The said treatment can in particular be carried out by inhibition of tumour growth, in particular by inhibition of farnesyl transferase, or alternatively by inhibition of the growth of tumours expressing the activated ras oncogene.
The therapeutic treatment may also be carried out conjointly with other therapeutic treatments including antineoplastic medicaments, monoclonal antibodies, immunological therapies or radiotherapies or biological-response modifiers. The response modifiers include, without implied limitation, lymphokines and cytokines such as interleukins, interferons P or 8) and TNF. Other chemotherapeutic agents which are useful in the treatment of disorders due to abnormal cell proliferation include, without implied limitation, alkylating agents such as nitrogen mustards, for instance mechlorethamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulphonates such as busulphan, nitrosoureas such as carmustine, lomusine, semustine and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogues, for instance methotrexate, pyrimidine 15 analogues such as fluorouracil and cytarabine, purine analogues such as mercaptopurine and thioguanine, natural products such as vinca alkaloids, for instance vinblastine, vincristine and vendesine, epipodophyllotoxins such as etoposide and teniposide, antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents such as coordination complexes of platinum, for example cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocorticoid suppressants such as mitotane and aminoglutethimide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, oestrogens such as diethylstilboestrol and ethinyloestradiol, antioestrogens such as tamoxifen, and androgens such as testosterone propionate and fluoxymesterone.
Another subject of the present invention is any combination of a product of general formula with one or more compatible and pharmacologically active compounds and/or a radiotherapy treatment, in order to obtain a synergic -61therapeutic effect, the said compounds preferably being active principles known for their inhibitory activity with respect to cell proliferation and particularly for their activity in the treatment of cancer; they may preferably be anti-proliferative compounds acting, at any one of the stages of the ras oncogene signalling pathway, as an inhibitor of tyrosine kinase, or another inhibitor of farnesyl transferase, or an inhibitor of HMG-Co-reductase, or the cytotoxic compounds commonly used in the treatment of cancer.
The products according to the invention can be used to prevent or delay the appearance or the reappearance of pathological conditions or to treat these pathological conditions.
The products according to the invention can be administered orally, parenterally or or intraperitoneally or rectally, preferably orally.
The compositions for oral administration comprise tablets, pills, powders or granules.
In these compositions, the active product according to the invention is mixed with 9999 15 one or more inert diluents, such as sucrose, lactose or starch. These compositions can 9o9o comprise substances other than diluents, for example a lubricant such as magnesium stearate.
•oo•• As liquid compositions for oral administration, solutions, suspensions, •syrups, elixirs and pharmaceutically acceptable emulsions, containing inert diluents 20 such as water or liquid paraffin, may be used. These compositions can also comprise substances other than diluents, for example wetting, sweetening or flavouring products.
The compositions according to the invention for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters, for example ethyl oleate, may be employed. These compositions can also contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, for example using a bacteriological filter, by incorporating sterilizing agents in the composition or by heating. They may also be prepared in the form of sterile solid compositions
/A
JI
which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
The compositions for rectal administration are suppositories which can contain, besides the active product, excipients such as cocoa butter.
The doses used for implementing the methods according to the invention are those which permit a prophylactic treatment or a maximum therapeutic response. The doses vary according to the administration form, the particular product selected and the features specific to the subject to be treated. In general, the doses are those which are therapeutically effective in the treatment of disorders due to an abnormal cell proliferation and in particular a cytostatic treatment. The products according to the invention can be administered as often and as long as necessary to obtain the desired therapeutic effect.
•The doses are generally, in man, between 0.1 and 10,000 mg/kg per day, preferably between 100 and 2000 mg/kg per day, preferably by the oral route. It is 15 understood that, in order to choose the most appropriate dosage, account should be i: taken of the administration route, the weight of the patient, his general state of health, his age and all the factors which can influence the effectiveness of the treatment.
Generally, the doctor will determine the appropriate posology according to the age, weight and all the other factors specific to the subject to be treated.
20 Compositions according to the invention are illustrated in Example 105.
The following examples are presented by way of illustration of the fee present invention and do not limit the present invention.
EXAMPLE 1 Preparation of methyl (3aRS,4SR.9SR,9aRS)-4,9-ethano-2-r2-(2methoxvphenyl)propenovll-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzorflisoindole-3a-carboxvlate Stage A 358 g (2.52 mol) of methyl iodide and 361 g (2.38 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene are successively added to a solution of 428 g (1.98 mol) of(RS)-3-oxo-6-phenylcyclohex-l-ene-l-carboxylic acid, which can be 4 0
S.
S.
*0 0*
S
O~
*5
S
*55*
A
S
-63obtained according to J. Org. Chem., 1971, 36, 3707, in 4.5 cm 3 of acetone and then the reaction mixture is brought to reflux for five hours. The acetone is subsequently distilled off and then the residue is stirred with 2.5 dm 3 of water. After cooling to 0 C, the precipitate formed is filtered off, washed with ice-cold water and then dried at 30 0 C. 423 g of methyl (RS)-3-oxo-6-phenylcyclohex-l-ene-1carboxylate are thus obtained in the form of a yellow powder, the characteristics of which are as follows: melting point 66 0
C
N.M.R. spectrum (300 MHz, CDC1 3 d in ppm): 2.1-2.4 (mt, 4H, H at 4 and at 3.72 3H, CH 3 4.25 (dt, 1H, H at 6.88 1H, H at 7.2-7.52 (mt, aromatic protons).
Stage B A solution of 170 g (0.77 mol) of methyl (RS)-3-oxo-6phenylcyclohex-1-ene-1-carboxylate and of 0.9 cm 3 of trifluoroacetic acid in 880 cm 3 15 of dichloro-methane is brought to reflux. 256.3 g (0.913 mol) of N-n-butoxymethyl- N-[(trimethylsilyl)methyl-benzylamine, which can be obtained according to Chem.
Pharm. Bull., 1985, 276, are then added over 15 minutes at reflux. The reaction mixture is then cooled to 20 0 C. After addition of 20 cm 3 of a saturated aqueous sodium hydrogencarbonate solution, the organic phase is separated by settling, 20 washed with water and then stirred with 900 g of silica (63-200 mesh) for minutes. The silica is filtered off and then washed with 1.5 cm 3 of dichloromethane. After concentrating the solvent under reduced pressure, 270 g of a brown oil are then obtained, which oil is taken up in 800 cm 3 of cyclohexane and 770 cm 3 of a normal aqueous methanesulphonic acid solution. After separation by settling, the organic phase is washed with two times 200 cm 3 of water. The combined aqueous phases are washed with two times 200 cm 3 of cyclohexane, then neutralized by addition of sodium hydrogencarbonate and extracted with 400 cm 3 and then two times 200 cm 3 of ethyl acetate. The combined organic phases are then washed with a half-saturated sodium chloride solution, dried over sodium sulphate and then concentrated under reduced pressure. 248 g of methyl (3aRS,4SR,7aRS)-2- 2' ii$%
ZZT
-64benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate are then obtained in the form of an orange-coloured oil, the characteristics of which are as follows: N.M.R. spectrum (300 MHz, CDC1 3 d in ppm): 2.4-2.65 (mt, 4H, H at 5 and at 2.85 (2 dt, 2H, H at 3.02 (2 dt, 2H, H at 3.2 (2 dt, 1H, H at 3.35 (mt, 1H, H at 7a), 3.5 (2 dt, 2H, benzyl 7-7.3 (mt, 10H, aromatic protons).
Stage C 5.1 cm 3 of 4-bromotoluene and 1 g of magnesium turnings in 100 cm 3 of diethyl ether are heated at reflux for one hour. 100 cm 3 of toluene are added and the mixture is heated to 60 0 C under a stream of nitrogen. After cooling to a temperature in the region of 5 C, a solution of 10 g of methyl (3aRS,4SR,7aRS)-2benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 80 cm 3 of toluene is added. The reaction mixture is stirred for one hour at a temperature in the region of 20C and then hydrolysed with 100 cm 3 of a saturated aqueous ammonium chloride solution. The aqueous phase is separated by settling and extracted with two times 15 75 cm 3 of ethyl acetate. The organic phases are combined, washed successively with 100 cm 3 of distilled water and 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure.
After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, 9 g of 20 methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(4-methylphenyl)-4phenyloctahydroisoindole-3a-carboxylate are obtained in the form of a white solid, the characteristics of which are as follows: melting point 164 C 'H N.M.R. spectrum (250 MHz, CDC1 3 d in ppm): 1.84 and 2.60 (d mt and mt, J 12.5 Hz, each 1H, CH 2 at from 2.05 to 2.20 (mt, 2H, 1H of the CH 2 at 1 and 1H of the CH 2 at 2.32 3H, ArCH 3 2.40 and 2.95 (2d, J 10.5 Hz, each 1H, CH 2 at 2.45 (mt, 1H, the other H of the CH 2 at 2.64 (mt, 1H, the other H of the CH 2 at 2.85 (mt, 1H, H at 7a), 3.32 3H, COOCH 3 3.40 and 3.70 (2d, J 1.25 Hz, each 1H, NCH 2 Ar), 3.50 (dd, J 12.5 and 3 Hz, 1H, H at 6.68 1H, OH at from 7.00 to 7.50 (mt, 10H, aromatic H at 4 and aromatic H of the benzyl), 7.12 and 7.40 (2d, J 8 Hz, each 2H, H at the ortho and meta positions of the aromatic at 7).
Stage D A mixture of 29 cm 3 of trifluoromethane-sulphonic acid and of 100 cm 3 of dichloromethane is added dropwise to a solution of 20 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(4-methyl-phenyl)-4phenyloctahydroisoindole-3a-carboxylate in 200 cm 3 of dichloromethane maintained at a temperature in the region of 0°C. The reaction mixture is stirred for 30 minutes at a temperature in the region of 0°C and 2 hours at a temperature in the region of 20°C and is then cooled to a temperature in the region of 0OC. 50 cm 3 of distilled water are then added and then the pH of the aqueous phase is brought to between 8 and 9 by addition of a 4N aqueous sodium hydroxide solution. The organic phase is separated by settling, washed successively with 100 cm 3 of distilled water and 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium 15 sulphate and concentrated under reduced pressure. After recrystallization from S" isopropanol, 18.2 g of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-4,9-ethano-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro- H-benzo[f]isoindole-3a-carboxylate are thus obtained in the form of a white solid, the characteristics of which are as follows: melting point 158 0
C
20 'H N.M.R. spectrum (300 MHz, CDC13, d in ppm): 1.61, 1.90 and 2.67 (3 mts, respectively 1H, 1H and 2H, CH 2
CH
2 from 2.50 to 2.60 (mt, 2H, 1H of the
CH
2 at 1 and 1H [lacuna] CH 2 at 2.57 3H, ArCH 3 2.95 J 10 Hz, the other H of the CH 2 at 3.37 J 10 Hz, the other H of the CH 2 at 3.44 (broad d, J 10 Hz, 1H, H at 9a), 3.54 and 3.85 (2d, J 12.5 Hz, each 1H, NCH 2 Ar), 3.57 (broad s, 1H, H at 3.72 3H, COOCH 3 6.70 (broad d, J 7.5 Hz, 1H, H at 8), from 7.10 to 7.60 (mt, 12H, H at 5, H at 6, H at 7, H at the ortho and meta positions of the aromatic at 9 and aromatic H of the benzyl).
Stage E 18 g of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-4,9-ethano-9-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate, in solution in 250 cm 3 of methanol, are reduced by 7.8 g of ammonium formate in the presence of 2 g of 10% palladium-on-charcoal by heating at reflux for two hours. After cooling, the catalyst is separated by filtration and rinsed with three times cm 3 of methanol and the filtrate is concentrated under reduced pressure. The residue is dissolved in 200 cm 3 of ethyl acetate and the organic phase is washed successively with 100 cm 3 of a saturated aqueous sodium hydrogen carbonate solution, 100 cm 3 of distilled water and 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. By stirring in 100 cm 3 ofpentane, the oil obtained crystallizes. By filtration, 13.2 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methylphenyl)- 2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate are obtained in the form of a white solid, the characteristics of which are as follows: S- melting point 118° C 'H N.M.R. spectrum (250 MHz, CDCI 3 d in ppm): 1.56, 1.78 and 2.24 (3 15 mts, respectively 1H, 1H and 2H, CH 2
CH
2 2.42 3H, ArCH 3 2.79 and 2.96 (2dd, respectively J 12.5 and 5.5 Hz and J 1.25 and 8 Hz, each 1H, CH 2 at 1), 3.10 and 3.39 (2 d, J 12.5 Hz, each 1H, CH 2 at 3.30 (mt, 1H, H at 9a), 3.51 (broad s, 1H, H at 3.60 3H, COOCH 3 6.56 (broad d, J 7.5 Hz, 1H, H at 8), from 6.95 to 7.45 (mt, 7H, H at 5, H at 6, H at 7 and H at the ortho and meta 20 positions of the aromatic at 9).
Stage F 36.6 g of (2-methoxyphenyl)acetic acid, in suspension in 110 cm 3 of bis(dimethylamino)methane, are cooled to a temperature in the region of 0 0
C.
110 cm 3 of acetic anhydride are added dropwise, the temperature of the reaction mixture not exceeding 40"C. The reaction mixture is stirred for 24 hours at a temperature in the region of 20°C and then cooled to a temperature in the region of 0°C. 500 cm 3 of distilled water are then added and stirring is continued for 2 hours at a temperature in the region of OC. The solid which has appeared is separated by filtration, washed with three times 100 cm 3 of distilled water and dried under reduced pressure at 40 0 C. 23 g of 2-(2-methoxyphenyl)propenoic acid are thus obtained in -67the form of a cream solid, the characteristics of which are as follows: melting point 145 C 'H N.M.R. spectrum (200 MHz, d6-DMSO, d in ppm): 3.74 3H, ArOCH 3 5.71 and 6.15 (2d, J 0.5 Hz, each 1H, =CH 2 from 6,90 to 7.50 (mt, 4H, aromatic from 11.5 to 13.5 (very broad unresolved peak, 1H, COOH).
Stage G A solution of 3.05 cm 3 of oxalyl chloride in 150 cm 3 of dichloromethane is added dropwise to a solution of 6.31 g of 2-(2methoxyphenyl)propenoic acid in 150 cm 3 of dichloromethane containing 5 drops of N,N-dimethylformamide. The reaction mixture is stirred for a further two hours at a temperature in the region of 20 0 C, then cooled to a temperature in the region of 0°C and run dropwise into a solution of 12.3 g of methyl (3aRS,4SR,9RS,9aRS)-4,9ethano-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3acarboxylate in 250 cm 3 of dichloromethane and 10 cm 3 of triethylamine, the 15 temperature being maintained in the region of 0 0 C. The reaction mixture is stirred for a further one hour at a temperature in the region of 0OC, then for one hour at a temperature in the region of 20°C and poured into 200 cm 3 of distilled water. The organic phase is separated by settling, washed with two times 200 cm 3 of distilled water and then 200 cm 3 of a saturated aqueous sodium chloride solution, dried over 20 magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (70/30 by volume) mixture, 14.9 g of methyl (3aRS,4SR,9RS,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro- H-benzo[f]isoindole-3a-carboxylate are obtained in the form of a white solid, the characteristics of which are as follows: melting point 152'C 'H N.M.R. spectrum (250 MHz, d6-DMSO, at a temperature of 383 K, d in ppm): 1.44, 1.68 and from 2.00 to 2.30 (3 mts, respectively 1H, 1H and 2H,
CH
2
CH
2 2.40 3H, ArCH 3 from 3.35 to 3.50 (mt, 3H, CH 2 at 1 and H at 9a), 3.46 (mt, 1H, H at 3.55 3H, COOCH 3 3.60 and 4.10 (2d, J 12.5 Hz, each -68- 1H, CH 2 at 3.73 3H, ArOCH 3 5.54 and 5.70 (2s, each 1H,=CH 2 6.46 (broad d, J 7.5 Hz, 1H, H at from 6.90 to 7.40 (mt, 11H, H at 5, H at 6, H at 7, H at the ortho and meta positions of the aromatic at 9 and aromatic H at the ortho, meta and para positions with respect to the OCH 3 EXAMPLE 2 Preparation of (3aRS.4SR.9RS,9aRS)-4.9-ethano-2-r2-(2methoxyphenyl)propenoyll-9-(4-methylphenyl)-2,,3a,4,9,9a-hexahydro-1Hbenzo[flisoindole-3a-carboxvlic acid 14.7 g of methyl (3aRS,4SR,9RS,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carboxylate are heated at reflux for six hours in 400 cm 3 of Sethanol in the presence of 43.5 cm 3 of a normal aqueous sodium hydroxide solution.
The reaction mixture is subsequently concentrated under reduced pressure and the S• S*resiude dissolved in 250 cm 3 of distilled water. The aqueous phase is washed with r 15 three times 200 cm 3 of diethyl ether and then acidified with a 4N aqueous o• hydrochloric acid solution to a pH in the region of 2. The crystals which appear are separated off by filtration, washed with three times 400 cm 3 of distilled water and then 200 cm 3 of petroleum ether and dried under reduced pressure at 40'C. 12.6 g of (3aRS,4SR,9RS,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4- 20 methylphenyl)-2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylic acid are Sthus obtained in the form of a white solid, the characteristics of which are as follows: 9 S- melting point 142 0
C
H N.M.R. spectrum (400 MHz, d6-DMSO, at a temperature of 413 K, d in ppm): 1.42, 1.65, 2.00 and 2.15 (4 mts, each 1H, CH 2
CH
2 2.40 3H, ArCH 3 from 3.20 to 3.40 (mt, 3H, CH 2 at 1 and H at 9a), 3.55 (mt, 1H, H at 3.60 and 4.06 (2d, J 12.5 Hz, each 1H, CH 2 at 3.68 3H, OCH 3 5.53 and 5.70 (2 s, each 1H, =CH 2 6.45 (broad d, J 7.5 Hz, 1H, H at 6.95 (broad t, J 7.5 Hz, 1H, aromatic H at the para position with respect to the OCH 3 7.03 (broad d, J 7.5 Hz, 1H, aromatic H at the ortho position with respect to the OCH 3 from 6.90 to 7.30 (mt, 9H, H at 5, H at 6, H at 7 and aromatic H at the meta positions with respect to -69the OCH 3 and aromatic H at the ortho and meta positions of the aromatic at 9).
EXAMPLE 3 Isolation of the dextrorotatory enantiomer of (3aRS,4SR.9RS,9aRS)-4.9-ethano-2-f2- (2-methoxvphenyl)propenoyl]-9-(4-methylphenvl)-2,3,3a,4,9,9a-hexahydro- 1Hbenzorf]isoindole-3a-carboxvlic acid 500 mg of (3aRS,4SR,9RS,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-lHbenzo[f]isoindole-3a-carboxylic acid are resolved on a chiral silica column, carrying grafts, elution being carried out with a mixture of dichloromethane, of isopropanol and of n-heptane (85/10/5 by volume). On collecting the second fraction eluted (retention time 60 minutes), 220 mg of the dextrorotatory enantiomer are obtained after concentrating under reduced pressure, the characteristics of which enantiomer are as follows: melting point 225 C 15 mass spectrum M/Z 493 and 449 (M+-CO 2 optical rotation: [a]j 63.3 1.0° (c 0.5, methanol).
The chiral silica can be prepared in the following way: 948 g of aminopropyl silica (100 A, 10 tim, NH 2 Macherey-Nagel) are suspended in 3 dm 3 of N,N-dimethylformamide in a 6-dm 3 three-necked flask.
20 180 g of the anhydride of N-(tert-butoxycarbonyl)- 1l-aminoundecanoic acid are added and the reaction mixture is stirred for 18 hours at a temperature in the region of 20C. The silica is separated by filtration and washed successively with 2 times 2500 cm 3 of dichloromethane and then 2 times 2500 cm 3 of N,N-dimethylformamide.
The silica, thus washed, is resuspended in 3 litres of N,N-dimethylformamide and 180 g of the anhydride of N-(tert-butoxycarbonyl)-1 1-aminoundecanoic acid are added and then the reaction mixture is stirred for 18 hours at a temperature in the region of 20°C. The silica is separated by filtration, washed successively with 2 times 2500 cm 3 of dichloromethane, 2 times 2500 cm 3 of tetrahydrofuran, 2 times 2500 cm 3 of methanol and 2 times 2500 cm 3 of diethyl ether and then dried under reduced pressure at a temperature in the region of 20 0 C. 971 g of silica, denoted by the term "BOC-C, -C 3 -silica", are thus obtained in the form of a white powder, the structure of which is confirmed by the infrared spectrum and the elemental analysis (found) of which is: C 9.85, H 2.05, N 1.05.
971 g of"BOC-C-C 3 -silica" silica are suspended in 2500 cm 3 of dichloromethane and 470 g ofimidazole in a 6-dm 3 three-necked flask. 850 cm 3 of dimethyloctylchlorosilane are added dropwise and the reaction mixture is stirred for 16 hours at a temperature in the region of 20 0 C. The solid obtained is separated by filtration and washed successively with 2 times 2500 cm 3 of dichloromethane, two times 2500 cm 3 of methanol, 2 times 2500 cm 3 of tetrahydrofuran, 2 times 2500 cm 3 of dichloromethane and 2 times 2500 cm 3 of diethyl ether and then dried under reduced pressure at a temperature in the region of 20°C. 1179 g of silica, denoted by the term "BOC-C,,-C 3 -silica-O-Si(CH 3 2
(CH
2 7 CH3", are thus obtained in the form of a white powder, the structure of which is confirmed by the infrared spectrum and the elemental analysis (found) of which is: C 13.9, H 2.83, N 1.16.
15 1178 g of "BOC-C, 1
-C
3 -silica-O-Si(CH 3 2
(CH
2 7
CH
3 silica are *suspended in 2500 cm 3 of a 5 by volume solution of trifluoroacetic acid in 0 dichloromethane in a 6-dm 3 three-necked flask. The reaction mixture is stirred at 20°C. The silica is separated by filtration and washed successively with 2 times 2500 cm 3 of dichloromethane, 2 times 2500 cm 3 of a 20 dichloromethane/diisopropylethylamine (70/30 by volume) mixture, 2500 cm 3 of dichloromethane, 2 times 2500 cm 3 of tetrahydrofuran, 2 times 2000 cm 3 of methanol .and 2 times 2000 cm 3 of diethyl ether and then dried under reduced pressure at a temperature in the region of 50'C. 1080.5 g of silica, denoted by the term 3 silica-O-Si(CH 3 2
(CH
2 7
CH
3 are thus obtained in the form of a white powder, the structure of which is confirmed by the infrared spectrum and the elemental analysis (found) of which is: C 12.6, H 2.44, N 1.05.
1080 g of "C -C 3 -(silica)-O-Si(CH 3 2
(CH
2 7
CH
3 silica are suspended in 2500 cm 3 of N,N-dimethylformamide, which has been dried over 4A molecular sieve, in a 6-dm 3 three-necked, round-bottomed flask. 108 g of 3 dinitrobenzoyl)-L-phenylalanine and 75 g of N-ethoxycarbonyl-2-ethoxy-1,2-
I
a a a.
dihydroquinoline are added. The reaction mixture is stirred overnight. The silica is separated by filtration on sintered glass and is then washed with 2 times 2500 cm 3 of dichloromethane, 2 times 2500 cm 3 of tetrahydrofuran, 2500 cm 3 of N,N-dimethylformamide and 2500 cm 3 of dichloromethane. The silica, thus washed, is resuspended in 2500 cm 3 of N,N-dimethylformamide. 108 g of dinitrobenzoyl)-L-phenylalanine and 75 g of N-ethoxycarbonyl-2-ethoxy-1,2dihydroquinoline are successively added and the reaction mixture is then stirred overnight at 20°C. The silica is separated by filtration on sintered glass and is washed successively with 2 times 2500 cm 3 of dichloromethane, 2 times 2500 cm 3 of tetrahydrofuran, 2 times 2500 cm 3 of methanol and 2 times 2500 cm 3 of diethyl ether.
After drying at 60 0 C under reduced pressure (2.7 kPa), 1093.6 g of silica, denoted by the term "DNB-L-Phe-CI-C 3 (silica)-O-Si(CH 3 2
(CH
2 7
CH
3 are obtained in the form of a pale yellow powder, the structure of which is confirmed by its infrared spectrum and the elemental analysis (found) of which is: C 14.5, H 2.4, N 1.68.
519 g of "DNB-L-Phe-Cl-C 3 (silica)-O-Si(CH 3 2
(CH
2 7 CH3" silica are suspended in 3000 cm 3 of N,N-dimethylformamide, dried over 4A molecular sieve, in a 4-dm 3 three-necked, round-bottomed flask. 450 cm 3 oftrimethylsilylimidazole are added over 15 minutes and the reaction mixture is then stirred overnight. The silica is separated by filtration and is washed successively with 2 times 1500 cm 3 of tetrahydrofuran, 2 times 1500 cm 3 of methanol, 2 times 1500 cm 3 of acetone and 2 times 1500 cm 3 of dichloromethane. After drying at a temperature of 60 0 C under reduced pressure (2.7 kPa), 519 g of silica, denoted by the term "DNB-L-Phe-Ci-
C
3 (silica)-[O-Si(CH 3 2
(CH
2 7
CH
3 ]-[O-Si(CH 3 3 are obtained in the form of a pale yellow powder, the structure of which is confirmed by its infrared spectrum and the elemental analysis (found) of which is: C 15.3, H 1.8, N 2.6.
The anhydride of N-(tert-butoxycarbonyl)- 11-aminoundecanoic acid can be prepared in the following way: 30.1 g ofN-(tert-butoxycarbonyl)-11-aminoundecanoic acid are dissolved in 480 cm 3 of ethyl acetate. This solution is cooled to 5 C and then, while maintaining it at this temperature, a solution of 10.63 g of 1,3- 7--l -0V ri -72dicyclohexylcarbodiimide in 120 cm 3 of ethyl acetate is added over 10 minutes. The reaction mixture is stirred for 1 hour at 5' 0 C and then for 16 hours at a temperature in the region of 20'C. The precipitate formed is separated by filtration and washed with cm 3 of ethyl acetate. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 30'C. The solid obtained is dried at 20'C under reduced pressure (2.7 kPa). 3 1 g of the anhydride of N-(tert-butoxycarbonyl)- 1-aminoundecanoic acid are thus obtained, with a yield in the region of 100 N-(tert-Butoxycarbonyl)- I I-aminoundecanoic acid can be prepared according to J. Org. Chem., 41, .1350 (1976).
EXAMPLE 4 Isolation of the laevorotatory enantiomer of (3 aRS .4SR,9RS .9aRS)-4,9-ethano-2- r2- (2-methoxyphenyl)n2ropenoyll-9-(4-methylphenyl)-2,3 .3 a,49,9a-hexahydro- 1Hbenzorflisoindole-3a-carboxylic acid 500 mg of (3aRS,4SR,9RS,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylic acid are resolved on a chiral silica column, carrying grafts, elution being carried out with a dichloromethane/ isopropanolln-heptane (85/10/5 by volume) mixture. On collecting first fraction eluted (retention time 47 minutes), 240 mg of the laevorotatory are obtained after concentrating under reduced pressure, the characteristics of which enantiomer are as follows: melting point 225'C mass spectrum M/Z 493 anid 449 (M'-CO 2 optical rotation: [a]2'5 76.0 1.20 (c 0.5, methanol).
EXAMPLE Preparation of (3aRS .4SR.9SR.9aRS)-4,9-ethano-2-r(2-methoxyphenvl)acetvl]-9-(4methylphenyl)-2,3 .3 a4,9,9a-hexahydro-l1H-benzo rflisoindole-3 a-carboxylic acid Stage A 362 mg (2.17 mmol) of 2-methoxyphenylacetic acid, 456 mg (2.38 mmol) of I-ethyl-3-[(3-dimethyl-amnino)propyl]carbodiimide and 59 mg
Y
(0.43 mmol) of N-hydroxybenzotriazole hydrate are successively added to a solution of 755 mg (2.17 mmol) of methyl (3aRS,4SR,9RS,9aRS)-4,9-ethano-9-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate, obtained in Stage E of Example 1, in 20 cm 3 of dichloromethane. After stirring overnight at room temperature, 15 cm 3 of dichloromethane are added, washing is carried out with two times 15 cm 3 of water, drying is carried out over magnesium sulphate and the solvent is evaporated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (90/10 by volume) mixture, 820 mg of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl]-9-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo [fisoindole-3 a-carboxylate are obtained, after concentrating the solvent under reduced pressure, in the form of a white powder, the characteristics of which are as follows: melting point 189°C mass spectrum M/Z 495 (M Stage B By carrying out the reaction as in Example 2, but from 819 mg (1.65 mmol) of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)acetyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3acarboxylate at reflux for 18 hours in 17 cm 3 of a normal aqueous sodium hydroxide solution and 17 cm 3 of methanol, 720 mg of (3aRS,4SR,9SR,9aRS)-4,9ethano-2-[(2-methoxyphenyl)acetyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[f]isoindole-3a-carboxylic acid are obtained, after recrystallization from cm 3 of diisopropyl ether, in the form of a white powder, the characteristics of which are as follows: melting point 182 C H N.M.R. spectrum (400 MHz, d6-DMSO, at a temperature of 423 K, 8 in ppm): 1.40, 1.64, 1.95 and 2.10 (4 mts, each 1H, CH 2
CH
2 2.41 3H, ArCH 3 from 3.30 to 3.65 (mt, 6H, CH 2 at 1, NCOCH 2 Ar, 1H of the CH 2 at 3 and H at 9a), 3.48 (mt, 1H, H at 3.75 3H, OCH 3 4.18 J 12.5 HJz, 1H, the other H of -c' <'7o the CH 2 at 6.46 (broad d, J 7.5 Hz, 1H, H at 6.90 (broad t, J 7.5 Hz, 1H, aromatic H in the para position with respect to the OCH 3 6.96 (broad d, J 7.5 Hz, 1H, aromatic H in the ortho position with respect to the OCH 3 from 7.00 to 7.35 (mt, 5H, H at 5, H at 6, H at 7 and aromatic H at the meta position with respect to the
OCH
3 7.30 (limit AB, 4H, aromatic H at the ortho and meta positions of the aromatic at 9).
EXAMPLE 6 Preparation of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxvphenvl)-2-[(2methoxyphenvl)acetvl]-2,3.3a,4,9.9a-hexahydro-1H-benzo[flisoindole-3a-carboxvlic acid Stage A 2.07 cm 3 (16.5 mmol) of 4-bromoanisole and 402 mg (16.5 mmol) of magnesium turnings in 20 cm 3 of diethyl ether are heated at reflux under an argon atmosphere for three hours. After cooling to 0 C, 1.36 g (5.5 mmol) of anhydrous 15 cerium chloride are added and then a solution of 2 g (5.5 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydro-isoindole-3a-carboxylate, obtained in Stage B of Example 1, in 5 cm 3 of dry diethyl ether is run in dropwise at a temperature in the region of 5 C and under an argon atmosphere. The reaction mixture is stirred for one hour at a temperature in the region of 0OC and then S 20 overnight at room temperature. After cooling to 0°C, the reaction mixture is hydrolysed by 15 cm 3 of a saturated aqueous ammonium chloride solution. The aqueous phase is separated by settling and extracted with two times 50 cm 3 of ethyl acetate. The organic phases are combined, washed successively with 25 cm 3 of distilled water and 25 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (60/40 by volume) mixture, 1.345 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(4-methoxyphenyl)- 4-phenyloctahydroisoindole-3a-carboxylate are obtained in the form of a white solid, the characteristic of which is as follows: (f ih3 7
S
r
~I\
r melting point 136 0
C
Stage B By carrying out the reaction as in Stage D of Example 1, but from 1.343 g (2.85 mmol) of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(4methoxyphenyl)-4-phenyloctahydroisoindole-3a-carboxylate and from 4.56 cm 3 of trifluoromethanesulphonic acid in 65 cm 3 of dichloromethane for 30 minutes at a temperature in the region of OC and then overnight at room temperature, 863 mg of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-methoxyphenyl)- 2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (90/10 by volume) mixture, in the form of a white solid, the characteristic of which is.as follows: melting point 127 0
C
Stage C By carrying out the reaction as in Stage E of Example 1, but from 839 mg (1.85 mmol) of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4methoxyphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3a-carboxylate and from 0.35 g (5.5 mmol) of ammonium formate in the presence of 0.27 g of palladium-on-charcoal in 20 cm 3 of methanol, heating being carried out at reflux for 3 hours, 559 mg of methyl (3aRs,4SR,9SR,9aRS)-4,9-ethano-9-(4methoxyphenyl)-2,3,3a,4,9,9a-hexahydro-1IH-benzo[fjisoindole-3a-carboxylate are obtained, after stirring the foam obtained in 30 cm' of pentane, in the form of a white solid, the characteristic of which is as follows: melting point 112 0
C
Stage D By carrying out the reaction as in Stage A of Example 5, but from 548 mg (1.51 mmol) of methyl (3aRs,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3a-carboxylate, from 251 mg (1.51 mmol) of 2-methoxyphenylacetic acid, from 318 mg (1.66 mmol) of 1-ethyl-3- [3-(dimethylamino)propyl]carbodiimide and from 41 mg (0.3 mmol) of N- 33 -76hydroxybenzotriazole hydrate in 15 cm 3 of dichloromethane, 575 mg of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[(2methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3acarboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate, (90/10 by volume) mixture, in the form of a white powder, the characteristics of which are as follows: melting point 1690 mass spectrum M/Z 511 Stage E By carrying out the reaction as in Example 2, but from 566 mg (1.1 mmol) of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[(2methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3acarboxylate at reflux for eighteen hours in 11.5 cm 3 of a normal aqueous sodium 15 hydroxide solution and 7.5 cm' of methanol, 385 mg of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[(2- .methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro- H-benzo[f]isoindole-3a-carboxylic acid are obtained, after recrystallization from 10 cm 3 of diisopropyl ether, in the form of a white powder, the characteristics of which are as follows: melting point 163°C 'H N.M.R. spectrum (400 MHz, d6-DMSO, at a temperature of 393 K, 6 in ppm): 1.36, 1.61, 1.90 and 2.07 (4 mts, each 1H, CH 2
CH
2 from 3.30 to 3.65 (mt, 6H, CH 2 at 1, NCOCH 2 Ar, 1H of the CH 2 at 3 and H at 9a), 3.46 (mt, 1H, H at 4), 3.73 (broad s, 3H, OCH 3 3.80 3H, OCH 3 of the aromatic at 4.15 (d, J 12.5 Hz, 1H, the other H of the CH 2 at 6.45 (broad d, J 7.5 Hz, 1H, H at 8), 6.90 (broad t, J 7.5 Hz, 1H, aromatic H at the para position with respect to OCH 3 6.96 (broad d, J 7.5 Hz, 1H, aromatic H at the ortho position with respect to the
OCH
3 7.06 J 8 Hz, 2H, aromatic H at the ortho positions with respect to the
OCH
3 for the aromatic at from 7.00 to 7.30 (mt, 5H, H at 5, H at 6, H at 7 and 3 aromatic H at the meta positions with respect to the OCH 3 7.30 J 8 Hz, 2H, -77aromatic H at the meta positions with respect to the OCH 3 for the aromatic at 9).
EXAMPLE 7 Preparation of (3aRS,4SR9SR,9aRS)-4.9-ethano-2-[(2-methoxyphenvl)acetyll-9-(4methvlsulphanvlphenvl-2,3 .3a,4.9,9a-hexahvdro-1H-benzo[flisoindole-3acarboxvlic acid Stage A By carrying out the reaction as in Stage A of Example 6, but from 1.34 g (6.6 mmol) of 4-bromothioanisole and 161 mg (6.6 mmol) of magnesium turnings at reflux for three hours in 4 cm 3 of diethyl ether and then, successively, from 543 mg (2.2 mmol) of anhydrous cerium chloride and from a solution of 800 mg (2.2 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo- 4-phenyloctahydroisoindole-3a-carboxylate, obtained in Stage B of Example 1, in 2 cm' of diethyl ether, 679 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7hydroxy-7-(4-methylsulphanylphenyl)-4-phenyloctahydroisoindole-3a-carboxylate 15 are obtained, after purification by flash chromatography on silica gel (230- 400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (80/20 by volume) mixture, in the form of a white solid, the characteristic of which is as follows: melting point 124-6 0
C
Stage B By carrying out the reaction as in Stage D of Example 1, but from .676 mg (1.39 mmol) of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(4methylsulphanylphenyl)-4-phenyloctahydroisoindole-3a-carboxylate and from 2.22 cm 3 of trifluoromethanesulphonic acid in 34cm' of dichloromethane for thirty minutes at a temperature in the region of 0 0 C and then seventy hours at room temperature, 366 mg of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9- (4-methylsulphanylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3acarboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (90/10 by volume) mixture, in the form of a white solid, the characteristic of which is as follows: melting point= 105-7 0
C
Stage C A solution of 246 mg (0.52 mmol) of methyl (3aRS,4SR,9SR,9aRS)- 2-benzyl-4,9-ethano-9-(4-methylsulphanylphenyl)-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate in 10 cm of dichloromethane is cooled to OoC under an argon atmosphere. 115 mg (0.79 mmol) of 2-chloroethyl chloroformate are then added and then the reaction mixture is stirred overnight at room temperature.
After concentrating the solvent under reduced pressure, the residue is heated at reflux for four hours in 10 cm' of methanol containing 1.5 cm 3 of a 1M solution of hydrochloric acid in methanol. The crystals formed are filtered off, washed with two times 1 cm 3 of ice-cold methanol and then neutralized by stirring in 10 cm 3 of a 00 decinormal solution of sodium hydroxide. After extracting with dichloromethane and concentrating to dryness, 145 mg of methyl (3aRS,4SR,9SR,9aRS)-4,9- 15 ethano-9-(4-methylsulphanylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole- 3a-carboxylate are obtained in the form of a white foam, the characteristic of which is as follows: melting point 90-4'C Stage D By carrying out the reaction as in Stage A of Example 5, but from 145 mg (0.38 mmol) of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methylsulphanylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fJisoindole-3a-carboxylate, from 64 mg (0.38 mmol) of 2-methoxyphenylacetic acid, from 91 mg (0.42 mmol) of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and from 10 mg (0.076 mmol) of N-hydroxybenzotriazole hydrate in 5 cm of dichloromethane, 182 mg of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)acetyl]-9-(4-methylsulphanylphenyl)-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[f]isoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane/ethyl acetate (80/20, then 70/30, by volume) mixtures, in the form of a 1/ -79white powder, the characteristics of which are as follows: melting point 137°C mass spectrum M/Z 527 Stage E By carrying out the reaction as in Example 2, but from 180 mg (0.34 mmol) of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)acetyl]-9-(4-methylsulphanylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole- 3a-carboxylate at reflux for eighteen hours in 3.7 cm 3 of a normal aqueous sodium hydroxide solution and 3.7 cm 3 of methanol, 144 mg of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)acetyl]-9-(4methylsulphanylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3acarboxylic acid are obtained, after recrystallization from 5 cm 3 of diisopropyl ether, in the form of a white powder, the characteristics of which are as follows: melting point =145°C 15 'H N.M.R. spectrum (250 MHz, d6-DMSO, at a temperature of 393 K, 6 in ppm): 1.40, 1.63, 1.92 and 2.10 (4 mts, each 1H, CH 2
CH
2 2.59 3H, SCH 3 from .3.30 to 3.70 (mt, 6H, CH 2 at 1, NCOCHAr, 1H of the CH 2 at 3 and H at 9a), 3.50 (mt, 1H, H at 3.73 (broad s, 3H, OCH 3 4.18 J 12.5 Hz, 1H, the other H of the CH 2 at 6.48 (broad d, J 7.5 Hz, 1H, H at 6.92 (broad t, J 7.5 Hz, 1H, *0.
96* 20 aromatic H at the para position with respect to OCH 3 7.00 (broad d, J 7.5 Hz, 1H, aromatic H at the ortho position with respect to the OCH 3 from 7.05 to 7.35 (mt,
S
5H, H at 5, H at 6, H at 7 and aromatic H at the meta positions with respect to the
OCH
3 7.35 and 7.45 (2 broad d, J 8 Hz, each 2H, aromatic H at the ortho and meta positions of the aromatic at 9).
EXAMPLE 8 Preparation of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenvl)-2-(2methoxvphenvl)acetyl]-23,3 a.4,9,9a-hexahvdro-1H-benzo[flisoindole-3a-carboxvlic acid Stage A By carrying out the reaction as in Stage A of Example 6, from 6.1 cm 3
OJ'"
.0 of a 1M solution of 4-fluorophenylmagnesium bromide in diethyl ether and then, successively, from 1.36 g (5.5 mmol) of anhydrous cerium chloride and from a solution of 2 g (5.5 mmol) of methyl (3aRs,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate, obtained in Stage B of Example 1, in 20 cm 3 of diethyl ether, 507 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-(4fluorophenyl)-7-hydroxy-4-phenyloctahydroisoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (60/40 by volume) mixture, in the form of a white solid, the characteristic of which is as follows: melting point 163 0
C
Stage B By carrying out the reaction as in Stage D of Example 1, from 433 mg 1 (0.94 mmol) of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-(4-fluorophenyl)-7- 15 hydroxy-4-phenyloctahydroisoindole-3a-carboxylate and from 1.51 cm 3 of 9 trifluoromethanesulphonic acid in 20 cm 3 of dichloromethane for thirty minutes at a temperature in the region of 0'C and then 70 hours at room temperature, 360 mg of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-fluorophenyl)- •2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate are obtained, after 20 purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (90/10 by volume) mixture, in the form of a white solid, the characteristic of which is as 9 follows: melting point 157 0
C
Stage C By carrying out the reaction as in Stage E of Example 1, but from 358 mg (0.81 mmol) of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4fluorophenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate and from 153 mg (2.43 mmol) of ammonium formate in the presence of 120 mg of palladium-on-charcoal in 20 cm 3 of methanol, heating being carried out at reflux for 3 hours, 236 mg of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4fluorophenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylate are obtained, after stirring the foam obtained in 15 cm 3 of pentane, in the form of a white solid, the characteristic of which is as follows: melting point= I 63'C StageD.
By carrying out the reaction as in Stage A of Example 5, from 235 mg (0.67 mmol) of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)- 2,3,3 a,4,9,9a-hexahydro-l1H-benzo~flisoindole-3 a-carboxylate, from 112 mg (0.67 mmol) of 2-methoxyphenylacetic acid, from 142 mng (0.74 mmol) of 1-ethyl-3- [3-(dimethylamino)propyl]carbodiimide hydrochloride and from 19 mg (0.076 mmol) of N-hydroxybenzotriazole hydrate in 10 cm 3 of dichloromethane, 230 mg (680/o) of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2- [(2-methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo(fjlisoindole-3acarboxylate are obtained, after purification by flash chromatography on silica gel (23 0-400 mesh), elution being carried out with cyclohexane/ethyl acetate (90/10, then 80/20, by volume) mixtures, in the form of a white powder, the characteristics of which are as follows: Soo**: melting point =216TC mass spectrum M/Z 4.99 Stage E By carrying out the reaction as in Example 2, but from 228 mg (0.45 mmol) of methyl (3 aRS,4SR,9SR,9alRS)-4,9-ethano-9-(4-fluorophenyl)-2-[(2methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 acarboxylate at reflux for eighteen hours in 4.7 cm 3 of a norm al aqueous sodium hydroxide solution and 5 cm 3 of methanol, 171 mg of (3aRS,4SR,9SR,9aR-S)- 4,9-ethano-9-(4-fluorophenyl)-2-[(2-methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9ahexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid are obtained, after recrystallization from 5 cm 3 of diisopropyl ether, in the form of a white powder, the characteristics of which are as follows: -82melting point 250 C 'H N.M.R. spectrum (400 MHz, d6-DMSO, at a temperature of 423 K, d in ppm): 1.40, 1.64, 1.95 and 2.10 (4 mts, each 1H, CH 2
CH
2 2.41 3H, ArCH 3 from 3.30 to 3.65 (mt, 6H, CH 2 at 1, NCOCH 2 Ar, 1H of the CH 2 at 3 and H at 9a), 3.48 (mt, 1H, H at 3.75 3H, OCH 3 4.18 J 12.5 Hz, 1H, the other H of the CH 2 at 6.46 (broad d, J 7.5 Hz, 1H, H at 6.90 (broad t, J 7.5 Hz, 1H, aromatic H at the para position with respect to the OCH 3 6.96 (broad d, J 7.5 Hz, 1H, aromatic H at the ortho position with respect to the OCH 3 from 7.00 to 7.35 (mt, 5H, H at 5, H at 6, H at 7 and aromatic H at the meta positions with respect to the OCH 3 7.30 (limit AB, 4H, aromatic H at the ortho and meta positions of the aromatic at 9).
EXAMPLE 9 Preparation of (3aRS,4SR,9SR.9aRS)-4.9-ethano-2-r(2-methoxvphenvl)acetvl1-9-(3methvlphenvl)-2.3,3a,4.9,9a-hexahvdro-lH-benzo[flisoindole-3a-carboxvlic acid 15 Stage A By carrying out the reaction as in Stage A of Example 6, but from 2.42 cm 3 of a 1M solution of meta-tolylmagnesium bromide in tetrahydrofuran and then, successively, from 543 mg (2.2 mmol) of anhydrous cerium chloride and from .:.0o a solution of 800 mg (2.2 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo- 20 4-phenyloctahydroisoindole-3a-carboxylate, obtained in Stage B of Example 1, in 10 cm 3 of diethyl ether, 505 mg of methyl (3aRS,4SR,7Rs,7aRS)-2-benzyl-7hydroxy-7-(3-methylphenyl)-4-phenyloctahydroisoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (80/20 by volume) mixture, in the form of a white solid, the characteristic of which is as follows: melting point 117-9°C Stage B By carrying out the reaction as in Stage D according to Example 1, but from 669 mg (1.47 mmol) of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy- 7-(3-methylphenyl)-4-phenyloctahydroisoindole-3a-carboxylate and from 2.35 cm 3 of trifluoromethanesulphonic acid in 33 cm of dichloromethane for thirty minutes at a temperature in the region of OC and then forty-eight hours at room temperature, 582 mg of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3-methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (90/10 by volume) mixture, in the form of a white solid, the characteristic of which is as follows: melting point 113-5 C Stage C By carrying out the reaction as in Stage E of Example 1, but from 578 mg (1.27 mmol) of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3methyl-phenyl)-2,3,3a,4,9,9a-hexahydro-lH-benzo[flisoindole-3a-carboxylate and e 15 from 241 mg (3.82 mmol) of ammonium formate in the presence of 185 mg of .4 palladium-on-charcoal in 20 cm 3 of methanol, heating being carried out at reflux for 3 hours, 412 mg of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1 H-benzo[fl-isoindole-3a-carboxylate are obtained, after stirring the foam obtained in 10 cm 3 of pentane, in the form of a white solid, the characteristic of which is as follows: see* melting point 103'C 6:604: StageD By carrying out the reaction as in Stage A of Example 6, but from 409 mg (1.18 mmol) of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3a-carboxylate, from 196 mg (1.18 mmol) of 2-methoxy-phenylacetic acid, from 248 mg (1.29 mmol) of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and from 32 mg (0.076 mmol) of N-hydroxybenzotriazole hydrate in 12 cm 3 of dichloromethane, 509 mg of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)acetyl]-9-(3-methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3ao& -84carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (90/10 by volume) mixture, in the form of a white powder, the characteristics of which are as follows: melting point 132°C mass spectrum M/Z 495 Stage E By carrying out the reaction as in Example 2, but from 506 mg (1.02 mmol) of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)acetyl]-9-(3-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3acarboxylate at reflux for eighteen hours in 10.3 cm 3 of a normal aqueous sodium hydroxide solution and 7 cm 3 of methanol, 424 mg of (3aRS,4SR,9SR,9aRS)- 4,9-ethano-2-[(2-methoxyphenyl)acetyl]-9-(3-methylphenyl)-2,3,3a,4,9,9ahexahydro-lH-benzo[flisoindole-3a-carboxylic acid are obtained, after 15 recrystallization from 5 cm of diisopropyl ether, in the form of a white powder, the characteristics of which are as follows: melting point 138°C 'H N.M.R. spectrum (250 MHz, d6-DMSO, at a temperature of 393 K, d in ppm): 1.40, 1.66, 1.95 and 2.10 (4 mts, each 1H, CH 2
CH
2 2.43 3H, ArCH 3 20 from 3.30 to 3.65 (mt, 6H, CH 2 at 1, NCOCH 2 Ar, 1H of the CH 2 at 3 and H at 9a), 3.48 (mt, 1H, H at 3.73 (broad s, 3H, OCH 3 4.18 J 12.5 Hz, 1H, the other H of the CH 2 at 6.45 (broad d, J 7.5 Hz, 1H, H at 6.92 (broad t, J 7.5 Hz, 1H, 0 aromatic H at the para position with respect to the OCH 3 6.98 (broad d, J 7.5 Hz, 0, 1H, aromatic H at the ortho position with respect to the OCH 3 from 7.00 to 7.35 (mt, 8H, H at 5, H at 6, H at 7, aromatic H at the meta position with respect to the
OCH
3 and aromatic H at the ortho and para positions with respect to the CH 3 for the aromatic at 7.40 J 8 Hz, 1H, aromatic H at the meta position with respect to the CH 3 for the aromatic at 9).
.p
Y.
Z
EXAMPLE Preparation of (3aRS,4SR.9SR.,9aRS)-4,9-ethano-9-(3-methoxvphenvl)-2-[(2methoxyphenyl)acetyl-2,3,3a,4,9,9a-hexahydro-1H-benzofflisoindole-3a-carboxylic acid Stage A By carrying out the reaction as in Stage A of Example 6, but from 1.56 cm 3 (12.4 mmol) of 3-bromoanisole and from 302 mg (12.4 mmol) of magnesium turnings at reflux for one hour in 5 cm of dry diethyl ether, followed successively by 1.02 g (4.13 mmol) of anhydrous cerium chloride and by a solution of 1.5 g (4.13 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4phenyloctahydroisoindole-3a-carboxylate, obtained in Stage B of Example 1, in 8 cm 3 of diethyl ether, 945 mg of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7hydroxy-7-(3-methoxyphenyl)-4-phenyloctahydroisoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), 15 elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (80/20 by volume) mixture, in the form of a white solid, the characteristic of which is *as follows: melting point 118 C Stage B By carrying out the reaction as in Stage D of Example 1, but from a 941 mg (1.99 mmol) of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3methoxyphenyl)-4-phenyloctahydroisoindole-3a-carboxylate and from 3.19 cm' of trifluoromethanesulphonic acid in 45 cm 3 of dichloromethane for 30 minutes at a temperature in the region of 00C and then forty-eight hours at room temperature, 755 mg of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-4,9-ethano-9-(3methoxyphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a cyclohexane/ethyl acetate (90/10 by volume) mixture, in the form of a white solid, the characteristic of which is as follows: -86melting point 117 0
C
Stage C By carrying out the reaction as in Stage E of Example 1, but from 747 mg (1.65 mmol) of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-4,9-ethano-9-(3methoxyphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate and from 311 mg (4.94 mmol) of ammonium formate in the presence of 240 mg of palladium-on-charcoal in 18 cm' of methanol, heating being carried out at reflux for three hours, 501 mg of methyl (3aRS,4SR,9RS,9aRS)-4,9-ethano-9- (3-methoxyphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[f]-isoindole-3a-carboxylate are obtained, after stirring the foam obtained in 10 cm' of pentane, in the form of a white solid, the characteristic of which is as follows: melting point 96-8 0
C
Stage D By carrying out the reaction as in Stage A of Example 5, but from 500mg (1.38 mmol) of methyl (3aRS,4SR,9RS,9aRS)-4,9-ethano-9-(3methoxyphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fisoindole-3a-carboxylate, from S* 229 mg (1.38 mmol) of 2-methoxy-phenylacetic acid, from 291 mg (1.52 mmol) of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and from 37 mg (0.27 mmol) of N-hydroxybenzotriazole hydrate in 14 cm 3 of dichloromethane, 451 mg of methyl (3aRS,4SR,9RS,9aRS)-4,9-ethano-9-(3-methoxyplienyl)-2- ~[(2-methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3acarboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with cyclohexane and then with a Scyclohexane/ethyl acetate (80/20 by volume) mixture, in the form of a white powder, the characteristics of which are as follows: melting point 128C mass spectrum M/Z 5.11 Stage E By carrying out the reaction as in Example 2, from 450 mg (0.88 mmol) of methyl (3aRS,4SR,9RS,9aRS)-4,9-ethano-9-(3-methoxyphenyl)-2- -u 2 7-C a a a a a a [(2-methoxyphenyl)-acetyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3acarboxylate at reflux for 18 hours in 4.7 cm 3 of a normal aqueous sodium hydroxide solution and 5 cm 3 of methanol, 391 mg of (3aRS,4SR,9SR,9aRS)-4,9-ethano- 9-(3-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]-2,3,3a,4,9,9a-hexahydro-lHbenzo[f]isoindole-3a-carboxylic acid are obtained, after recrystallization from 10 cm 3 of diisopropyl ether, in the form of a white powder, the characteristics of which are as follows: melting point 135 C 'H N.M.R. spectrum (250 MHz, d6-DMSO, at a temperature of 393 K, d in ppm): 1.40, 1.63, 1.94 and 2.10 (4 mts, each 1H, CH 2
CH
2 from 3.35 to 3.70 (mt, 6H, CH 2 at 1, NCOCH 2 Ar, 1H of the CH 2 at 3 and H at 9a), 3.50 (mt, 1H, H at 4), 3.73 (broad s, 3H, OCH 3 3.87 3H, OCH 3 of the aromatic at 4.18 J 12.5 Hz, 1H, the other H of the CH 2 at 6.48 (broad d, J 7.5 Hz, 1H, H at from 6.85 to 7.35 (mt, 10H, H at 5, H at 6, H at 7, aromatic H at the ortho, meta and para position with respect to the OCH 3 and aromatic H at the ortho and para positions with respect to the OCH 3 for the aromatic at 7.43 J 8 Hz, 1H, aromatic H at the meta position with respect to the OCH 3 for the aromatic at 9).
EXAMPLE 11 Preparation of methyl (3aRS.4SR.9SR.9aRS)-9-(3,4-dimethylphenyl)-4,9-ethano-2- [(2-methoxyphenvl)acetyll-2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3acarboxvlate acid Stage A 2.3 cm 3 of 4-bromo-ortho-xylene and 0.42 g of magnesium turnings in a mixture of 20 cm 3 of diethyl ether and 20 cm 3 of tetrahydrofuran are heated at reflux for one hour. After cooling to a temperature in the region of-7'C, a solution of 3.11 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole- 3a-carboxylate in 20 cm 3 of diethyl ether is added over 25 minutes. The reaction mixture is stirred for four hours at a temperature in the region of 25'C and then hydrolysed by 50 cm 3 of a saturated aqueous ammonium chloride solution. The aqueous phase is separated by settling and extracted with 25 cm 3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, 1.995 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3,4dimethylphenyl)-4-phenyl-octahydroisoindole-3a-carboxylate are obtained, the characteristic of which compound, used as is in the following stage, is as follows: mass spectrum M/Z 469 (Me) and 410 (M'-CO 2 Stage B By carrying out the reaction as in Stage D of Example 1, but starting from 1.99 g of the mixture obtained in the preceding stage, in solution in 100 cm 3 of dichloromethane, maintained at a temperature in the region of and from 3.7 cm 3 of trifluoromethane-sulphonic acid, stirring being carried out for 72 hours at a temperature in the region of 25 0 C, 1.63 g of methyl (3aRS,4SR,9RS,9aRS)-2benzyl-9-(3,4-dimethylphenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro-1H- 15 benzo[f]isoindole-3a-carboxylate are obtained in the form of a brown oil, the .**characteristic of which compound, used as is in the following stage, is as follows: mass spectrum M/Z 451 SStage
C
The reaction is carried out as in Stage E of Example 1, but starting from 1.63 g of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-9-(3,4-dimethylphenyl)-4,9ethano-2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate in 40 cm 3 of methanol and from 0.68 g of ammonium formate in the presence of 0.41 g of palladium-on-charcoal, heating being carried out at reflux for two hours, 0.79 g of methyl (3aRS,4SR,9RS,9aRS)-9-(3,4-dimethylphenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate is obtained in the form of a white solid, the characteristic of which is as follows: mass spectrum M/Z 361 Stage D By carrying out the reaction as in Stage A of Example 5, but from 0.79 g of methyl (3aRS,4SR,9RS,9aRS)-9-(3,4-dimethylphenyl)-4,9-ethano- (1ST I)
'A
<A r -89- 2,3,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylate, from 0.44 g of 2-methoxyphenylacetic acid, from 0.5 g of 1 -ethyl-3-[3- (dimethylamino)propyl]carbo-diimide hydrochloride and from 0.35 g of N-hydroxybenzotriazole hydrate in 35 cm 3 of dichioromethane, 0.7 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[(2methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 acarboxylate is obtained, after purification by flash chromatography on 37 g of silica gel (23 0-400 mesh), elution being carried out with pure dichioromethane and then with a dichloromethane/ethanol (99/1 by volume) mixture, in the form of a foam which is recrystallized in the following way: this foam is dissolved in 5 cm 3 of absolute ethanol, water is added until the solution becomes cloudy and then the mixture is cooled for one hour at a temperature in the region of 0 0 C. 0.61 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[(2methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 acarboxylate is thus obtained in the form of a yellow powder, the characteristics of which are as follows: melting point 8 8 *C -mass spectrum M/Z 509 EXAMPLE 12 Preparation of (3 aRS.4SR.9SR,9aRS)-9-(3 .4-dimethyl-phenvyl)-4,9-ethano-2-Y2- ~methoxyphenyl)acetyl] -2,3.3 a,4,9,9a-hexahydro-l1H-benzorflisoindole-3 a-carboxylic acid By carrying out the reaction as in Example 2, from 637 mg of methyl (3 aRS,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[(2methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 acarboxylate at reflux for 18 hours in 1.9 cm 3 of a normal aqueous sodium hydroxide solution and 60 cm 3 of ethanol, 176 mg of (3aRS,4SR,9SR,9aRS)-9-(3,4-dimethylphenyl)-4,9-,ethano-2-[(2-methoxyphenyl)acetyl] -2,3,3 a,4,9,9a-hexahydro-l1Hbenzo[flisoindole-3a-carboxylic acid are obtained, after recrystallization from 5 cm 3 of diisopropyl ether, in the form of a white powder, the characteristics of which are as follows: melting point 257°C mass spectrum M/Z 495 and 451 (M-CO 2 EXAMPLE 13 Preparation of (3aRS,4SR.9SR.9aRS)-3a-N-benzvlcarbamoyl-4,9-ethano-2-r2-(2methoxyphenvl)propenovll-9-(4-methlphenyl)-2,3,3a,4,9,9a-hexahydro-lHbenzo[flisoindole A solution of 0.19 cm 3 of oxalyl chloride in 5 cm 3 of dichloromethane is added dropwise to a solution of 1 g of (3aRS,4SR,9RS,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carboxylic acid in 10 cm 3 of dichloromethane containing 1 drop of N,N-dimethylformamide. The reaction mixture is stirred for a further 2 hours at a temperature in the region of 20'C, then cooled to a temperature in the region of 0 C and run dropwise into a solution of 0.22 cm 3 of benzylamine in 10 cm 3 of dichloromethane and 0.57 cm 3 of triethylamine, the temperature being maintained in the region of 0OC. The reaction mixture is stirred for a further 15 minutes at a temperature in the region of 0°C and then for two hours at a temperature in the region of 20 0 C, and poured into 50 cm 3 of distilled water. The organic phase is separated by settling, washed with 50 cm 3 of distilled water and then 50 cm 3 of a 20 saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (50/50 by volume) mixture, 0.8 g of (3aRS,4SR,9SR,9aRS)-3a-N-benzylcarbamoylo 4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9ahexahydro-lH-benzo[f]isoindole is obtained in the form of a white solid, the characteristics of which are as follows: melting point 227°C 'H N.M.R. spectrum (300 MHz, d6-DMSO, at a temperature of 413 K, d in ppm): 1.40, 1.64, 2.02 and 2.15 (4 mts, each 1H, CH 2
CH
2 2.39 3H, ArCH 3 3.31 and 3.40 (respectively mt and d (broad), J 13 Hz, each 1H, CH 2 at 3.50 and 4.20 -91- (respectively d and d (broad), J 13 Hz, each 1H, CH 2 at 3.59 (mt, 1H, H at 9a), 3.61 (broad s, 1H, H at 3.71 3H, AiOCH 3 4.22 (limit AB, 2H, CH 2 NAr), 5.52 and 5.67 (2s, each 1H, =CH 2 6.44 (broad d, J 7.5 Hz, 1H, H at 6.95 (broad t, J 7.5 Hz, 1H, aromatic H at the para position with respect to the OCH 3 7.01 (broad d, J 7.5 Hz, 1H, aromatic H at the ortho position with respect to the OCH 3 from 6.95 to 7.35 (mt, 14H, H at 5, H at 6, H at 7, aromatic H at the meta positions with respect to the OCH 3 H at the ortho and meta positions of the aromatic at 9 and aromatic H of the benzyl), 7.75 (unresolved peak, 1H, CONH).
EXAMPLE 14 Preparation of benzvl (3aRS,4SR.9SR,9aRS)-49-ethano-2-r2-(2methoxyphenvl)propenovl-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzorflisoindole-3a-hydroxamate By carrying out the reaction as in Example 13, but from 2.49 g of (3aRS,4SR,9RS,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo(flisoindole-3a-carboxylic acid in 20 cm 3 of dichloromethane containing 2 drops of N,N-dimethylformamide, from a solution of 0.48 cm 3 of oxalyl chloride in 5 cm 3 of dichloromethane and from a solution of 0.8 g of O-benzylhydroxylamine hydrochloride in a mixture of 2.1 cm' of triethylamine and of 20 cm 3 of dichloromethane, 2.4 g of benzyl *20 (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3a-hydroxamate are obtained in the form of a white solid, the characteristics of which are as follows: melting point 227'C 'H N.M.R. spectrum (300 MHz, d6-DMSO, at a temperature of 413 K, d in ppm): 1.38, 1.61, 1.98 and 2.10 (4 mts, each 1H, CH 2
CH
2 2.39 3H, ArCH 3 3.26 and 3.38 (respectively dd and d (very broad), J 13 and 9 Hz and J 13 Hz, each 1H, CH 2 at 3.46 and 4.14 (respectively d and d (broad), J 13 Hz, each 1H, CH 2 at 3.50 (mt, 1H, H at 3.52 (dt, J 9 and 3 Hz, 1H, H at 9a), 3.72 3H, ArOCH), 4.63 and 4.70 (2 d, J 11 Hz, each 1H, OCH 2 Ar), 5.52 and 5.68 (respectively s and s (broad), each 1H, =CH 2 6.44 (broad d, J 7.5 Hz, 1H, H at 8), C 'C *S
C.
C C
C
OSC
C.
C).
C..
C
C
C
C
C
C 6.95 (broad t, J 7.5 Hz, 1H, aromatic H at the para position with respect to the
OCH
3 from 7.00 to 7.40 (mt, 15H, H at 5, H at 6, H at 7, aromatic H at the meta and ortho positions with respect to the OCH 3 H at the ortho and meta positions of the aromatic at 9 and aromatic H of the benzyl), 10.83 (unresolved peak, 1H, CONH).
EXAMPLE Preparation of (3aRS.4SR.9SR,9aRS)-3a-carbamovl-4.9-ethano-2-[2-(2methoxvphenvl)propenovll-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzo[flisoindole A solution of 0.24 cm 3 of oxalyl chloride in 5 cm 3 of dichloromethane is added dropwise to a solution of 1.24 g of(3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2- (2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-lHbenzo[flisoindole-3a-carboxylic acid in 10 cm 3 of dichloromethane containing 1 drop of N,N-dimethylformamide. The reaction mixture is stirred for a further two hours at a temperature in the region of 200C and then concentrated under reduced pressure.
15 The residue is dissolved in 10 cm 3 of dioxane and run dropwise into 10 cm 3 of a aqueous ammonia solution, the temperature being maintained in the region of OC.
The reaction mixture is stirred for a further one hour at a temperature in the region of 0°C and then filtered. The precipitate is washed successively with three times 50 cm 3 of distilled water and 50 cm 3 of diisopropyl ether and then dried under reduced pressure at a temperature in the region of 40°C. 0.85 g of(3aRS,4SR,9SR,9aRS)-3acarbamoyl-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)- 2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole is thus obtained, after recrystallization from methanol, in the form of a white solid, the characteristics of which are as follows: melting point: >260 0
C
TH N.M.R. spectrum (300 MHz, d6-DMSO, at a temperature of 413 K, d in ppm): 1.38, 1.60, 1.98 and 2.12 (4 mts, each 1H, CH 2
CH
2 2.39 3H, ArCH 3 3.26 and 3.36 (respectively dd and d (very broad), J 13 and 9 Hz and J 13 Hz, each 1H, CH 2 at 3.48 and 4.16 (respective d and d (broad), J 13 Hz, each 1H, CH 2 at 3.50 (dt, J 9 and 3 Hz, 1H, H at 9a), 3.56 (mt, 1H, H at 3.72 3H, ArOCH 3 5;52 and 5;68 (respectively s and s (broad), each 1H, =CH 2 6.42 (broad d, J 7.5 Hz, 1H, H at 6.70 (unresolved peak, 2H, CONH 2 6.95 (broad t, J Hz, 1H, aromatic H at the para position with respect to the OCH 3 7.03 (broad d, J Hz, 1H, aromatic H at the ortho position with respect to OCH 3 from 7.00 to 7.40 (mt, 9H, H at 5, H at 6, H at 7, aromatic H at the meta positions with respect to the
OCH
3 and H at the ortho and meta positions of the aromatic at 9).
EXAMPLE 16 Preparation of (3aRS,4SR,9SR.9aRS)-4.9-ethano-2-[2-(2-methoxyphenyl)propenvl]- 9-(4-methvlphenl)-2,3,3a,4,9,9a-hexahydro-1H-benzofflisoindole-3a-hydroxamic acid 0.61 cm 3 of anisole and then 0.72 g of aluminium chloride are added to a solution of 1.3 g of benzyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-
H-
benzo[flisoindole-3a-hydroxamate in a mixture of 10 cm 3 of nitromethane and 15 10 cm 3 of dichloromethane cooled to a temperature in the region of -15 C. The reaction mixture is stirred for one hour at a temperature in the region of 20°C and then concentrated under reduced pressure. The residue is taken up in 50 cm 3 of a S" normal aqueous hydrochloric acid solution and extracted with two times 50 cm 3 of dichloromethane. The extracts are combined, washed successively with 50 cm 3 of 20 distilled water and 50 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (230-400 mesh), elution being carried *9 999 out with a dichloromethane/methanol (90/10 by volume) mixture. 0.75 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3a-hydroxamic acid is thus obtained, after recrystallization from acetonitrile, in the form of a cream solid, the characteristics of which are as follows: melting point 252°C 'H N.M.R. spectrum (300 MHz, d6-(CD 3 2 SO, at a temperature of 413 K, d in ppm): 1.36, 1.60, 1.98 and 2.08 (4 mts, each 1H, CH 2
CH
2 2.39 3H, ArCH 3 3.26 i 7 and from 3.30 to 3.45 (respectively dd and mt, J 13 and 9 Hz, each 1H, CH 2 at 1), 3.43 and 4.12 (respectively d and d (broad), J 13 Hz, each 1H, CH, at 3.50 (dt, J 9 and 3 Hz, 1H, H at 9a), 3.56 (mt, 1H, H at 3.72 3H, ArOCH 3 5;52 and 5;68 (respectively s and s (broad), each 1H, =CH 2 6.42 (broad d, J 7.5 Hz, 1H, H at 6.95 (broad t, J 7.5 Hz, 1H, aromatic H at the para position with respect to the
OCH
3 7.03 (broad d, J 7.5 Hz, 1H, aromatic H at the ortho position with respect to the OCH 3 from 7.00 to 7.40 (mt, 9H, H at 5, H at 6, H at 7, aromatic H at the meta positions with respect to the OCH 3 and H at the ortho and meta positions of the aromatic at At room temperature, the signals are observed corresponding to the exchangeables: 8.70 (unresolved peak, 1H, CONH), 10.65 (unresolved peak, 1H,
OH).
I
II-^
EXAMPLE 17 Preparation of (3aRS.4SR.9SR,9aRS)-4,9-ethano- 2-[2-(2-methoxyphenvl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-lHbenzofflisoindole-3a-N-(3-pyridvlmethyl)carboxamide A solution of 0.24 cm 3 of oxalyl chloride in 5 cm 3 of dichloromethane is added dropwise to a solution of 1.24 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano- 2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carboxylic acid in 10 cm 3 of dichloromethane and one drop of N,N-dimethylformamide. The reaction mixture is stirred for two hours at a temperature in the region of 20 0 C, then cooled to a temperature in the region of 0 0
C
and run onto a solution of 0.26 cm 3 of 3-(aminomethyl)pyridine and of 0.7 cm 3 of triethylamine in 10 cm 3 of dichloromethane cooled to a temperature in the region of 0 C. The reaction mixture is stirred at a temperature in the region of 0OC for fifteen minutes and then in the region of 20°C for two hours, and then run into 15 100 cm 3 of distilled water. The aqueous phase is separated by settling and extracted with two times 50 cm 3 of dichloromethane. The organic phases are combined, S. washed with 50 cm 3 of distilled water and then 50 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), 20 elution being carried out with a dichloromethane/methanol (95/5 by volume) .o mixture, and crystallization by reflux in isopropanol, 1.0 g of (3aRS,4SR,9SR,9aRS)- 4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9ahexahydro-lH-benzo[f]isoindole-3a-N-(3-pyridylmethyl)carboxamide is obtained, the characteristics of which compound are as follows: melting point: 234°C.
H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 393 K, d in ppm): 1.40, 1.62 and from 1.90 to 2.20 (3 mts, respectively 1H, 1H and 2H,
CH
2
CH
2 2.39 3H, ArCH 3 from 3.20 to 3.40 (limit AB, 2H, CH 2 at 3.44 J 12.5 Hz, 1H, 1H of the CH 2 at from 3.55 to 3.65 (mt, 2H, CH at 4 and CH at 9a), 3.68 3H, ArOCH 3 from 4.10 to 4.35 (mt, 3H, the other H of the CH 2 at 3 and V;.S
NCH
2 Ar), 5;51 and 5;68 (2 s, each 1H, CH 2 6.42 (broad d, J 7.5 Hz, 1H, H at 8), from 6.90 to 7.50 (mt, 13H, H at 5, H at 6, H at 7, aromatic H of the 2methoxyphenyl, aromatic H of the 4-methyiphenyl, H at 4 of the pyridyl and H at of the pyridyl), 8.05 (unresolved peak, 1H, CONH), 8.39 (broad s, 1H, H at 2 of the pyridyl), 8.44 (broad d, J 5 Hz, 1H, H at 6 of the pyridyl).
I. r. 90
K:
A,,
-97- EXAMPLE 18 Isolation of the dextrorotatory enantiomer of (3aRS ,4SR.9SR,9aRS)-4,9-ethano- 2-r2-(2-methoxphenyvlpropenoyl-9-(4-methylphenyl)2. ,3 a.499a-hexahydro- 1Hbenzo rflisoindole-3 a-N-(3 -pvridylmethvl)carboxamide 12 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole- 3a-N-(3-pyridylmethyl)carboxamide, obtained in Example 17, are resolved, in 12 injections of 1 g, on a Whelk 01 (SS) chiral silica column, elution being carried out with an n-heptane/dichloromethane/propanol (50/50/2 by volume) mixture. On collecting the first fraction eluted (retention time 42 min), 4.78 g of the dextrorotatory enantiomer of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3 ,3a,4,9,9a-hexahydro-1Hbenzo [flisoindole-3a-N-(3-pyridylmethyl)carboxamide are obtained, after concentrating the solvent under reduced pressure, the characteristics of this product being as follows: melting point 2 1 O' mass spectrum M/Z 583 optical rotation: [a]3' 5 104.6 1.60 (c 0.5, methanol) 0 .0
C)
S
S
S
S~iPr -98- EXAMVPLE 19 Isolation of the levorotatory enantiomer of (3aRS.4SR,9SR,9aRS)-4,9-ethano-2-r2- (2-methoxyphenyl)propenovl] -9-(4-methvlphenyl)-2,3,3 a,4,9,9a-hexahydro- 1Hbenzofflisoindole-3 a-N-(3 -pvrdvlmethyl)carbo xamide 12 g of (3aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3 a-N- (3-pyridylmethyl)carboxamide, obtained in Example 17, are resolved, in 12 injections of 1 g, on a Whelk 0 1 (SS) chiral silica colum n, elution being carried out with an n-heptane/dichloromethane/propanol (50/50/2 by volume) mixture. On collecting the second fraction eluted (retention time 65 min), 4.86 g of the levorotatory enantiomer of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1Hbenzo [flisoindole-3 a-N-(3 -pyridylmethyl)carboxamide are obtained, after concentrating the solvent under reduced pressure, the characteristics of this product 15. being as follows: '00, melting point =2 mass spectrum M/Z 583 optical rotation: [a]32 5 102.2+11.5' (c methanol) -99- EXAMPLE Preparation of (3dRS.4SR,9SR.9aRS)-4,9-ethano- 2- r2-(2-methoxyphenylpropenoyll-9-(4-methylphenyl)>2,3 3 a,4,9,9a-hexahydro-l1Hbenzo rflisoindole-3 a-N-(4-pyrdvlmethyl)carboxamide By carrying out the reaction as in Example 17, but from 1.24 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid, from one drop of N,N-dimethylformamide, from 0.24 cm 3 of oxalyl chloride, [lacuna] 0.26 cm 3 of 4-(aminomethyl)pyridine and from 0.7 cm 3 of triethylamine, 0.7 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- -methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1H-benzojflisoindole- 3a-N-(4-pyridylmethyl)carboxamide is obtained, after crystallization from a mixture of equal volumes of isopropanol and of diisopropyl ether, the characteristic of which product is as follows: melting point =202'C.
EXAMPLE 21 :~:Preparation of methyl (3aRS4S R.9SR,9aRS)-4,9-ethano-2-r2- 2methoxyphenflpropenovll-9-(4-methylphenvl)-2,3 .3 a,4,99a-hexaqhydro-l1Hb enzo rfl isoindo le- 3 a-hydroxamate A solution of 0.24 cm 3 of oxalyl chloride in 5 cm 3 of dichloromethane 0 is added dropwise to a solution of 1.24 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano- 2 -[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3 ,3a,4,9,9a-hexahydro-I1H- **benzo[flisoindole-3a-carboxylic acid in 10 cm 3 of dichioromethane and one drop of S N,N-dimethylformnamide. The reaction mixture is stirred for two hours at a temperature in the region of 20'C and then run onto a solution of 0.21 g of O-methylhydroxylamine hydrochloride in a mixture of 1.05 cm 3 of triethylamnine and of 10 cm 3 of dichioromethane cooled to a temperature in the region of 0 0 C. The reaction mixture is stirred at a temperature in the region of 00 C for thirty minutes and then at a temperature in the region of 20'C for one hour, and then run into 50 cm 3 Of distilled water. The organic phase is separated by settling, washed with two times -100cm' of distilled water, two times 20 cm 3 of a normal aqueous sodium hydroxide solution, 50 cm of distilled water and 50 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure.
After recrystallization from 20 cm 3 of refluxing isopropanol, 0.95 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-hydroxamate is obtained, the characteristics of which product are as follows: melting point 256'C 'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 383 K, d in ppm): 1.38, 1.62 and 1.90 to 2.20 (3 mts, respectively 1H, 1H and 2H, CH 2
CH
2 2.40 3H, ArCH 3 from 3.15 to 3.45 (respectively dd and mt, J 12 and 9 Hz, 2H,
CH
2 at from 3.30 to 3.60 (mt, 3H, CH at 9a, CH at 4 and 1H of the CH 2 at 3.48 3H, NOCH 3 3.71 3H, ArOCH), 4.14 (broad d, J 12.5 Hz, 1H, the other H of the CH 2 at 5.52 and 5.69 (2 s, each 1H, =CH 2 6.43 (broad d, J 7.5 Hz, 1H, H at from 6.90 to 7.40 (mt, 11H, H at 5, H at 6, H at 7 and aromatic H of the 2methoxyphenyl and aromatic H of the 4-methylphenyl).
0009 EXAMPLE 22 Preparation of(3aRS4SR.9SR9aRS)-49-ethano- 2-[2-(2-methoxvphenvl)propenovll-9-(4-methylphenyl)-2,3 .3a.4,9,9a-hexahdro- 1H- 20 benzorflisoindole-3a-N',N'-dimethylcarbohvdrazide **a A solution of 0.24 cm of oxalyl chloride in 5 cm of dichloromethane is added dropwise to a solution of 1.24 g of (3aRS,4SR,9SR,9aRS)-4,9-ethanoa ae* *2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H- GO 10 CM benzo[fisoindole-3a-carboxylic acid in 10 cm of dichloromethane and one drop of N,N-dimethylformamide. The reaction mixture is stirred for two hours at a temperature in the region of 20C and then run onto a solution of 0.2 cm 3 of N,N-dimethylhydrazine and of 0.7 cm' of triethylamine in 10 cm' of dichloromethane cooled to a temperature in the region of 0 0 C. The reaction mixture is stirred at a temperature in the region of 00C for thirty minutes and then at a temperature in the region of 20'C for one hour and then run into 50 cm 3 of distilled
-V
~ji
~G?
-101water. The organic phase is separated by settling, washed with 50 cm 3 of distilled water, two times 25 cm of a normal aqueous sodium hydroxide solution, 50 cm' of distilled water and 50 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol (97.5/2.5 by volume) mixture, and recrystallization from 50 cm 3 of an isopropanol/diisopropyl ether (1/9 by volume) mixture, 0.95 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[f]isoindole- 3a-N',N'-dimethylcarbohydrazide is obtained, the characteristics of which compound are as follows: melting point: 230 0
C
'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 383 K, d in ppm): 1.38, 1.60 and from 1.90 to 2.20 (3 mts, respectively 1H, 1H and 2H, 15 CH 2 2.40 3H, ArCH 3 2.47 6H, N(CH 3 2 3.21 and 3.35 (respectively dd and mt, J 12 and 9 Hz, each 1H, CH 2 at 3.40 and 4.19 (respectively d and d (broad), J 13 Hz, each 1H, CH 2 at from 3.50 to 3.65 (mt, 2H, CH at 9a and CH at 3.71 3H, ArOCH), 5.51 and 5.69 (2 s, each 1H, =CH 2 6.42 (broad d, J Hz, 1H, H at from 6.90 to 7.40 (mt, 11H, H at 5, H at 6, H at 7, aromatic H of the 2-methoxyphenyl and aromatic H [lacuna] 4-methylphenyl), 8.41 (unresolved peak, 1H, CONH).
EXAMPLE 23 Preparation of (3aRS.4SR,9SR9aRS)-49-ethano- 2-r2-(2-methoxvphenvl)propenovl-9-(4-methylphenvl)-2,3,3a,4,9,9a-hexahydro- 1Hbenzorflisoindole-3a-N'-phenlcarbohdrazide By carrying out the reaction as in Example 22, but from 0.5 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-carboxylic acid, from one drop of N,N-dimethylformamide, from 0.095 cm 3 of oxalyl chloride, from 0.098 cm 3 9 J ,3 of N-phenylhydrazine and from 0.28 cm' of triethylamine, 0.22 g of -102- (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole- 3a-N'-phenylcarbohydrazide is obtained, after crystallization from 10 cm 3 of diisopropyl ether, the characteristics of which compound are as follows: melting point: 220 0
C.
C
C C
C
C
C
CC*
C
C
C.
C.
CC
C C~ -103- EXAMPLE 24 Preparation of (3 aRS,4SR,9SR,9aRS')-4,9-ethano- 2-r2 -(2-methoxyphenyl)pronenoyl] -9-(4-methylphenyl)Y2,3 3a,4,9,9a-hexahvdro-l1Hbenzofflisoindole-3 a-N'.N'-pentamethylenecarbohydrazide By carrying out the reaction as in Example 22, but from 0.5 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid, from one drop of N,N-dimethylformamide, from 0.095 cm 3 of oxalyl chloride, from 0.095 cm 3 of 1-aminopiperidine and from 0.28 cm 3 of triethylamine, 0.06 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(4methylphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole- 3 a-N',N'-pentamethylenecarbohydrazide is obtained, after purification by flash 0: chromatography on silica gel (230-400 mesh), elution being carried out with ethyl acetate, and after crystallization from diisopropyl ether, the characteristics of which 15 compound are as follows: .0 melting point: 220'C.
EXAMPLE :000 Preparation of (3aRS4S R,9SR.9aRS)-4,9-ethano-2-r2-(methoxyphenyl)propenoyll- 9-(4-methylphenyl)-3a-phenylsulphonylaminocarbonyl-2,3 .3 a,4,99a-hexahydro-l1H-, 0 20 benzorflisoindole solution of 0.096 cm 3 of oxalyl chloride in 0.5 cm 3 Of dichloromethane is added dropwise to a solution of 0.5 g of (3aRS,4SR,9SR,9aRS)- 4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylic acid in 5 cm 3 of dichloromethane and one drop of N,N-dimethylformamide. The reaction mixture is stirred for two hours at a temperature in the region of 20'C and then run into a mixture of 0. 12 g of a suspension of sodium hydride in petroleum jelly and 0.31 g of benzendsulphonamide in 5 cm 3 of N,N-dimethylformamide. The reaction mixture is stirred at a temperature in the region of 2 0 'C for three days. 10 cm 3 of distilled water are subsequently added and the mixture is extracted with two times 20 cm 3 of dichlorornethane. The organic -104extracts are combined, washed with 20 cm 3 of distilled water and then 20 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol (98/2 by volume) mixture, and crystallization from diisopropyl ether, 0.005 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(methoxyphenyl)propenoyl]-9-(4methylphenyl)-3a-phenylsulphonylaminocarbonyl-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole is obtained, the characteristics of which compound are as follows: melting point: approximately 166°C.
'H N.M.R. spectrum (400 MHz, d6-(CD 3 2 SO, at a temperature of 393 K, d in ppm): 1.35, 1.58, 1.97 and 2.09 (4 mts, each 1H, CH 2 2.39 3H, ArCH 3 3.20 and 3.31 (respectively dd and d (broad), J 12.5 and 9 Hz and J 12.5 Hz, each 1H,
CH
2 at from 3.40 to 3.50 (mt, 1H, CH at 9a), 3.45 and 4.14 (respectively dd and d (broad), J 13 Hz, each 1H, CH 2 at 3.59 (mt, 1H, CH at 3.66 3H, 15 ArOCH 3 5.45 and 5.65 (2 s, each 1H, =CH 2 6.35 (mt, 1H, H at from 6.85 to 7.60 (mt, 14H, H at 5, H at 6, H at 7, aromatic H of the 2-methoxyphenyl, aromatic H of the 4-methylphenyl, aromatic H at the meta positions of the phenylsulphonyl and aromatic H at the para position of the phenylsulphonyl), 7.77 J 8 Hz, 2H, aromatic H at the ortho positions of the phenylsulphonyl), 8.00 (broad s, 1H, o S 20 CONH).
EXAMPLE 26 Preparation of (3aRS,4SR,9SR,9aRS)-4.9-ethano- 2-[2-(2-methoxvphenvl)propenovl]-9-(4-methylphenvl-2,3,3a.4,9,9a-hexahydro- Hbenzorflisoindole-3a-N-(N-oxo-3-pyridvl)methvlcarboxamide 0.20 g of sodium carbonate and 6 cm 3 of distilled water are added to a solution of 0.29 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole- 3a-N-(3-pyridylmethyl)carboxamide in 8 cm 3 of chloroform. The mixture is cooled to a temperature in the region of OC and 0.11 g of meta-chloroperbenzoic acid is added. The reaction mixture is stirred for one hour at 2 0 C and then for twenty-two NJ( 1
CC~
-105hours at a temperature in the region of 2 0 C. 0.22 g of meta-chloroperbenzoic acid is again added and the mixture is stirred for four hours at a temperature in the region of and then diluted with 10 cm 3 of dichloromethane. The organic phase is separated by settling, washed with three times 5 cm 3 of a 10% aqueous sodium sulphite solution, three times 5 cm' of a saturated aqueous sodium hydrogencarbonate solution and 5 cm' of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by recrystallization from 8 cm' of isopropyl acetate to give 0.25 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]- 9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-N-(N-oxo-3pyridyl)methylcarboxamide, the characteristics of which are as follows: melting point 250'C.
'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 383 K, d in ppm): 1.40, 1.62 and from 1.90 to 2.25 (3 mts, respectively 1H, 1H and 2H,
CH
2
CH
2 2.40 3H, ArCH), from 3.20 to 3.50 (limit AB, 2H, CH 2 at 3.44 J 12.5 Hz, 1H, 1H of the CH 2 at from 3.50 to 3.65 (mt, 1H, CH at 9a), 3.57 (mt, 1H, CH at 3.70 3H, ArOCH 3 from 4.00 to 4.30 (mt, 3H, the other H of the
CH
2 at 3 and NCH 2 Ar), 5.51 and 5.68 (2 s, each 1H, =CH 2 6.41 (broad d, J 7.5 Hz, 1H, H at from 6.90 to 7.40 (mt, 13H, H at 5, H at 6, H at 7, aromatic H 20 of the 2-methoxy-phenyl, H at 4 of the N-oxopyridyl, H at 5 of the N-oxopyridyl and 0..
aromatic H of the 4-methylphenyl), 8.00 (broad s, 1H, H at 2 of the N-oxopyridyl), 8.05 (broad d, J 5 Hz, 1H, H at 6 of the N-oxopyridyl), 8.11 (broad t, J 5 Hz, 1H,
CONH).
EXAMPLE 27 Preparation of (3aRS,.4SR,9SR.,9aRS)-4,9-ethano- 2-[2-(2-methoxyphenvl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9.9a-hexahydro- 1Hbenzorflisoindole-3 a-N'-(4-methoxyphenvl)carbohdrazide 0.21 g of 4-methoxyphenylhydrazine hydrochloride, 0.23 g of 1-ethyl- 3-[(dimethylamino)propyl]carbodiimide hydrochloride, 0.08 g of N-1-hydroxybenzotriazole hydrate and 0.17 cm of triethylamine are successively -106added to a solution of 0.49 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano- 2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1Hbenzo[flisoindole-3a-carboxylic acid in 10 cm 3 of dichioromethane. The reaction mixture is stirred for twenty hours at a temperature in the region of 20'C and then diluted with 15 cm 3 of dichioromethane. The organic phase is washed with three times 10 cm 3 of distilled water, dried over magnesium sulphate in the presence of 3S charcoal and concentrated under reduced pressure. By crystallization from 10 cm 3 Of isopropyl acetate, 0.36 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano- 2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3 a,4,9,9a-hexahydro-l1Hbenzo [flisoindo le-3 a-N'-(4-methoxyphenyl)carbohydrazide is obtained, the characteristics of which are as follows: melting point= I190'C.
'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 S0, at a temperature of 383 K, d in ppm): 1.40, 1.62 and from 1.90 to 2.25 (3 mts, respectively 1H, 1H and 2H,
CH
2
CH
2 2.38 3H, ArCH 3 3.25 (dd, J 12 and 9 Hz, lH, 1H of the CH 2 at 1), 3.39 (broad d, J 12 Hz, 1H, the other H of the CH 2 at 3.48 and 4.22 (respectively d and d (broad), J 12.5 Hz, each 1H, CH 2 at 3.56 (mnt, 1H, CH at 9a), from 3.60 to 3.75 (mt, I1H, CH at 3.68 6H, the 2 ArOCH 3 5.52 and 5.69 (2 s, each I1H, =CH 2 6.42 (broad d, J 7.5 Hz, 1H, H at 6.56 and 6.69 (2 d, J 8 Hz, each 2H, aromatic H at the ortho and meta positions with respect to the OCH 3 6.80 (broad s, 1H, ArNH), from 6.90 to 7.40 (mt, 1 1H, H atS5, H at 6, H at 7, aromatic H of the 2-methoxyphenyl and aromatic H of the 4-methylphenyl), 9.46 (broad s, 1H, -CONH).
EXAMPLE 28 Preparation of (3 aRS .4SR.9SR,9aRS)-4,9-ethano- 2-f 2-(2-methoxyphenvl)propenoyl] -9-(4-methylphenvl)-2,3 .3 a,4,99a-hexahydro- 1Hbenzorflisoindole-3 a-N'-methyl-N'-phenvlcarbohydrazide By carrying out the reaction as in Example 27, but from 0.49 g of (3 aRS,48R,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[f] isoindole-3 a-carboxylic acid, 0.14 cm 3 7~F~ -107of N-methyl-N-phenylhydrazine, 0.23 g of 1-ethyl- 3-[(dimethylamino)propyl]carbodiimide hydrochloride, 80 mg of N-ihydroxybenzotriazole hydrate and 0. 17 cm' of triethylamine, 0.22 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-lIH-benzo[flisoindole-3 a-N'-methyl-N'phenylcarbohydrazide is obtained, after crystallization from 5 cm 3 of isopropanol, the characteristic of which compound is as follows: -melting point 240TC.
EXAMPLE 29 Preparation of (3aRS,4SR9SR9aRS)-4,9-ethano- 2-r2-(2-methoxyphenvl)propenoyl]-9-(4-methylphenl)-2,3 .3 a,4,99a-hexahydro-l1H-.
benzo[flisoindole-3 a-N'-(2-methylphenvl)carbohydrazide By carrying out the reaction as in Example 27, but from 0.4 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] 15 9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid, 0.16 g of N-(2-methylphenyl)hydrazine, 0.19 g of 1-ethyl- 3 -[(dimethylamino)propyl]carbodiimide hydrochloride, 60 mg of N-ihydroxybenzotriazole hydrate and 0. 14 cm' of triethylamine, 0.28 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] 20 9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N'- *9(2-methylphenyl)carbohydrazide is obtained, after crystallization from 7.5 cm.
3 of isopropyl acetate, the characteristic of which compound is as follows: melting point =235T 0 EXAMVPLE Isolation of the dextrorotatory enantiomer of (3 aRS,4SR.9SR.9aRS)-4,9-ethano-2-[2- (2-methoxyphenflacetyl]-9-(4-methylphenyfl-2,3 .3 a.4,9 9a-hexahvdro- 1Hbenzorflisoindole-3a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-Ethano-2-[2-(2-methoxyphenyl)acetyl]-9- (4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid, obtained in Example 5, can be resolved, on a chiral silica colun carrying 7A -108grafts, by carrying out the resolution as in Example 3. On collecting the second fraction eluted by a mixture of dichioromethane, of isopropanol and of n-heptane (85/10/5 by volume), 70 mg of the dextrorotatory enantiomer of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)acetyl]-9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- IH-benzo [flisoindole- 3a-carboxylic acid are obtained, after concentrating under reduced pressure, the characteristics of which compound are as follows: melting point 205' 0
C.
mass spectrum M/Z 481 optical rotation: [a]32 5 59.5 +0.Q9' (c methanol) -109- EXAMPLE 31 Preparation of methyl (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro- 14-benzodioxin-6-vl)- 4.9-ethano-2-[2-(2-methoxyphenyl)propenovl]-2,3,3a,4,9,9a-hexahydro-1Hbenzo[flisoindole-3a-carboxylate Stage A 7.1 cm 3 of 1,4-benzodioxane are added, under an argon atmosphere, to a solution of 6.3 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 60 cm 3 of dichloromethane stabilized over amylene; this solution is cooled by a bath of ice-cold water and 10.7 cm 3 of 99% trifluoromethanesulphonic acid are run in over 5 minutes. After stirring in the cold bath, the temperature is allowed to rise to a temperature in the region of 20°C and reaction is allowed to take place at this temperature for twenty-one hours, under an argon atmosphere. 200 cm 3 of distilled water are then run in, followed by 300 cm 3 of ethyl acetate. The organic phase is separated by settling and washed successively 15 three times with 180 cm 3 of a 1N aqueous sodium hydroxide solution and then 240 cm 3 of a saturated aqueous sodium chloride solution, and then dried over magnesium sulphate. After filtration, the organic phase is evaporated under reduced pressure to give 10.8 g of an oil. This oil is purified by flash chromatography on an 8-cm diameter column containing 430 g of silica gel (230-400 mesh), elution being 20 carried out successively with 1 dm 3 of the cyclohexane/ethyl acetate (98/2 by volume) mixture, then 2 dm 3 of the cyclohexane/ethyl acetate (95/5 by volume) mixture and then the cyclohexane/ethyl acetate (90/10 by volume) mixture, 50-cm 3 fractions being collected. After concentrating the solvent under reduced pressure, 5.41 g of impure methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(2,3-dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3acarboxylate are obtained in the form of a white foam, which can be used as is in the following stage, the characteristics of which compound are as follows: mass spectrum M/Z 481 'H N.M.R. spectrum (300 MHz, CDC1 3 d in ppm): 1.45, 1.65 and from 2.40 to 2.55 (3 mts, respectively 1H, 1H and 2H, CH 2
CH
2 2.31 and 3.20 (2 d, J 10 Hz, -110- *000 0*ee 0 0* 0* *0 0 0 *000 09 0O 0 0 0 0 0 0* 0* 0 each 1H, CH 2 at from 2.35 to 2.45 (mt, 1H, 1H of the CH 2 at 2.81 J Hz, IH, the other H of the CH 2 at from 3.00 to 3.20 (mt, 1H, CH at 9a), from 3.30 to 3.45 and 3.71 (respectively mt and d (broad), J 13 Hz, each 1H, NCH 2 Ar), 3.39 (broad s, 1H, CH at 3.55 3H, COOCH 3 4.31 4H, OCH 2 CH20), 6.63 (broad d, J 7.5 Hz, 1H, H at from 6.85 to 7.40 (mt, 11H, H at 5, H at 6, H at 7, aromatic H of the benzyl and aromatic H of the 1,4-benzodioxanyl).
Stage B By carrying out the reaction as in Example 1, Stage E, starting from 5.4 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(2,3-dihydro-1,4-benzodioxin-6yl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-carboxylate, from 2.16 g of ammonium formate and from 1.35 g of 10% palladium hydroxideon-charcoal in 80 cm 3 of refluxing methanol for five hours, 4 g of impure methyl (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate are obtained in the form of an off-white foam, which can be used as is in the following stage, the characteristic of which compound is as follows: mass spectrum (DCI):M/Z 392 Stage C By carrying out the reaction as in Example 1, Stage G, starting from a 20 solution of 0.275 g of 2-(2-methoxyphenyl)propenoic acid in 5 cm 3 of dichloromethane containing 4 drops ofN,N-dimethylformamide, a solution of 0.2 cm 3 of oxalyl chloride in 7 cm 3 of dichloromethane is added dropwise. The reaction mixture is stirred for a further two hours at a temperature in the region of 20°C and then cooled to a temperature in the region of O°C; the introduction is then carried out, over twenty minutes, of a solution of 0.73 g of impure methyl (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate in 15 cm 3 of dichloromethane, followed by 0.4 cm 3 of triethylamine. The reaction mixture is stirred at the same temperature for one hour and 100 cm 3 of distilled water are run in; dilution is carried out with dichloromethane, so as to bring the organic phase to C~r' -111approximately 200 cm 3 The pH is brought to 11 by running in 10 cm 3 of a 32% aqueous ammonia solution, the aqueous phase is separated by settling and then the organic phase is washed with successively 100 cm 3 of a 1N aqueous hydrochloric acid solution, then 100 cm 3 of distilled water and then 100 cm 3 of a saturated aqueous sodium chloride solution. After drying over magnesium sulphate, the organic phase is evaporated to give 0.75 g of an oil, which is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (60/40 by volume), 10-cm 3 fractions being collected. The fractions containing the good product (140 to 650 cm 3 are combined and evaporated without going to dryness to give an oil, which is taken up in diisopropyl ether; 465 mg of methyl (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,9-ethano- 2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole- 3a-carboxylate are thus obtained in the form of a white powder, the characteristics of which are as follows: 15 melting point 184°C.
mass spectrum M/Z 551 (M) 'H N.M.R. spectrum (400 MHz, d6-(CD 3 2 SO, at a temperature of 403 K, d in ppm): 1.40, 1.58, 1.96 and 2.12 (4 mts, each 1H, CH 2
CH
2 from 3.25 to 3.45 (mt, .3H, CH 2 at 1 and CH at 9a), 3.42 (mt, 1H, CH at 3.52 3H, COOCH 3 3.60 and S 20 4.06 (respectively d and d (broad), J 13 Hz, each 1H, CH 2 at 3.73 3H, ArOCH 3 4.31 4H, OCH 2 CH20), 5.54 and 5.68 (2 s, each 1H, =CH 2 6.51 (broad Sd, J 7.5 Hz, 1H, H at from 6.75 to 7.35 (mt, 10H, H at 5, H at 6, H at 7, aromatic H of the 2-methoxyphenyl and aromatic H of the 1,4-benzodioxanyl).
EXAMPLE 32 Preparation of (3aRS.4SR,9SR.9aRS)-9-(2.3-dihydro-1.4-benzodioxin-6-vl)-4,9ethano-2-[2-(2-methoxvphenvl)-propenovl]-2,3,3a,4,99a-hexahvdro-lH-benzorf]isoindole-3a-carboxylic acid By carrying out the reaction as in Example 2, but from 5.43 g of methyl (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,9-ethano- 2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-
{I
-112- 3a-carboxylate, obtained in the preceding example, and from 40 cm 3 of a normal aqueous sodium hydroxide solution in 150 cm 3 of refluxing dioxane for sixteen hours, then addition of 50 cm 3 of a normal aqueous sodium hydroxide solution, at reflux for four hours, and then 3.5 cm 3 of a 1ON aqueous sodium hydroxide solution, at reflux for sixteen hours, 3.76 g of a beige-coloured solid are obtained after taking up in diisopropyl ether. By dissolving in 50 cm 3 of absolute ethanol and then diluting with 12.5 cm 3 of distilled water, 2.64 g of (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4benzodioxin-6-yl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9ahexahydro-l1H-benzo[f]isoindole-3a-carboxylic acid are obtained in the form of a white powder, the characteristics of which are as follows: melting point 78 0
C.
mass spectrum M/Z 537 'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 383 K, d in ppm): 1.38, 1.57, 1.94 and 2.11 (4 mts, each 1H, CH 2
CH
2 from 3.20 to 3.45 (mt, 15 3H, CH 2 at 1 and CH at 9a), 3.42 (mt, 1H, CH at 3.59 and 4.06 (respectively d and d (broad), J 13 Hz, each 1H, CH 2 at 3.73 3H, ArOCH 3 4.31 4H,
OCH
2 CH20), 5.54 and 5.69 (2 s, each 1H, =CH 2 6.50 (broad d, J 7.5 Hz, 1H, H at from 6.75 to 7.40 (mt, 1OH, H at 5, H at 6, H at 7, aromatic H of the 2-methoxyphenyl and aromatic H of the 1,4-benzodioxanyl).
EXAMPLE 33 S. Preparation of (3aRS,.4SR.9SR.9aRS)-9-(2,3-dihydro-1, .4-benzodioxin-6-vl)-4,9ethano-2-r2-(2-methoxvphenyl)ropenovl]-2,3,3a,4,9,9a-hexahydro-1Hbenzo rflisoindole-3a-N-(3-pvridvlmethvl)carboxamide By carrying out the reaction as in Example 13, and by starting from 0.5 g of (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1,4-benzodioxin-6-yl)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3acarboxylic acid, from 0.24 cm 3 of oxalyl chloride and from 0.5 cm 3 of N,Ndimethylformamide, in 20 cm 3 of dichloromethane, for 2 hours, then evaporation to dryness, taken up in 20 cm 3 of dichloromethane and addition of 0.09 cm 3 of 3aminomethylpyridine and of 0.26 cm 3 of triethylamine in 15 cm 3 of dichloromethane; -113then, after stirring for eighteen hours at a temperature in the region of 20 0
C,
successively running in 50 cm 3 of distilled water and 40 cm 3 of a normal aqueous sodium hydroxide solution; dilution with 200 cm 3 of dichloromethane; separation by settling and washing of the organic phase with two times 100 cm 3 of a-normal aqueous hydrochloric acid solution, then 200 cm 3 of a saturated aqueous sodium chloride solution and finally drying over magnesium sulphate, 0.38 g of a greenyellow foam is obtained, which foam is recrystallized from diisopropyl ether to produce 249 mg of a yellow solid, which is then purified on a Merck 60F254 preparative silica plate, elution being carried out with the dichloromethane/methanol (90/10 by volume) mixture. An orange-coloured oil is thus obtained which, taken up in diisopropyl ether, gives 165 mg of (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9ahexahydro-lH-benzo[f]isoindole-3a-N-(3-pyridylmethyl)carboxamide in the form of a white powder, the characteristics of which are as follows: 015 melting point 228 0
C.
mass spectrum M/Z 627 'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 373 K, d in ppm): 1.38, 1.56, 1.93 and 2.10 (4 mts, each 1H, CH 2
CH
2 from 3.20 to 3.55 (mt, 3H, CH 2 at 1 and CH at 9a), 3.43 J 12.5 Hz, 1H, 1H of the CH 2 at 3.57 (broad s, 1H, CH at 3.71 3H, ArOCH 3 from 4.05 to 4.30 (mt, 3H, the other H of the CH 2 at 3 and NCH 2 Ar), 4.31 4H, OCH 2 CH20), 5.52 and 5.70 (2s, each 1H,
=CH
2 6.48 (mt, 1H, H at from 6.75 to 7.45 (mt, 12H, H at 5, H at 6, H at 7, aromatic H of the 2-methoxyphenyl, aromatic H of the 1,4-benzodioxanyl, H at 4 of the pyridyl and H at 5 of the pyridyl), 8.10 (mt, 1H, CONH), 8.38 (broad s, 1H, H at 2 of the pyridyl), 8.45 (broad d, J 5 Hz, 1H, H at 6 of the pyridyl).
EXAMPLE 34 Isolation of the dextrorotatorv enantiomer of (3aRS.4SR,9SR.9aRS)-9-(2.3-dihydro- 1,4-benzodioxin-6-vl)-4,9-ethano-2-[2-(2-methoxyphenv)propenoyl]-2,3,3a,4,9,9ahexahydro- 1 H-benzo flisoindole-3a-N-(3-pvridvlmethvl)carboxamide By carrying out the reaction as in Example 18, but from 17 g of -114- (3aRS,4SR,9SR,9aRS)-9-(2,3-dhydro-1 ,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 a-N- (3-pyridylmethyl)carboxamide, in 10 successive injections, on a Whelk 01 (SS) chiral silica colum, elution being carried out with an n-heptane/ethanolltniethylamine (70/30/0.05 by volume) mixture and the first product eluted (retention time 45 min) being isolated, 8.4 g of the dextrorotatory enantiomer of (3 aRS,4SR,9SR,9aRS)-9-(2,3 -dihydro- 1,4-benzodioxin-6-yl)-4,9ethano-2-[2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro-l1Hbenzo [fjisoindole-3 a-N-(3 -pyridylmethyl)carboxamide are obtained, after concentrating the solvent under reduced pressure, in the formn of a white powder, the characteristics of which are as follows: mass spectrum MIZ 627 optical rotation: [a]"2 5 +103.2 1.5' (c 0.5, methanol).
EXAMPLE L 15 Isolation of the levorotatory enantiomer of (3aRS,4SR,9SR,9aRS)-9-(2.3-dihydro- 1 .4-benzodioxin-6-yl)-4,9-ethano-2-r2-(2-methoxvphenvl)propenoyl-2.3.3 a,4.9.9ahexahydro- 1H-benzof flisoindole-3 a-N-(3-pyridylmethyl)carboxamide By carrying out the reaction as in Example 19, but from 17 g of see (3 aRS ,4SR,9SR,9aRS)-9-(2,3 -dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N- (3-pyridylmethyl)carboxamide, in 10 successive injections, on a Whelk 01 (SS) chiral silica colum-n, elution being carried out with a mixture of n-heptane, of ethanol and of triethylamine (70/30/0.05 by volume) and the second product eluted (retention time 67 min) being isolated, 6.6 g of the levorotatory enantiomer of (3 aRS ,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N- (3 -pyridylmethyl)carboxamide are obtained, after concentrating the solvent under reduced pressure, in the form of a white powder, the characteristics of which are as follows: 1310 mass spectrum M/Z 627 -115-
C
C
CCC.
C
C
C
C
optical rotation: 5 =-102 1.50* (c methanol).
EXAMPLE 36 Preparation of (3 aRS,4SR,9SR,9aRS)-9-(2.3 -dihydro- 1 4-benzodioxin-6-vlY-4,9ethano-2-r2-(2-methoxyphenyl)propenoyll -2,3,3 a,4,9,9a-hexahydro- 1Hbenzorflisoindole-3 a-N-(2-thienylmethyl)carboxamide By carrying out the reaction as in Example 33, and by starting from g of (3 aRS,4SR,9SR,9aRS)-9-(2,3-dihydro-1I,4-benzodioxin-6-yl)-4,9-ethano- 2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole- 3a-carboxylic acid, from.0.24 cm 3 of oxalyl chloride, from 0. 1 cm 3 of N,N-dimethylformamide, in 20 cm 3 of dichloromethane, and then from 0. 1 cm 3 of 2-(aminomethyl)thiophene and from 0.26 cm 3 of triethylamine in 15 cm 3 Of dichioromethane, 29 mg of (3 aRS,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4-benzodioxin- 6-yl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1Hbenzo[f] isoindole-3 a-N-(2-thienylmethyl)carboxamide are obtained, after lyophilization, in the form of a powder, the characteristics of which are as follows: melting point 134TC mass spectrum M/Z 632 (MW).
EXAMPLE 37 Preparation of (3 aRS,4SR,9SR.9aRS)-4,9-ethano-2-r(2-methoxyphenyl)acetYll-9- 20 (3,4.5 -trimethylphenyl)-2,3 .3 a,4,99a-hexahydro- IH-benzorflisoindole-3 a-carboxylic acid Stage A By canrying out the reaction as in Example 3 1, Stage A, starting from 3.49 g of methyl (3 aRS,4SR,7aiRS)-2-[(2-methoxyphenyl)acetyl] -7-oxo- 4-phenyloctahydroisoindole-3a-carboxylate in 40 cm 3 of dichioromethane stabilized over amylene, from 3.34 cm 3 of 1, 2,3-trimethylbenzene and from 5.1 cm 3 of trifluoromethanesulphonic acid; after stirring for eighteen hours at a temperature in the region of 20'C, 2.8 cm 3 of trifluoromethanesuiphonic anhydride are added and the reaction mixture is stirred for a further 18 hours. 263 mng of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)acetyl] Th
N
('A
-116trimethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylate are thus obtained in the form of a white powder, the characteristics of which are as follows: -melting point= 159'C.
mass spectrum M/Z 523 Stage B By carrying out the reaction as in Example 2, from 192 mg of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)acetyl] trimethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylate at reflux for eighteen hours in 0.55 cm' of 1N aqueous sodium hydroxide solution and cm 3 of ethanol, 69.3 mng of (3aRS,4SR,9SR,9aRS)-4,9-ethano- 2- [(2-methoxyphenyl)acetyl]-9-(3 ,4,5 -trimethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-I1Hbenzo[flisoindole-3a-carboxylic acid are obtained, after recrystallization from 5 cm 3 00:0 .of diisopropyl ether, in the form of a white powder, the characteristics of which are 15 as follows: melting point 260'C.
:o mass spectrum MIZ 509 EXAMPLE 38 Preparation of (3 aRS .4SR,9SR,9aRS)-4,9-ethano-2r2-(2-methoxyphenl)propenoyll-9-(2-methylphenl)-2,3 .3 a,4,99a-hexahydro- 1Hbenzorflisoindole-3 a-carboxylic acid Stage A By carrying out the reaction as in Stage C of Example 1, but from 1.33 cm 3 of 2-bromotoluene, from 0.27 g of magnesium turnings and from 2 g of methyl (3 aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3 acarboxylate, 2.2 g of methyl (3 aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7- (2-methylphenyl)-4-phenyloctahydroisoindole-3 a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (90/10 by volume) mixture, in the form opf a pale-yellow foam, used as is in the subsequent syntheses.
I-7\ -117- Stage B A mixture of 3.2 cm 3 of trifluoromethanesulphonic acid and of 3 cm 3 of dichloromethane is added dropwise to a solution of 2.2 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(2-methylphenyl)-4phenyloctahydroisoindole-3a-carboxylate in 20 cm 3 of dichloromethane maintained at a temperature in the region of 0OC. The reaction mixture is stirred for thirty minutes at a temperature in the region of 0°C and twenty hours at a temperature in the region of 20'C and then cooled to a temperature in the region of OC. The pH is then brought to 8 by addition of a normal aqueous sodium hydroxide solution. The aqueous phase is separated by settling and extracted with three times 50 cm 3 of dichloromethane. The organic phases are combined, washed with three times 100 cm 3 of distilled water and 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure.
1.9 g of methyl (3aRS,4SR)-2-benzyl-7-(2-methylphenyl)-4-phenyl- 1,3,3a,4,5,6- S: 15 hexahydroisoindole-3a-carboxylate are thus obtained in the form of an oil, used as is in the subsequent syntheses, the characteristics of which are as follows: 'H N.M.R. spectrum (250 MHz, CDC1 3 with addition of a few drops of d4-
CD
3 COOD, d in ppm): 1.90 (mt, 1H, 1H of the CH 2 at 2.17 3H, ArCH 3 from 2.40 to 2.55 (mt, 2H, the other H of the CH 2 at 5 and 1H of the CH 2 at 2.66 (mt, 1H, the other H of the CH 2 at 3.08 (dd, J 11 and 2.5 Hz, 1H, CH at 3.32 (mt, 1H, 1H of the CH 2 at 3.63 3H, COOCH 3 from 3.60 to 3.70 (mt, 1H, 1H of the
CH
3 at 3.75 J 11.5 Hz, the other H of the CH 2 at 3.92 J 10 Hz, the other H of the CH 2 at 3.98 and 4.32 (2 d, J 11 Hz, each 1H, NCH 2 Ar), from 6.90 to 7.40 (mt, 14H, aromatic H of the phenyl, aromatic H of the benzyl and aromatic H of the 2-methylphenyl).
Stage C A mixture of 5.8 cm 3 of trifluoromethanesulphonic acid and of 5 cm 3 of dichloromethane is added dropwise to a solution of 1.9 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-7-(2-methylphenyl)-4-phenyl-1,3,3a,4,5,6hexahydroisoindole-3a-carboxylate in 50 cm 3 of dichloromethane maintained at a -118temperature in the region of 0OC. The reaction mixture is stirred for one hour at a temperature in the region of 0°C and ninety-six hours at a temperature in the region of 20 0 C and then cooled to a temperature in the region of 0°C. The pH is then brought to 8 by addition of a normal aqueous sodium hydroxide solution. The organic phase is separated by settling, washed with 100 cm 3 of distilled water and 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/5 by volume) mixture. 0.85 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(2-methylphenyl)-2,3,3a,4,9,9ahexahydro-lH-benzo[f]isoindole-3a-carboxylate is obtained in the form of an oil, used as is in the subsequent syntheses.
Stage D By carrying out the reaction as in Stage E of Example 1, but from 15 0.85 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(2-methylphenyl)- 2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate, from 0.37 g of ammonium formate and from 0.15 g of 10% palladium-on-charcoal, 0.6 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(2-methylphenyl)-2,3,3a,4,9,9ahexahydro-lH-benzo[f]isoindole-3a-carboxylate is obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (70/30 by volume) mixture, in the form of a colourless oil, used as is in the subsequent syntheses.
Stage E By carrying out the reaction as in Stage G of Example 1, but from 0.6 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(2-methylphenyl)-2,3,3a,4,9,9ahexahydro-lH-benzo[f]isoindole-3a-carboxylate, from 0.31 g of 2-(2methoxyphenyl)propenoic acid and from 0.15 cm 3 of oxalyl chloride, 0.51 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(2methylphenyl)-2,3,3a,4,9,9a-hexahydro- H-benzo[f]isoindole-3a-carboxylate is obtained, after purification by flash chromatography on silica gel (230-400 mesh), -119elution being carried out with a cyclohexane/ethyl acetate (70/30 by volume) mixture, in the form of an off-white foam, used as is in the subsequent syntheses.
Stage F By carrying out the reaction as in Example 2, but from 0.51 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(2methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3a-carboxylate in cm 3 of a normal aqueous sodium hydroxide solution and 15 cm 3 of ethanol, 0.22 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9- (2-methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3a-carboxylic acid is obtained, after recrystallization from isopropanol, the characteristic of which compound is as follows: melting point: above 260'C 'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 393 K, d in ppm): from 1.15 to 1.50 and from 2.05 to 2.35 (2 mts, each 2H, CH 2
CH
2 2.25 (s, o 15 3H, ArCH 3 3.13 (dd, J 12 and 9 Hz, 1H, 1H of the CH 2 at 3.31 (broad d, J *12 Hz, 1H, the other H of the CH 2 at 3.44 (mt, 1H, CH at 3.60 and 4.05 (respectively d and d (broad), J= 12.5 Hz, each 1H, CH 2 at 3.75 3H, ArOCH), 5.54 and 5.69 (2 s, each 1H, =CH 2 6.62 (broad d, J 7.5 Hz, 1H, H at from 6.90 .2 to 7.45 (mt, 1 1H, H at 5, H at 6, H at 7, aromatic H of the 2-methoxyphenyl and aromatic H of the 2-methylphenyl).
EXAMPLE 39 Preparation of methyl (3aRS4SR9SR9aRS)-49-ethano- 2-[2-(2-methoxvphenvyl)propenovll-9-r(4-trifluoromethyl)phenvl]-2,3,3a,4,9,9ahexahydro- 1 H-benzo[flisoindole-3a-carboxvlate Stage A 0.8 g of magnesium turnings is added to a solution of 7.2 g of 4-(trifluoromethyl)bromobenzene in 40 cm 3 of dry diethyl ether. The reaction mixture is spontaneously brought to reflux for ten minutes and is then heated at reflux for twenty minutes. The reaction mixture is subsequently cooled and a solution of 5.6 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole- C& -120- 3a-carboxylate in 40 cm 3 of dry diethyl ether is added over fifteen minutes at a temperature in the region of 10°C. The reaction mixture is stirred for ten minutes at a temperature in the region of 10 0 C and then poured into 150 cm 3 of a saturated aqueous ammonium chloride solution. The aqueous phase is separated by settling and extracted with three times 75 cm 3 of diethyl ether. The organic phases are combined, washed successively with three times 75 cm 3 of distilled water, dried over magnesium sulphate in the presence of 3S charcoal and concentrated under reduced pressure. After crystallization from 25 cm 3 of pentane, 5.2 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-[(4-trifluoromethyl)phenyl]-4phenyloctahydroisoindole-3a-carboxylate are obtained in the form of a beige solid, the characteristic of which is as follows: melting point 164°C.
Stage B 4 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-[(4trifluoromethyl)phenyl]-4-phenyloctahydroisoindole-3a-carboxylate are added to 20 cm 3 of trifluoromethanesulphonic acid cooled to a temperature in the region of 0 0 C. The reaction mixture is stirred for 3 hours at a temperature in the region of and then cooled to a temperature in the region of 10 0 C. 50 cm 3 of distilled water are then added and then the pH of the aqueous phase is brought to between 8 and 9 by addition of a 30% aqueous sodium hydroxide solution, the temperature always being maintained in the region of 10 to 15°C with a bath containing an e ethanol/dry ice mixture. The aqueous phase is separated by settling and extracted with three times 75 cm 3 of ethyl acetate. The organic extracts are combined, washed with three times 75 cm 3 of distilled water, dried over magnesium sulphate in the presence of 3S charcoal and concentrated under reduced pressure. 3.4 g of methyl (3aRS, 4 SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-[(4-trifluoromethyl)phenyl]- 2,3,3a,4,9,9a-hexahydro-lH-benzo[flisoindole-3a-carboxylate are thus obtained in two crops, after crystallization from petroleum ether, in the form of a white solid, the characteristic of which is as follows: melting point: 132 0
C.
f I P ¢y -121- Stage C By carrying out the reaction as in-Stage E of Example 1, but from 3.4 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-[(4-trifluoromethyl)phenyl]-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3a-carboxylate, from 1.3 g of ammonium formate and from 0.4 g of 10% palladium-oncharcoal, 2.2 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4trifluoromethylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3acarboxylate are obtained in the form of a white solid, a characteristic of which is as follows: melting point 172'C.
Stage D By carrying out the reaction as in Stage G of Example 1, but from 1.4 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-[(4-trifluoromethyl)phenyl]- 15 2,33a,4,9,9a-hexahydro- 1 H-benzo[fjisoindole-3a-carboxylate, from 0.62 g of 2-(2- 15 methoxyphenyl)propenoic acid, from 0.94 cm of triethylamine and from 0.3 cm 3 of oxalyl chloride, 1.3 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano- 2-[2-(2-methoxyphenyl)propenoyl]-9-(4-trifluoromethyl)phenyl]-2,3,3a,4,9,9ahexahydro-1H-benzo[fjisoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (50/50 by volume) mixture, and crystallization from diisopropyl ether, the characteristics of which compound are as follows: S- melting point 163 0
C.
1 H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 373 K, d in ppm): 1.45, 1.72 and from 1.95 to 2.25 (3 mts, respectively 1H, 1H and 2H,
CH
2
CH
2 from 3.20 to 3.45 (mt, 3H, CH 2 at 1 and CH at 9a), 3.48 (mt, 1H, CH at 4), 3.55 3H, COOCH 3 3.61 and 4.11 (respectively d and d (broad), J 12.5 Hz, each 1H, CH 2 at 3.70 3H, ArOCH 3 5.55 and 5.68 (2 s, each 1H, =CH 2 6.36 (broad d, J 7.5 Hz, 1H, H at from 6.90 to 7.40 (mt, 7H, H at 5, H at 6, H at 7 and aromatic H of the 2-methoxyphenyl), 7.59 and 7.83 (2 broad d, J 8 Hz, each 2H, aromatic H of the 4-trifluoromethylphenyl).
3'X -122- EXAMPLE Preparation of (3 aRSASR.9SR.9aRS)-4,9-ethano- 2 -r 2 2 -methoxvphenyl)roenovl9(4-triflujoromethyl)phenyl-2,3 .3aA49,9ahexahydro-l1H-benzorfl isoindole-3 a-carboxylic acid By canrying out the reaction as in Example 2, but from 1. 1 g of methyl (3 aRS, 4
SR,
9
SR,
9 aRS)-4,9ethano-2[2-(2-methoxyphenyl)propenoyl] -9- 4 -trifluoromethyl)phenyl] -2,3,3 a,4,9,9a-hexahydro- 1 H-benzo[fjisoindole-3acarboxylate, from 9.8 cm 3 of a normal aqueous sodium hydroxide solution and cm 3 of methanol, 0.65 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano- 2 2 2 -methoxyphenyl)propenoyly9(4-trifluoromethyl)phenyl].2,3,3a a,4,9,9ahexahydro-lH-benzo[flisoindole3a-carboxylic acid is obtained, after crystallization from diisopropyl ether, base/acid passage and recrystallization from 8 cm 3 Of isopropyl acetate, the characteristic of which compound is as follows: melting point 153'C.
15 EXAMPLE 41 Isolation of the dextrorotatory enantiomer of 3 aRS.4SR.9SR.9aRS)-4.9-ethano-
C
2 -r 2 2 -methoxvphenl)oropenovly9[(4-trifluoromethvl)phenyly12.3.3 a.4.9.9ahexahydro-l1H-benzorflisoindole-3a-carboxylic acid 11 g of (3aRS,4SR,9SR,9aRS)-4,9.ethano- 20 2 2 2 -methoxyphenyl)propenoyl]y9-[( 4 -trifluoromethyl)phenyl] -2,3 ,3a,4,9,9a- Chexahydro-1H-benzo[fjisoindole3a-carboxylic acid, obtained in Example 40, are C resolved on a chiral silica column canrying N-( 3 C. grafts, in 4 successive injections and by eluting with a mixture of n-heptane, of dichloromethane and of ethanol (50/50/1 by volume). On collecting the first fractions eluted (retention time 31 min), 5 g of the dextrorotatory enantiomer of 3 aRS, 4
SR,
9 SR,9aRS)49ethano-2-[2(2-methoxyhenyrl)propenoyl]-9 4 -trifluoromethyl)phenyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[fiisoindole-3 acarboxylic acid are obtained, after concentrating under reduced pressure, in the form of a white powder, the characteristics of which are as follows: melting point 228'C -123mass spectrum M/Z 547 optical rotation: [a]21 5 63.1 1.20 (c 0.5, methanol) The chiral stationary phase carrying phenylalanine grafts can be prepared according to the synthesis described in Example 3, by replacing N-(3,5-dinitrobenzoyl)-(S)-phenylalanine by N-(3 EXAMPLE 42 Preparation of (3 aRS .4SR,9SR,9aRS)-4,9-ethano- 2-r2-(2-methoxyphenyl)propenovll-9-[(4-trifluoromethyl)phenl -2.3,3 a,4.9.9ahexahydro- 1H-benzorflisoindole-3 a-N-(3-pvridylmethyl)carboxamide 0.24 cm 3 of 3-(aminomethyl)pyridine, 0.46 g of 1-ethyl-3-[3- (dimethylamino)propyl]carbodiimide hydrochloride and 0. 16 g of N- I -hydroxybenzotriazole hydrate. are successively added to a solution of 1. 1 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9- 15 [(4-trifluoromethyl)phenyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a- *..carboxylic acid in 20 cm 3 of dichloromethane. The reaction mixture is stirred for forty-eight hours at a temperature in the region of 20'C. The organic phase is washed with three times 10 cm 3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. After recrystallizing from 15 cm 3 Of isopropanol, 0.95 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano- 999999 2-[2-(2-methoxyphenyl)propenoyl]-9-[(4-trifluoromethyl)phenyl]-2 3a,4 9a- .9 hexahydro- 1 -ezfionoe3aN(-pyridylmethyl)carboxamide is obtained, 9 the characteristic of which is as follows: -melting point =214TC.
EXAMPLE 43 Preparation of (3 aRS .4SR,9SR.9aRS)-4,9-ethano- 2-r2-(2-methoxyphenvlmrop2enoyll-9-f(4-trifluoromethvl)p2henvl-2.3,3 a,4,9,9ahexalhydro- 1H-benzorflisoindole-3 a-N'-benzoylcarbohydrazide .0.16 gof benzoylhydrazine, 0.23 gof 1-ethyl-3-[3- (dimethylamnino)propyl]carbodiimide hydrochloride and 81 mng of -124- N-1-hydroxybenzotriazole hydrate are successively added to a solution of 0.55 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-1j2-(2-methoxyphenyl)propenoyl]-9- [(4-trifluoromethyl)phenyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 acarboxylic acid in 10 cm' of dichioromethane. The reaction mixture is stirred for twenty hours at a temperature in the region of 20'C and then filtered through sintered glass. The precipitate is washed successively with three times 1.5 cm' of dichloromethane and then three times 2.5 cm 3 of distilled water. 0.34 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[j2-(2-methoxyphenyl)propenoyl] trifluoromethyl)phenyl]-2 ,3 ,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N'benzoylcarbohydrazide is thus obtai ned, the characteristics of which are as follows: melting point 275 0
C.
'H N.M.R. spectrum (250 NMz, d6-(CD 3 2 S0, at a temperature of 383 K, d in ppm): 1.44, 1.70, 2.01 and 2.18 (4 nits, each I1H, CH 2
CH
2 from 3.20 to 3.40 (limit AB, 2H, CH 2 at from 3.55 to 3.85 (mnt, 3H,1lH of the CH 2 at 3, CH at 9a and CH :15 at 3.72 3H, ArOCHA) 4.36 (broad d, J 12.5 Hz, 1H, the other H of the CH 2 at 5.57 and 5.70 (2 s, each 1H, =CH 2 6.34 (broad d, J 7.5 Hz, 1H, H at from *6.85 to 7.60 (mt, 1 OH, H atS5, H at 6, H at 7, aromatic H at the meta positions of the benzoylcarbohydrazide, aromatic H at the para position of the benzoylcarbohydrazide and aromatic H of the 2-methoxyphenyl), 7.60 and 7.85 (2d, J 8 Hz, each 2H, aromatic H of the 4-trifluoromethyiphenyl), 7.81 J =8 Hz, 2H, aromatic H at the ortho positions of the benzoylcarbohydrazide), 9.66 and 9.91 (2 broad s, each I1H,
CONHINHCO).
EXAMPLE 44 Preparation of (3 aRSA.SR.9SR,9aRS)-4,9-ethano- 2-[2-(2-methoxyphenyl)propenoyll-9-(4-trifluoromethylphenl)-2.3,3 a,4,9.9ahexahydro-l1H-benzo[flisoindole-3 a-N'-phenvlcarbohydrazide 0.12 cm 3 of phenylhydrazine, 0.23 g of 1-ethyl-3-[3- (dimethylamino)propyl]carbodiimide hydrochloride and 81 mg of N-1-hydroxybenzotriazole hydrate are successively added to a solution of 0.55 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-trifluoro- -125methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylic acid in cm 3 of dichloromethane. The reaction mixture is stirred for twenty hours at a temperature in the region of 20 0 C. The reaction mixture is diluted with 15 cm 3 of dichloromethane, washed with three times 10 cm 3 of distilled water, dried over magnesium sulphate in the presence of 3S charcoal and concentrated under reduced pressure. After recrystallizing from 10 cm 3 of isopropanol, 0.21 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-trifluoromethylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-N'-phenylcarbohydrazide is obtained, the characteristics of which compound are as follows: melting point: 226'C.
'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 383 K, d in ppm): 1.44, 1.69 and from 1.95 to 2.25 (3 mts, respectively 1H, 1H and 2H,
CH
2
CH
2 from 3.20 to 3.45 (limit AB, 2H, CH 2 at 3.52 and 4.26 (respectively d and d (broad), J 12.5 Hz, each 1H, CH 2 at 3.63 (mt, 1H, CH at 9a), 3.69 3H, 15 ArOCH 3 3.75 (mt, 1H, CH at 5.55 and 5.68 (2 s, each 1H, =CH 2 6.35 (broad d, J 7.5 Hz, 1H, H at 6.60 J 7.5 Hz, 2H, aromatic H at the ortho positions of the phenylcarbohydrazide), 6.70 J 7.5 Hz, 1H, aromatic H at the para position of the phenylcarbohydrazide), from 6.90 to 7.45 (mt, 10H, H at 5, H at 6, H at 7, aromatic H at the meta positions of the phenylcarbohydrazide, aromatic H of the 2-methoxyphenyl and ArNH), 7.61 and 7.82 (2d, J 8 Hz, each 2H, aromatic H of the 4-trifluoromethylphenyl), 9.52 (broad s, 1H, CONH).
S. EXAMPLE Preparation of methyl (3aRS,4SR.9SR.9aRS)-4.9-ethano- 2-[2-(2-methoxvphenvy)propenoyl]-9-(2-naphthyl)-2,3,3a,4,9,9,9a-hexahydro-1Hbenzo[flisoindole-3a-carboxylate Stage A 21.4 g of hydrazine hydrate are added to a solution of 40 g of methyl 2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate, obtained in Stage B of Example 1, in 300 cm 3 of ethanol and then the reaction mixture is brought to reflux for two hours thirty minutes. After concentrating the solvent under reduced pressure, -126the residue is taken up in water and extracted with dichloromethane. The organic phase is separated by settling, washed with water and dried over magnesium.
sulphate. After concentrating under reduced pressure, 38.73 g of methyl (3aRs,4SR,7aRS)-2-benzyl-7-hydrazono-4-phenyloctahydroisoindole-3a-carboxylate are obtained in the form of a brown'oil, the characteristics of which are as follows: mass spectrum M/Z 377 IR spectrum (in solution in dichloromethane): 3400 cm-' nNH 3080, 3060, 3045, 3030 cm-' n CH, aromatic 2950, 2800 cm' n CH, aliphatic 2730 cm-' n CH, N(CH,)3 1720 cm-' n C=O, methyl ester 1605, 1495, 1455, 1435 cm-' respiration of the aromatic nuclei 1435 cm-' d, CH 3 methyl ester 15 1220 cm-' n O-C=O, methyl ester Stage B 52.07 g of iodine, in solution in 250 cm 3 of tetrahydrofuran, are added dropwise to a solution of 37.75 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7- X. 20 hydrazono-4-phenyloctahydroisoindole-3a-carboxylate in 200 cm 3 of tetrahydrofuran and 43 cm 3 of triethylamine. Stirring is maintained at room temperature for one hour after the end of the addition. 1 dm 3 of water and 1 dm 3 of ethyl acetate are then added. The organic phase is separated by settling, washed successively with a saturated sodium hydrosulphite solution and then with a saturated sodium chloride solution, and dried over magnesium sulphate. After concentrating the solvent under reduced pressure, the residue is purified by flash chromatography on silica gel (230- 400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (95/5 by volume). 22.25 g (47 of methyl (3aRS,4SR,7aRS)-2-benzyl-7iodo-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate are thus obtained in the form of a yellow pasty solid, the characteristics of which are as follows: le mass spectrum M/Z 473 -127- IR spectrum (in solution in carbon tetrachloride): 3080, 3060, 3030 cm-' n CH, aromatic 2925, 2800 cm' n CH, aliphatic 2730 cm-' n CH, N(CH 2 3 1730 cm' n C=O, methyl ester 1600, 1495, 1455, 1435cm-' respiration of the aromatic nuclei 1435 cm' d, CH 3 methyl ester 1210 cm-' n O-C=O, methyl ester 700 cm- g CH, aromatic Stage C 240 mg of tetrakis(triphenylphosphine)palladium and then a solution of 0.69 g of 2-naphthylboronic acid, isolated in the trimer anhydride form, in 20 cm 3 of methanol are added to a solution of 2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7iodo-4-phenyl-2,3,a,4,5,7a-hexahydroisoindole-3a-carboxylate in 40 cm 3 of toluene.
45 cm 3 of a 2N aqueous sodium carbonate solution are added dropwise and the reaction mixture is brought to reflux for four hours. After cooling, 80 cm 3 of water and 60 cm 3 of ethyl acetate are added. The organic phase is separated by settling, washing with water to neutrality and dried over magnesium sulphate. After 20 concentrating the solvent under reduced pressure, the residue is purified by flash o chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume). 1.33 g (67 of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(2-naphthyl)-4-phenyl-2,3,3a,4,5,7ahexahydro-lH-isoindole-3a-carboxylate are thus obtained in the form of a white foam, the characteristic of which is as follows: mass spectrum M/Z 473 Stage D By carrying out the reaction as in Stage C of Example 38, but from 1.66 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(2-naphthyl)-4-phenyl-2,3,3a,4,5,7ahexahydro-1H-isoindole-3a-carboxylate and from 1.9 cm 3 of trifluoromethanesulphonic acid in solution in 20 cm 3 of dry dichloromethane for four -128hours at room temperature, 1.22 g (51 of a white foam are isolated after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (95/5 by volume), the white foam mainly containing (approximately 90 by NMR quantitative determination) methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(2-naphthyl)- 2 3 3 a, 4 ,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate, which foam, used as is in the continuation of the synthesis, has the following characteristics: 'H N.M.R. spectrum (300 MHz, CDC13, d in ppm): from 1.40 to 2.00 and 2.52 (2 mts, each 2H, CH 2
CH
2 from 2.20 to 2.40 (mt, 2H, 1H of the CH 2 at 1 and 1H of the CH 2 at 2.68 (broad d, J 10 Hz, 1H, the other H of the CH 2 at 3.21 (broad d, J 10 Hz, the other H of the CH 2 at 3.31 and 3.67 J 12.5 Hz, 2H,
NCH
2 Ar), 3.36 (mt, 1H, CH at 9a), 3.45 (broad s, 1H, CH at 3.58 3H,
'COOCH
3 6.61 (broad d, J 7.5 Hz, 1H, H at from 6.91 to 8.00 (mt, 15H, H at H at 6, H at 7, aromatic H of the naphthyl and aromatic H of the benzyl).
L..O 15 Stage E 1.2 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(2naphthyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate, in solution in 50 cm 3 of methanol and 2 cm 3 of a 2M solution of hydrochloric acid in methanol, are stirred, in the presence of 115 mg of 10 palladium-on-charcoal, for five 20 hours at 50 0 C under hydrogen at atmospheric pressure. After filtering off the i catalyst, the solvent is concentrated under reduced pressure. 0.96 g (91 of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(2-naphthyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carboxylate hydrochloride is thus obtained in the form of a beige powder, the characteristics of which are as follows: melting point 260°C mass spectrum M/Z 383 Stage F By carrying out the reaction as in Stage G of Example 1, but from 0.96 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(2-naphthyl)-2,3,3a,4,9,9ahexahydro-1H-benzo[f]isoindole-3a-carboxylate hydrochloride, from 0.41 g of 2-(2- -129methoxyphenyl)propenoic acid, from 0.2 cm 3 of oxalyl chloride and from 0.64 cm of triethylamine in solution in 60 cm 3 of dichloromethane for twenty hours at room temperature, 1.15 g (78 of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(2-naphthyl)-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate are obtained, after purification on silica gel (230- 400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (70/30 by volume), in the form of a white powder, the characteristics of which are as follows: melting point 140-2 0
C
mass spectrum M/Z 473 EXAMPLE 46 Preparation of the sodium salt of (3aRS .4SR.9SR9aRS)-4,9-ethano-2-2-(2methoxvphenvl)propenoyll-9-(2-naphthyl)-2,3,3 a,4,9,9a-hexahydro- 1Hbenzorflisoindole-3a-carboxvlic acid 15 By carrying out the reaction as in Example 2, but from 1.15 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(2naphthyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3a-carboxylate at reflux for to five hours in 6.3 cm 3 of a normal aqueous sodium hydroxide solution and of 40 cm of ethanol, 50 mg (4.8 of the sodium salt of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2- 20 [2-(2-methoxyphenyl)propenoyl]-9-(2-iaphthyl)-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[fjisoindole-3a-carboxylic acid are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of dichloromethane and of methanol (95/5 by volume), and then by high performance liquid chromatography on C18 Waters grafted silica, elution being carried out with a mixture of water and of acetonitrile (70/30 by volume), in the form of a white solid, the characteristics of which are as follows: melting point 260'C mass spectrum M/Z 529 EXAMPLE 47 Preparation of methyl (3aRS,.4SR,9SR,9aRS)-49-ethano-2-[2-(2- -130methoxvphenyl)propenoyll-9-(5-methyl-2-thienyl)-2,3,3a,4,9,9a-hexahydro-lHbenzo flisoindole-3a-carboxvlate Stage A By carrying out the reaction as in Stage A of Example 31, but from 2 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3acarboxylate, from 0.8 cm 3 of 2-methylthiophene and from 3 cm 3 of trifluoromethanesulphonic acid in 30 cm 3 of dichloromethane for five hours at room temperature, 0.49 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(5methyl-2-thienyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate is obtained, after purification on silica gel (230-400 mesh), elution being carried out with mixtures of cyclohexane and ethyl acetate (95/5, then 90/10, by volume), in the form of a white powder, the characteristics of which are as follows: S* 'H N.M.R. spectrum (300 MHz, CDC1 3 d in ppm): 1.14, 1.66 and from 2.35 to 2.55 (3 mts, respectively 1H, 1H and 2H, CH 2
CH
2 2.29 and 3.18 J 10 Hz, 15 each 1H, CH 2 at from 2.35 to 2.55 and 3.00 (respectively mt and d, J 10 Hz, each 1H, CH 2 at 2.52 3H, ArCH 3 3.10 (broad d, J 8 Hz, 1H, CH at 9a), from 3.30 to 3.40 (mt, 2H, H at 4 and 1H of the NCH 2 Ar), 3.54 3H, COOCH 3 3.74 J 12.5 Hz, 1H, the other H of the NCH 2 Ar), 6.71 (mt, 1H, H at 6.71 and 6.74 (respectively mt and d, J 4 Hz, each 1H, aromatic H of the thienyl), from 6.95 20 to 7.45 (mt, 8H, H at 5, H at 6, H at 7 and aromatic H of the benzyl).
Stage B A solution of 0.48 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9ethano-9-(5-methyl-2-thienyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3acarboxylate and of 0.17 cm 3 of vinyl chloroformate in 5 cm 3 of dichloromethane is stirred at room temperature for eighteen hours. After concentrating the solvent under reduced pressure, the residue is purified by flash chromatography on silica gel, elution being carried out with a mixture of cyclohexane and of ethyl acetate (85/15 by volume), to give 0.37 g of a foam, which is redissolved in 7 cm 3 of methanol. 1.65 cm 3 of a normal aqueous hydrochloric acid solution are then added and the mixture is brought to reflux for three hours. After concentrating the solvent, -131the residue is recrystallized from a mixture of isopropanol and of isopropyl ether (50/50 by volume). 0.3 g (70 of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(5methyl-2-thienyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [f]isoindole-3 a-carboxylate hydrochloride is then obtained in the form of a pale-green solid, the characteristics of which are as follows: melting point 226-30'C mass spectrum M!Z 353 (MW).
Stage C By carrying out the reaction as in Stage G of Example 1, but from 0.58 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethanio-9-(5-methyl-2-thienyl)- 2,3,3 a,4,9,9a-hexahydro-l1H-benzo isoindole-3 a-carboxylate hydrochloride, from 0.27 g of 2-(2-methoxyphenyl)propenoic acid, from 0. 13 cm' of oxalyl chloride and from 0.42 cm' of triethylamine in solution in 35 cm' of dichloromethane for twenty hours at room temperature, 0.53 g (69 of methyl (3aRS,4SR,9SR,9aRS)-4,9- 15- etao2[-2mtoyhnlpoeny]--5 ehl2tin-, 3 ,3a,4,9,9ahexahydro-lH-benzo[flisoindole-3a-carboxylate is obtained, after purification on silica gel (230-400 mesh), elution being carried out with mixtures of cyclohexane and of ethyl acetate (80/20, then 60/40, by volume), in the form of a light-beige powder, the characteristics of which are as follows: 20 melting point= 1l2-5'C mass spectrum M/Z 513 (MW).
EXAMPLE 48 Preparation of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-r2-(2methoxyphenyl)p2ropenoyl] -9-(5-methyl-2-thienyl)-2.3 .3 a4,9,9a-hexahydro- lHbenzorflisoindole-3a-carboxylic acid By carrying out the reaction as in Example 2, but from 0.45 g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(5methyl-2-thienyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3 a-carboxylate at reflux for five hours in 2.6 cm 3 of a normal aqueous sodium hydroxide solution and of 15 cm 3 of ethanol, 285 mng of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-
ALL
-132methoxyphenyl)propenoyl]-9-(5-methyl-2-thienyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 Hbenzo[flisoindole-3a-carboxylic acid are obtained, after purification by recrystallization from diisopropyl ether, in the form of a light-beige solid, the characteristics of which are as follows: melting point 164-6'C -mass spectrum M/Z 499 (MW).
EXAMPLE 49 Preparation of methyl (3 aRS .4SR.9SR,9aRS)-9-(4-bromophenyl)-4,9-ethano-2 methoxyphenyl)-propenoyll-2,3 .3 a4,9,9a-hexahydro- 1H-benzor flisoindole-3 acarboxylate .5 S S
S
S
S
S
.5 a.
5* Stage A By carrying out the reaction as in Stage C of Example 45, but from 1 g of methyl (3 aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3 ,a,4,5,7ahexahydroisoindole-3a-carboxylate in 20 cm 3 of toluene, from 120 mng of 15 tetrakis(triphenylphosphine)palladium, from 0.46 g of 4-bromophenylboronic acid in cm 3 of methanol and from 15 cm 3 of a 2N aqueous sodium carbonate solution at reflux. for eighteen hours, 0.77 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4bromophenyl)-4-phenyl-2,3 ,3 a,4,5 ,7a-hexahydro-l1H-isoindole-3 a-carboxylate is obtained, after purification by flash chromatography on silica gel (23.0-400 mesh), 20 elution'being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of a white foam, the characteristic of which is as follows: mass spectrum M/Z 502 (MW).
Stage B By carrying out the reaction as in Stage C of Example 38, but from 0.77 g of methyl (3 aRS ,4SR,7aRS)-2-benzyl-7-(4-bromophenyl)-4-phenyl- 2,3,3 a,4,5 ,7a-hexahydro-1 H-isoindole-3 a-carboxylate and from 1.18 cm 3 of trifluoromethanesulphonic acid in 20 cm 3 of dichioromethane for eighteen hours at room temperature, 0.71 g of methyl (3 aRS ,4SR,9SR,9aRS)-2-benzyl-9-(4bromop henyl)-4,9-ethano-2 3a, 4,9, 9a-hexahydro-1H-benzofisoindole-3a- -133carboxylate is obtained in the form of a beige powder, used as is in the continuation of the synthesis, the characteristic of which is as follows: mass spectrum M/Z 502 Stage C By carrying out the reaction as in Stage B of Example 47, but from 0.71 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(4-bromophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-isoindole-3a-carboxylate and from 0.4 cm 3 of vinyl chloroformate for seventy-two hours at room temperature in 20 cm 3 of dichloromethane, and by then taking the concentrate up in 40 cm 3 of methanol and 5 cm 3 of a 6M solution of hydrochloric acid in dioxane at reflux for three hours, 0.45 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4-bromophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-isoindole-3a-carboxylate hydrochloride is obtained, after crystallizing from diisopropyl ether, in the form of white crystals, the characteristic of which is as follows: 15 mass spectrum M/Z 412 Stage D By carrying out the reaction as in Stage G of Example 1, but from 0.45 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4-bromophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate hydrochloride, from 20 0.21 g of 2-(2-methoxyphenyl)propenoic acid, from 0.10 cm 3 of oxalyl chloride and from 0.33 cm 3 of triethylamine in solution in 30 cm 3 of dichloromethane for twenty hours at room temperature, 0.25 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4bromophenyl)-4,9-ethano-2[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9ahexahydro-1H-benzo[f]isoindole-3a-carboxylate is obtained, after purification on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (70/30 by volume), in the form of a light-beige powder, the characteristics of which are as follows: melting point 190-2°C mass spectrum M/Z 572 EXAMPLE -134- Preparation of (3 aRS ,4SR,9SR.9aRS)-9-(4-bromophenl)-4,9-ethano-2- r2-(2methoxyphenyl)propenoyll -2,3,3 a,4,9.9a-hexahydro- 1H-benzo rflisoindo le-3 acarboxylic acid By carrying out the reaction as in Example 2, but from 0. 19 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(4-bromophenyl)-4,9-ethano-2 methoxyphenyl)-propenoyl]-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 acarboxylate at reflux for three hours in 0.44 cm 3 of a normal aqueous sodium hydroxide solution and of 10 cm 3 of ethanol, 120 mg of (3 aRS,4SR,9SR,9aRS)-9-(4-bromophenyl)-4,9-ethano-2- methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3acarboxylic acid are obtained, after purification by recrystallizing from diisopropyl ether, in the form of a white solid, the characteristics of which are as follows: melting point 1690 C mass spectrum M/Z =558 00 11
LL
-135- EXAMPLE 51 Preparation of (3aRS.4SR,9SR.,9aRS)-9-(3 ,4-dichlorophenvl')-4.9-ethano-2-r2-(2methoxyphenyl)-propenovll-2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3acarboxvlic acid Stage A By carrying out the reaction as in Stage A of Example 39, but from 3.6 g of 3,4-dichloro-bromobenzene, from 0.4 g of magnesium turnings in 20 cm of diethyl ether and from 2.9 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4phenyloctahydroisoindole-3a-carboxylate in 20 cm 3 of diethyl ether, 1.8 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-(3,4-dichlorophenyl)-7-hydroxy-4phenyloctahydroisoindole-3a-carboxylate are obtained, after recrystallization from 35 cm 3 of isopropanol, in the form of a white solid, the characteristic of which is as follows: melting point 144 0
C.
Crystallization by diisopropyl ether of the filtrate, brought to dryness, makes it possible to obtain an additional 0.6 g. The purification of this second filtrate by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, makes it possible to obtain,
S
after crystallization from diisopropyl ether, an additional 0.25 g.
Stage B By carrying out the reaction as in Stage D of Example 1, but from 1.2 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-(3,4-dichlorophenyl)-7-hydroxy- 4-phenyl-1,3,3a,4,5,6-hexahydroisoindole-3a-carboxylate, from 3 cm 3 of trifluoromethanesulphonic acid and from 45 cm' of dichloromethane, 1.1 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3,4-dichlorophenyl)-4,9-ethano-2,3,3a,4,9,9ahexahydro-l1H-benzo[f]isoindole-3a-carboxylate are obtained in the form of a white foam, used as is in the subsequent syntheses.
Stage C 0.18 cm 3 of vinyl chloroformate is added to a solution of 0.7 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3,4-dichlorophenyl)-4,9-ethano- -136- 2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate in 7.5 cm 3 of dichloromethane. The reaction mixture is stirred for twenty hours at a temperature in the region of 20°C and then concentrated under reduced pressure. The residue is diluted with 7.5 cm 3 of methanol. 14 cm 3 of a normal solution of hydrogen chloride gas in diethyl ether are added to this solution. The reaction mixture is stirred for twenty hours at a temperature in the region of20°C and then concentrated under reduced pressure. The residue is taken up in a mixture of 25 cm 3 of dichloromethane and 20 cm 3 of a saturated aqueous sodium hydrogencarbonate solution. The aqueous phase is separated by settling and extracted with two times 15 cm 3 of diethyl ether.
The organic phases are combined, washed with three times 15 cm 3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. After flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, and crystallization from 5 cm 3 of diisopropyl ether, 0.21 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3,4-dichlorophenyl)- 4,9-ethano-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate is thus obtained in the form of a white solid, the characteristic of which is as follows: melting point 185 C.
Stage D By carrying out the reaction as in Stage G of Example 1, but from 0.2 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3,4-dichlorophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate, from 0.1 g of 2-(2methoxyphenyl)propenoic acid, from 0.04 cm 3 of oxalyl chloride and from 0.14 cm 3 of triethylamine, 0.19 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(3,4-dichlorophenyl)- 4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carboxylate is obtained, after crystallization from diisopropyl ether, in the form of a white solid, the characteristic of which is as follows: melting point 150'C.
Stage E By carrying out the reaction as in Example 2, but from 0.16 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3,4-dichlorophenyl)-4,9-ethano-2-[2-(2i -137methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- I H-benzo[fl isoindole-3 acarboxylate, from 1.4 cm 3 of a normal aqueous sodium hydroxide solution and [lacuna] 3 cm 3 of methanol, 0.1 g of (3aRS,4SR,9SR,9aRS)-9-(3,4-dichlorophenyl)- 4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2 3a,4, 9, 9a-hexahydro-1Hbenzo[flisoindole-3a-carboxylic acid is obtained, after recrystallization from 2.5 cm 3 of isopropyl. acetate, the characteristic of which is as follows: melting point 168T 0 EXAMPLE 52 Preparation of methyl (3aRS .4SR,9SR,9aRS)-9-(4-chlorophenyl)-4.9-ethano-2- r2-(2methoxvtphenyl)-propenol -2,3,3 a.4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-.
carboxylate Stage A By canrying out the reaction as in Stage C of Example 1, but from 9.58 g of 4-chlorobromobenzene, from 1.2 g of magnesium turnings and from 9.1 g 15 of methyl (3 aRS ,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3 acarboxylate, 7.9 g of methyl (3 aRS,4SR,7RS,7aRS)-2-benzyl-7-(4-chlorophenyl)-7hydroxy-4-phenyloctahydroisoindole-3a-carboxylate are obtained, after recrystallization from 25 cm 3 of isopropanol, in the form of a white solid, the characteristic of which is as follows: melIting point 189TC.
':Stage B By carrying out the reaction as in Stage D of Example 1, but from g of methyl (3 aRS ,4SR,7RS ,7aSR)-2-benzyl-7-(4-chlorophenyl)-7-hydroxy-4phenyl-2,3 ,3 a,4,5 ,6-hexahydroisoindole-3 a-carboxylate, from 25 cm 3 of trifluoromethanesulphonic acid and from 80 cm 3 of dichioromethane, 6.35 g of methyl (3 aRS ,4SR,9SR,9aRS)-2-benzyl-9-(4-chlorophenyl)-4,9-ethano- 2,3,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylate are obtained, after crystallization from 100 cm 3 of isopropanol, in the form of a white solid, the characteristic of which is as follows: melting point 142T 0 -138- Stage C By carrying out the reaction as in Stage C of Example 5 1, but from 2.29 g of methyl (3 aRS ,4SR,9SR,9aRS)-2-benzyl-9-(4-chlorophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3a-carboxylate and from 0.98 cm 3 Of vinyl chioroformate in 7.5 cm.
3 of dichioromethane, and by then treating the intermediate, diluted in 25 cm 3 of methanol, with 8.5 cm' of a hexanormal solution of hydrogen chloride gas in dioxane, 0.8 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4chlorophenyl)-4,9-ethano-2 3a,4, 9,9 a-hexahydro-1H-benzo[flisoindole-3acarboxylate is obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol (98/2 by volume) mixture, in the formn of a light-coloured foam, used as is in the subsequent syntheses.
Stage D By carrying out the reaction as in Stage G of Example 1, but from g of methyl (3 aRS,4SR,9SR,9aRS)-9-(4-chlorophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-lH-benzo[flisoindole-3a-carboxylate, from 0.36 g of 2-(2methoxyphenyl)propenoic acid, from 0. 17 cm 3 of oxalyl chloride and from 0.57 cm 3 of triethylamine, 0.8 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(4-chlorophenyl)-4,9ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3 a,4,9,9a-hexahydro-l1Hbenzo[flisoindole-3a-carboxylate is obtained, the characteristic of which is as follows: -melting point EXAMPLE 53 Preparation of (3 aRS .4SR,9SR,9aRS)-9-(4-chlorop~henvl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyll-2,3 .3 a.4,99a-hexa hydro- 1H-benzorflisoindole-3 acarboxylic acid By carrying out, the reaction as in Example 2, but from 0. 7 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(4-chlorophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 acarboxylate, from 2 cm 3 of a normal aqueous sodium hydroxide solution and [lacuna] 30 cm 3 of ethanol, 0.45 g of (3aRS,4SR,9SR,9aRS)-9-(4-chlorophenyl)-4,9-ethano-2- U J -13 9- [2-(2-methoxyphenyl)-propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo lf-isoindole- 3a-carboxylic acid is obtained, after flash chromatography on silica gel (230- 400 mesh), elution being carried out with a dichioromethane/methanol (98/2 by volume) mixture, the characteristic of which is as follows: melting point: approximately 160'C.
EXAMPLE 54 Preparation of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-r2-(2methoxyphenyl)propenoyll-9-(4-methoxy-3 -methylpheny.l)-2,3 .3 a4,9,9a-hexahydro- 1 H-benzorflisoindole-3 a-carboxylic acid Stage A By carrying out the reaction as in Stage A of Example 3 1, but from 2 g of methyl (3 aRS ,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3 acarboxylate, from 2 g of 2-methylanisole and from 2.9 cm 3 of :::trifluoromethanesulphonic acid in 30 cm 3 of dichloromethane, 2.3 g of methyl 15 (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-methoxy-3-methylphenyl)- 2,3,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylate are obtained, after 5 purification by flash chromatography on silica gel (2.30-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (90/10 by volume) mixture, in the form of an off-white foamn, used as is in the subsequent syntheses.
Stage B By carrying out the reaction as in Stage E of Example 1, but from 2.3 g of methyl (3 aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-methoxy-3 methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylate, from 0.93 g of ammonium formate and from 0.5 g of 10% palladium-on-charcoal, 0.5 g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxy-3-methylphenyl)- 2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylate is obtained, after [lacuna] by flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol (99/1 by volume) mixture, and recrystallization from 20 cm 3 of isopropanol, in the form of a white solid, the characteristic of which is as follows: -140melting point 123'C.
Stage C By carrying out the reaction as in Stage G of Example 1, but from.
1.1 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxy-3-methylphenyl)- 2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3a-carboxylate, from 0.52 g of 2-(2methoxyphenyl)propenoic acid, from 0.25 cm 3 of oxalyl chloride and from 0.82 cm 3 of triethylamine, 0.85 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(4-methoxy-3-methylphenyl)-2,3,3a,4,9,9a-hexahydrolH-benzo[flisoindole-3a-carboxylate is obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichioromethane/methanol (99/1 by volume) mixture, and recrystallization from see:% *5 cm 3 of isopropanol, the characteristic of which compound is as follows: melting point 125C.
Stage D 15 By carrying out the reaction as in Example 2, but from 0.8 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4- 999999 methoxy-3-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3acarboxylate, from 2.25 cm 3 of a normal aqueous sodium hydroxide solution and [lacuna] 40 cm 3 of ethanol, 0.45 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(4-methoxy-3-methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-carboxylic acid is obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichioromethane/methanol (97.5/2.5 by volume) mixture, in the form of an amorphous white solid.
mass spectrum M/Z 523 (M) EXAMPLE Preparation of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-f2-(2methoxvphenvl)propenoyl]-9-(3-indolvl)-23 ,3 a.4,99a-hexahydro-1Hbenzorflisoindole-3a-carboxylate Stage A By carrying out the reaction as in Stage A of Example 3 1, but from -141- 3.63 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3acarboxylate, from 3.85 g of 1-phenylsulphonylindole and from 5.3 cm 3 of trifluoromethanesulphonic acid in 30 cm 3 of dichloromethane, 2.1 g of a crude product are obtained, after purification by flash chromatography on silica gel (230- 400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, which crude product is combined with a second batch originating from an experiment carried out with respect to the same amounts. The purification of this mixture by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/5 by volume) mixture, provides 1 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3-indolyl)-2,3,3a,4,9,9ahexahydro-lH-benzo[f]isoindole-3a-carboxylate in the form of an off-white foam, used as is in the subsequent syntheses, the characteristics of which are as follows: 1 H N.M.R. spectrum (300 MHz, CDC13, d in ppm): from 1.30 to 1.60 and 2.55 (2 mts, each 2H, CH 2
CH
2 2.11 and 2.65 (respectively dd and d, J 10 and 15 9 Hz and J 10 Hz, each 1H, CH 2 at 2.31 and 3.21 (2d, J 10 Hz, each 1H, CH 2 at 3.37 and 3.51 (2 d, J 12.5 Hz, each 1H, NCH 2 Ar), 3.42 (broad s, 1H, CH at from 3.50 to 3.70 (mt, 1H, CH at 9a), 3.59 3H, COOCH 3 6.81 (broad d, J= Hz, 1H, H at from 6.90 to 7.60 (mt, 13H, H at 5, H at 6, H at 7, aromatic H of the indole and aromatic H of the benzyl), 8.11 (broad s, 1H, NH).
20 Stage B By carrying out the reaction as in Stage C of Example 51, but from 1 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3-indolyl)- 2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate and from 0.285 cm 3 of vinyl chloroformate in 20 cm 3 of dichloromethane, and by then treating the intermediate, dissolved in 20 cm 3 of methanol, with 21.4 cm 3 of a normal solution of hydrogen chloride gas in diethyl ether, 0.3 g of methyl (3aRS,4SR,9SR,9aRS)-4,9ethano-9-(3-indolyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate is obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol (97.5/2.5 by volume) mixture, in the 30 form of an orange-coloured foam, used as is in the subsequent syntheses.
-142- Stage C By carrying out the reaction as in Stage G of Example 1 but from 0.3 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-indolyl)-2,3,3a,4,9,9ahexahydro- 1 H-benzo[flisoindole-3a-carboxylate, from 0.145 g of 2-(2methoxyphenyl)propenoic acid and from 0.07 cm 3 of oxalyl chloride, 0.16 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(3indolyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[f]isoindole-3a-carboxylate is obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (50/50 by volume) mixture, and crystallization from diisopropyl ether, the characteristics of which compound are as follows: so*: 0 mass spectrum M/Z 532 'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 383 K, d in 1 ppm): 1.46 and 2.16 (2 mts, each 2H, CH 2
CH
2 from 3.30 to 3.80 (mt, 4H, CH 2 at 1, CH at 9a and 1H of the CH 2 at 3.47 (mt, 1H, CH at 3.57 3H, COOCH 3 3.71 3H, ArOCH 3 4.10 (broad d, J 12.5 Hz, 1H, the other H of the CH 2 at 3), S0.5.52 and 5.67 (2 s, each 1H, =CH 2 6.65 (broad d, J 7.5 Hz, 1H, H at from 6.90 so.* to 7.88 (mt, 12H, H at 5, H at 6, H at 7, aromatic H of the indole and aromatic H of the 2-methoxyphenyl).
EXAMPLE 56 Preparation of (3aRS .4SR.9SR,9aRS)-49-ethano-9-(4-isopropylphenvl)-2-r(2methoxyphenvl)acetyll-2,3,3a,4,9,9a-hexahydro-1H-benzorflisoindole-3a-carboxylic acid Stage A By carrying out the reaction as in Stage A of Example 1, but from 6 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3acarboxylate in 60 cm 3 of dry diethyl ether and from a solution of 4isopropylphenylmagnesium bromide, prepared at the time of use from 4 g of 4bromoisopropylbenzene and 0.52 g of magnesium turnings in 7 cm 3 of dry diethyl 3- ether, for eighteen hours at room temperature, 3.3 g of methyl -143- (3aRS,4SR,7RS,7aRS)-2-benzyl-7-(4-isopropylphenyl)-7-hydroxy-4phenyloctahydroisoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a gradient of mixtures of cyclohexane and of ethyl acetate (from 98/2 to 80/20 by volume), in the form of a yellow oil, the characteristic of which is as follows: mass spectrum M/Z 483 Stage B By carrying out the reaction as in Stage D of Example 1, but from 1.7 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-(4-isopropylphenyl)-7-hydroxy-4phenyloctahydroisoindole-3a-carboxylate and from 2.3 cm 3 of trifluoromethanesulphonic acid in 22 cm 3 of dichloromethane for three hours at room temperature, 1.44 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9- (4-isopropylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate are obtained in the form of a brown viscous oil, used as is in the continuation of the 15 synthesis, the characteristic of which is as follows: mass spectrum M/Z 465 Stage C By carrying out the reaction as in Stage C of Example 45, but from 1.4 g (3 mmol) of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4- 20 isopropylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate and from 140 mg of 10% palladium-on-charcoal in 125 cm 3 of methanol and 3.3 cm 3 of a normal aqueous hydrochloric acid solution for four hours at room temperature under hydrogen at atmospheric pressure, 1.03 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[f]isoindole-3a-carboxylate hydrochloride are obtained, after crystallization from diisopropyl ether, in the form of a beige powder, the characteristic of which is as follows: mass spectrum M/Z 375 Stage D By carrying out the reaction as in Stage A of Example 5, but from -144- 500 mng of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)- 2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylate hydrochloride, from 240 mg of 2-methoxyphenylacetic acid, from 280 mg of I1-ethyl-3-[3- (dimethylamino)propyl)carbodiimide hydrochloride, from 16 mg of N- Ihydroxybenzotriazole hydrate and from 0.2 cm 3 of triethylamine in 55 cm 3 of dichioromethane, 460 mng of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4isopropylphenyl)-2-112-(methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro-l1Hbenzo[flisoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (240-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (70/30 by volume) mixture, in the form of a white powder, the characteristics of which are as follows: melting point 85-7' mass spectrum M/Z =523 By carrying out the reaction as in Example 2, but from 0.379 g of mehl(3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)-2-[2- (methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 a- ***carboxylate at reflux for three hours in 0.85 cm 3 of a normal aqueous sodium hydroxide solution and 15 cm 3 of ethanol, 170mig of (3aRS,4SR,9SR,9aRS)- 20 4,9-ethano-9-(4-isopropylphenyl)-2-[(2-methoxyphenyl)acetyl] -2,3,3 a,4,9,9,9ahexahydro-1H-benzo[tlisoindole-3a-carboxylic acid are obtained, after purification by stirring in ethyl acetate in the presence of silica gel (230-400 mesh) and then recrystallization from pentane, in the form of a white solid, the characteristics of which are as follows: melting point =135-6'C.
mass spectrum MIZ =509 (MW).
EXAMPLE 57 Preparation of (3 aRS 4SR.9SR,9aRS)-4,9-ethano-9-(4-isopropyl-phenvyl)-2-r2-(2methoxynhenyl)propenoyl]-2,3 .3 a.4,99a-hexahydro- 1H-benzo rflisoindole-3 acarboxylic acid -145- By carrying out the reaction as in Stage G of Example 1, but from 0.53 g of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)- 2,3,3 a,4,9,9a-hexahydro-I1H-benzo [flisoindole-3 a-carboxylate hydrochloride, obtained in Stage C of Example 56, from 0.25 g of 2-(2-methoxyphenyl)propenoic acid, from 0. 12 cm 3 of oxalyl chloride and from 0.4 cm' of triethylamine in solution of 30 cm 3 of dichioromethane for twenty hours at room temperature, 0.375 g (5 4%) of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3acarboxylate is obtained, after purification on silica gel (23 0-400 mesh), elution being 1 0 carried out with a gradient of mixtures of cyclohexane and of ethyl acetate (from 98/2 to 70/30 by volume), in the form of a white powder, the characteristics of which are too: 0 000 follows: melting point 98- 100'C mass spectrum M/Z 535 By carrying out the reaction as in Example 2, but from 0.32 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)-2-[2-(2methoxyphenyl)-propenoyl] -2,3,3 a,4,9,9a-hexahydro- I H-benzo[flisoindole-3 acarboxylate at reflux for two hours in 0.7 1 cm 3 of a normal aqueous sodium hydroxide solution and 15 cm 3 of ethanol, 190 mg of (3aRS,4SR,9SR,9aRS)- 20 4,9-ethano-9-(4-isopropylphenyl)-2- [2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylic acid are obtained, after purification by stirring in ethyl acetate in the presence of silica gel (23 0-400 mesh) and then recrystallization from pentane, in the form of a white solid, the characteristics of which are as follows: melting point 168-70'C -mass spectrum M!Z 521 (MW).
EXAMPLE 58 Preparation of methyl (3 aRS .48R,9SR.9aRS)-4,9-ethano-2-r2-(2methoxyphenvyl)propenoyll -9-(3-thienyl)-2.3,3 a,4,9,9a-hexahydro- 1H- 30 benzorflisoindole-3a-carboxylate -146- Stage A By carrying out the reaction as in Stage C of Example 45, but from 1.2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,a,4,5,7ahexahydroisoindole-3a-carboxylate in 30 cm 3 of toluene, from 150 mg of tetrakis(triphenylphosphine)palladium, from 0.35 g of 3-thienylboronic acid in cm 3 of methanol and from 28 cm 3 of a 2N aqueous sodium carbonate solution at reflux for three hours, 0.99 g of methyl (3aRS,4SR,7aRS)-2-benzyl-4-phenyl- 7-(3-thienyl)-2,3,3a,4,5,7a-hexahydro- 1 H-isoindole-3a-carboxylate is obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), in the form of a yellow oil, the characteristic of which is as follows: .mass spectrum M/Z 429 Stage B By carrying out the reaction as in Stage C of Example 38, but from 1.1 g of methyl (3aRS,4SR,7aRS)-2-benzyl-4-phenyl-7-(3-thienyl)-2,3,3a,4,5,7ahexahydro-1H-isoindole-3a-carboxylate and from 1.4 cm 3 of trifluoromethanesulphonic acid in 15 cm 3 of dichloromethane for eighteen hours at room temperature, 0.62 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9ethano-9-(3-thienyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-carboxylate is obtained in the form of a beige powder, used as is in the continuation of the synthesis, the characteristic of which is as follows: mass spectrum M/Z 429 Stage C By carrying out the reaction as in Stage B of Example 47, but from 0.62 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3-thienyl)- 2,3,3a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3a-carboxylate and from 0.19 cm 3 of vinyl chloroformate for seventy-two hours at room temperature in 10 cm 3 of dichloromethane, and by then taking the concentrate up in 20 cm 3 of methanol and 2.7 cm 3 of a 5M solution of hydrochloric acid in isopropanol at reflux for two hours, 0.48 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-thienyl)- -147- 2,3,3a,4,9,9a-hexahydro- 1 H-benzo[f]isoindole-3a-carboxylate hydrochloride is obtained, after crystallization from diisopropyl ether, in the form of a white solid, the characteristic of which is as follows: mass spectrum M/Z 339 Stage D By carrying out the reaction as in Stage G of Example 1, but from 0.48 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-thienyl)-2,3,3a,4,9,9ahexahydro-1 H-benzo[fjisoindole-3a-carboxylate hydrochloride, from 0.27 g of 2-(2methoxyphenyl)propenoic acid, from 0.12 cm' of oxalyl chloride and from 0.36 cm 3 of triethylamine in solution of 35 cm 3 of dichloromethane for twenty hours at room temperature, 0.40 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(3-thienyl)-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate is obtained, after purification by flash 1 chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (60/40 by volume), followed by recrystallization from diisopropyl ether, in the form of a white solid, the characteristics of which are as follows: melting point 174oC mass spectrum M/Z 499 i 20 Stage E S*By carrying out the reaction as in Example 2, but from 0.35 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(3thienyl)-2,3,3a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3a-carboxylate at reflux for three hours in 2.1 cm' of a normal aqueous sodium hydroxide solution and 12 cm 3 of ethanol, 340 mg of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(3-thienyl)-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylic acid are obtained, after purification by recrystallization from petroleum ether (40-65 0 in the form of a white solid, the characteristics of which are as follows: 3 Qz- melting point 170'C -148mass spectrum M/Z 485 EXAMPLE 59 Preparation of methyl (3aRS,4SR,9SR,9aRS)-49-ethano-9-(4-ethlphenyl)-2- r2-(2methoxvphenvl)propenovl-2,3,3a4,9,9a-hexahydro- 1H-benzorflisoindole-3acarboxvlate Stage A By carrying out the reaction as in Stage C of Example 45, but from 1.35 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,a,4,5,7ahexahydroisoindole-3a-carboxylate in 20 cm 3 of toluene, from 340 mg of tetrakis(triphenylphosphine)palladium, from 0.38 g of trimer anhydride of 4ethylphenylboronic acid in 10 cm 3 of methanol and from 15 cm' of a 2N aqueous sodium carbonate solution at reflux for eighteen hours, 0.92 g of methyl .(3aRS,4SR,7aRS)-2-benzyl-7-(4-ethylphenyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1Hisoindole-3a-carboxylate is obtained, after purification by flash chromatography on 15 silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of a viscous yellow oil, the characteristic of which is as follows: mass spectrum M/Z 451 Stage B :W 20 By carrying out the reaction as in Stage C of Example 38, but from 0.92 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4-ethylphenyl)-4-phenyl- 2,3,3 a,4,5,7a-hexahydro- 1H-isoindole-3a-carboxylate and from 1.18 cm' of trifluoromethanesulphonic acid in 18 cm 3 of dichloromethane for six hours at room temperature, 0.68 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9- (4-ethylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate is obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (95/5 by volume), in the form of a viscous yellow oil, the characteristic of which is as follows: mass spectrum M/Z 451 Stage C
?,AL
-149- By carrying out the reaction as in Stage E of Example 1, but from 0.68 g of methyl (3 aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-ethylphenyl)- 2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3a-carboxylate and from 0.27 g of ammonium formate in 40 cm 3 of methanol in the presence of 200 mg of 3% (w/w) palladium-on-charcoal at reflux for four hours, 0.47 g of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-ethylphenyl)-2,3 ,.3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate is obtained in the form of a yellow pasty solid, the characteristic of which is as follows: mass spectrum M/Z =461 (MW).
Stage D By carrying out the reaction as in Stage A of Example 5, but from See: 0.47 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-ethylphenyl)-2,3,3a,4,9,9ahexaydr- 1H-benzo [flisoindole-3 a-carboxylate, from 0.23 g of 2-(2methoxyphenyl)-propenoic acid, from 0.3 g of l-ethyl-3-[3- 15 (dimethylamino)propyl]carbodiimide hydrochloride and from 20 mg of N-ihydroxybenzotriazole hydrate in 30 cm 3 of dichloromethane for six hours at room be 0.temperature, 0.26 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4ethylphenyl)-2-[2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate is obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (70/30 by volume), in the form of a white powder, the characteristics of which are as follows: melting point 90-2'C mass spectrum M/Z 521 EXAMPLE Preparation of (3 aRS.4SR.9SR.9aRS)-4,9-ethano-9-(4-ethylphenl)-2-r2-(2methoxyphenyl)protpenoyl]-2,3 .3 a4,9,9a-hexahydro- 1H-benzof flisoindole-3 acarboxylic acid By carrying out the reaction as in Example 2, but starting from 0. 18 g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-ethylphenyl)-2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3 acarboxylate at reflux for three hours in 0.43 cm 3 of a normal aqueous sodium hydroxide solution and of 10 cm' of methanol, 59 mg of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-ethylphenyl)-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1 H-benizo [flisoindole-3acarboxylic acid are obtained, after purification by recrystallization from petroleum ether, in the form of a white solid, the characteristics of which are as follows: melting point 141'C mass spectrum IVlZ 507 (MW).
EXAMPLE 61 Preparation of methyl (3aRS .4SR,9SR.9aRS)-9-(2,3-dihydrobenzofuran-5-vl)-4,9ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 .3 a,4,99a-hexahydro- 1Hbenzofflisoindole-3a-carboxylate Stage A By carrying out the reaction as in Example 3 1, Stage A, but starting from 2.5 g of methyl (3 aRS ,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole- 3a-carboxylate in 250 cm 3 of dichioromethane, from 2.4 cm 3 of 2,3dihydrobenzofuran and from 4.25 cm 3 of trifluoromethanesulphonic acid; after stirring for 18 hours at a temperature in the region of 20'C, 1.56 g of methyl w20 (3 aRS,4SR,9SR,,9aRS)-2-benzyl-9-(2,3-dihydrobenzofiuran-5-yl)-4,9-ethano- ~2,3 ,3a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylate are obtained in the form of an orangey-yellow oil, used as in the following stage, the characteristic of which is as follows: mass spectrum M/Z =465 Stage B By carrying out the reaction as in Stage E of Example 1, but from 1.56 g of methyl (3 aRS ,4SR,9SR,9aRS)-2-benzyl-9-(2,3 -dihydrobenzofuran-5 -yl)- 4,9-ethano-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylate, from 0.63 g of ammonium formate and from 0.2 g of 10% palladium-on-charcoal in 30 cm 3 of methanol at refiux. for 5 hours, 0.995 g of impure methyl -151- (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5-yl)-4,9-ethano-2,3,3a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate is obtained in the form of an orangecoloured lacquer, which can be used as is in the following stage, the characteristic of which is as follows: mass spectrum (DCI): M/Z 376 Stage C By carrying out the reaction as in Stage G of Example 1, but from a solution of 0.45 g of 2-(2-methoxyphenyl)propenoic acid in 20 cm 3 of dichloromethane containing 4 drops of N,N-dimethylformamide and from 0.54 cm 3 of oxalyl chloride, after one night at a temperature in the region of 200C, by evaporating to dryness and by taking up the residue in 20 cm 3 of dichloromethane; by then pouring this solution onto the solution of 0.99 g of methyl (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5-yl)-4,9-ethano-2,3,3a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate, obtained in the preceding stage, 15 with 0.31 cm 3 of triethylamine added, in 20 cm 3 of dichloromethane, 39 mg of methyl (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5-yl)-4,9-ethano-2-[2-(2a methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3acarboxylate are obtained in the form of a beige solid, the characteristics of which are as follows: 9.99 20 melting point 200 0 C (dec) mass spectrum M/Z 535 (Me) EXAMPLE 62 Preparation of (3aRS,.4SR.,9SR9aRS)-9-(23-dihydrobenzofuran-5-vl)-4,9-ethano-2r2-(2-methoxvphenvl)propenovll-2,3, 3a,4,99a-hexahydro-1H-benzorflisoindole-3acarboxvlic acid By carrying out the reaction as in Example 2, but from 7.21 g of methyl (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3acarboxylate, prepared in the preceding example, from 50 cm 3 of a normal aqueous sodium hydroxide solution and from 100 cm of dioxane for three hours at reflux, UT d~hvC-) -152- 3.44 g of (3 aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5-yl)-4,9-ethano-2-{2-(2methoxyphenyl)propenoyl]-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo~f]isoindole-3 acarboxylic acid are obtained, after crystallization from 80 cm 3 of an ethanol/water (75/25 by volume) mixture, in the form of a white crystalline powder, the characteristics of which are as follows: melting point 241' 0
C
mass spectrum M/Z 521 (MW) EXAMPLE 63 Preparation of (3 aRS .4SR.9SR,9aRS)-9-(2.3 -dihydrobenzofuran-5 -yl)-4.9-ethano-2r2-(2-methoxyphenyvnvropenovll-2,3 .3a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a- N-(3-pyridylmethvl)carboxamide By carrying out the reaction as in Example 42, but from 522 mg of (3 aRS,48R,9SR,9aRS)-9-(2,3 -dihydrobenzofuran-5-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[f]isoindole-3 acarboxylic acid, from 0. 122 cm 3 of 3-(aminomethyl)pyridine, from 0.23 g of 1 -ethyl- 3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and from 80 mg of N-1hydroxybenzotriazole hydrate in 15 cm 3 of dichloromethane, 462 mg of (3 aRS ,4SR,9SR,9aRS)-9-(2,3 -dihydrobenzofuiran-5-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3 a-N-(3 pyridyhnethyl)carboxamide are obtained in the form of a white powder, the characteristics of which are as follows: melting point 238C C(dec) mass spectrum M/Z 611 (We) 1 H N.M.R. spectrum (400 Mffz, d6-(CD 3 2 S0, at a temperature of 383 K, d in ppm): 1.40, 1.60, 199 and 2.14 (4 nits, each I1H, CH 2
CH
2 3.29 and 3.41 (respectively dd and d (broad), J 12 and 9 Hz and J 12 Hz, each 1H, CH 2 at 1), 3.26 (broad t, J 8.5 Hz, 2H, ArCH 2 of the 2,3-dihydrobenzofuran), 3.47 and 4.17 (2d, J =12.5 Hz, each 1H, CH 2 at 3.53 (mnt, 1H, CH at 9a), 3.56 (broad s, 1H, CH at 3.70 3H, ArOCHA) 4.22 (AB, J ==15 and 6 Hz, 2H, NCH 2 Ar), 4.60 J= 8.5 Hz, 2H, CH 2 0 of the 2,3-dihydrobenzoftiran), 5.52 and 5.68 (2 s, each lH, -153-
=CH
2 6.48 (mt, 1H, H at from 6.75 to 7.50 (mt, 12H, H at 5, H at 6, H at 7, aromatic H of the 2-methoxyphenyl, aromatic H of the 2,3-dihydrobenzofuran, H at the 4 position of the pyridyl and H at the 3 position of the pyridyl), 7.96 (mt, 1H, CONH), 8.38 (broad s, 1H, H at 2 of the pyridyl), 8.44 (broad d, J 5 and 1.5 Hz, 1H, H at 6 of the pyridyl).
EXAMPLE 64 Preparation of methyl (3aRS,.4SR.,9SR,9aRS)-4,9-ethano-9-(4-fluorophenl)-2- r2-(2methoxphenvl)propenoll-23.3a,49.9a-hexahydro- 1H-benzo[flisoindole-3acarboxvlate Stage A By carrying out the reaction as in Stage A of Example 39, but from 2.8 g of 4-fluorobromobenzene, from 0.4 g of magnesium turnings in 20 cm' of diethylether and from 2.9 g of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-7-oxo-4- Sphenyloctahydroisoindole-3a-carboxylate in 20 cm' of diethyl ether, 1.2 g of methyl 15 (3aRS,4SR,7RS,7aRS)-2-benzyl-7-(4-fluorophenyl)-7-hydroxy-4phenyloctahydroisoindole-3a-carboxylate are obtained, after crystallization from 40 cm 3 of an isopropanol/diisopropyl ether (50/50 by volume) mixture, in the form of *wo a white solid, the characteristic of which is as follows: melting point= 130 0
C.
The purification of this filtrate by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, makes it possible to obtain an additional 1.2 g.
Stage B By carrying out the reaction as in Stage C of Example 38, but from 2.2 g of methyl (3aRS,4SR)-2-benzyl-7-(4-fluorophenyl)-7-hydroxy-4-phenyl- 2,3,3a,4,5,6-hexahydroisoindole-3a-carboxylate, from 6.3 cm 3 of trifluoromethanesulphonic acid and from 21 cm 3 of dichloromethane, 1.0 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-fluorophenyl)-2,3,3a,4,9,9ahexahydro-1 H-benzo[f]isoindole-3a-carboxylate is obtained, after recrystallization from 24 cm 3 of diisopropyl ether, in the form of a white solid, the characteristic of -154which is as follows: melting point 135 C.
By concentrating the filtrate and crystallization from 25 cm 3 of petroleum ether, an additional 0.75 g is obtained.
Stage C By carrying out the reaction as in Stage E of Example 1, but from g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-fluorophenyl)- 2,3,3a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3a-carboxylate, from 0.64 g of ammonium formate and from 0.2 g of 10% palladium-on-charcoal, 1.0 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2,3,3a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate is obtained in the form of a white solid, the characteristic of which is as follows: melting point 145C.
Stage D 15 By carrying out the reaction as in Stage G of Example 1, but from g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2,3,3a,4,9,9ahexahydro-1H-benzo[fjisoindole-3a-carboxylate, from 0.51 g of 2-(2methoxyphenyl)propenoic acid, from 0.24 cm' of oxalyl chloride and from 0.79 cm 3 of triethylamine, 0.7 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4- 20 fluorophenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate is obtained, after crystallization from 16 cm' of isopropanol, in the form of a white solid, the characteristic of which is as follows: melting point= 165 0
C
L.
-155- EXAMPLE Preparation of (3aRS.4SR,9SR.9aRS)-4,9-ethao-9-(4-fluorophenyl-2-[2-(2methoxvphenvl)propenoyll-2.3 ,3a,4.9,9a-hexahdro- 1H-benzorflisoindole-3acarboxylic acid By carrying out the reaction as in Example 2, but from 0.85, g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2- methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3acarboxylate, from 8.5 cm 3 of a'normal aqueous sodium hydroxide solution and from cm 3 of methanol, 0.65 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)- 2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole- 3a-carboxylic acid is obtained, after crystallization from aqueous acidic medium, the GO characteristic of which compound is as follows: melting point 170'C.
EXAMPLE 66 Preparation of methyl (3 aRS.4SR.9SR9aRS)-9-(4-chloro-3 -fluorophenvl)-4.9ethano-2-[2-(2-methoxyphenyl)-propenovl-2,3 3 a,499a-hexahvdro- 1Hbenzorflisoindole-3a-carboxylate Stage A By carrying out the reaction as in Stage C of Example 1, but from 6.3 g of 4-chloro-3-fluorobromobenzene, from 0.73 g of magnesium turnings and from 5.45 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4phenyloctahydroisoindole-3a-carboxylate, 4.8 g of methyl (3aRS,4SR,7RS,7aRS)-2benzyl=7-(4-chloro-3-fluorophenyl)-7-hydroxy-4-phenyloctahydroisoindole-3acarboxylate are obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/5 by volume) mixture, and recrystallization from 75 cm 3 of isopropanol, in the form of a white solid, the characteristic of which is as follows: melting point 175'C.
Stage B By carrying out the reaction as in Stage D of Example 1, but from K_~fN 4' -156- 4.6 g of methyl (3aRS,4SR,7RS,7aSR)-2-benzyl-7-(4-chloro-3-fluorophenyl)-7hydroxy-4-phenyloctahydroisoindole-3a-carboxylate, from 12.4 cm 3 of trifluoromethanesulphonic acid and from 50 cm of dichloromethane, 3 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(4-chloro-3-fluorophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1 H-benzo[fjisoindole-3a-carboxylate are obtained, after crystallization from 25 cm of isopropanol, in the form of a white solid, the characteristic of which is as follows: melting point 136C.
Stage C By carrying out the reaction as in Stage C of Example 51, but from 2.8 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(4-chloro-3-fluorophenyl)-4,9ethano-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3a-carboxylate and from 1.95 cm of vinyl chloroformate in 40 cm 3 of dichloromethane, and by then treating the intermediate, dissolved in 40 cm 3 of methanol, with 59 cm 3 of a normal solution of hydrogen chloride gas in diethyl ether, 1 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4chloro-3-fluorophenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole- 3a-carboxylate is obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol (97.5/2.5 by volume) mixture, in the form of a yellow foam, used as is in the subsequent syntheses.
Stage D By carrying out the reaction as in Stage G of Example 1, but from 1.4 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4-chloro-3-fluorophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3a-carboxylate, from 0.67 g of 2-(2methoxyphenyl)propenoic acid, from 0.33 cm 3 of oxalyl chloride and from 1.06 cm 3 of triethylamine, 1.5 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4-chloro-3fluorophenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate are obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (70/30 by volume) mixture, and recrystallization from an isopropanol/diisopropyl ether (1/1 by volume) mixture, the characteristic of which -157compound is as follows: melting point 173'C.
EXAMPLE 67 Preparation of (3 aRS .4SR9SR9aRS)-9-(4-chloro-3-fluorophenvl)-49-ethano2[2..
(2-methoxyphenvl)propenoyll-2,3,3a,4,9.9a-hexahdro- 1H-benzorflisoindole-3acarboxylic acid By carrying out the reaction as in Example 2, but from 1.2 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4-chloro-3-fluorophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3acarboxylate, from 3.3 cm 3 of a normal aqueous sodium hydroxide solution and [lacuna] 20 cm 3 of ethanol, 1.15 g of (3aRS,4SR,9SR,9aRS)-9-(4-chloro-3fluorophenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9ahexahydro- 1H-benzo[flisoindole-3a-carboxylic acid are obtained, after recrystallization from 5 cm of isopropanol, the characteristic of which compound is as follows: melting point 170 0
C.
EXAMPLE 68 Preparation of methyl (3 aRS .4SR.9SR9aRS)-49-ethano-2-r2-(2methoxphenvl)propenoyl]-9-(3-methylphenyl)-23 ,3 a.4,99a-hexahydro-1H- 20 benzorflisoindole-3 a-carboxvlate IStage A By carrying out the reaction as in Stage C of Example 1, but from 3.68 cm 3 of 3-bromotoluene, from 0.73 g of magnesium turnings and from 5.45 g of methyl 3 aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole.3a carboxylate, 4.2 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3methylphenyl)-4-phenyloctahydroisoindole 3a-carboxylate are obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/5 by volume) mixture, and recrystallization from cm 3 of isopropanol, in the form of an orangey-yellow foam, used as is in the subsequent syntheses.
C)
-158- Stage B By carrying out the reaction as in Stage C of Example 38, but from 4.2 g of methyl (3 aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3-methylphenyl)-4phenyloctahydroisoindole-3a-carboxylate, from 12.4 cm 3 of trifluoromethanesuiphonic acid and from 42 cm 3 of dichioromethane, 4 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3-methylphenyl)-2,3,3a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate are obtained in the form of an orange-coloured foam, used as is in the subsequent syntheses.
Stage C By carrying out the reaction as in Stage E of Example 1, but from 4 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3-methylphenyl)- 2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-carboxylate, from 1.73 g of ammonium formate and from 0.75 g of 10% palladium-on-charcoal, 3 g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-methylphenyl)-2,3 ,3a,4,9,9a- 15 hexahydro-1H-benzo[flisoindole-3a-carboxylate are obtained in the form of a yellow A &oil, used as is in the subsequent syntheses.
Stage D By carrying out the reaction as in Stage G of Example 1, but from 3 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -rethylphenyl)-2,3 ,3 a,4,9,9a- 0:609: 20 hexahydro-1H-benzo[flisoindole-3a-carboxylate, from 1.54 g of 2-(2methoxyphenyl)propenoic acid, from 0.74 cm 3 of oxalyl chloride and from 2.45 cm 3 of triethylamine, 2.5 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(3-methylphenyl)-2 ,3,3a,4,9,9a-hexahydro-1Hbenzo[flisoindole-3a-carboxylate are obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (50/50 by volume) mixture, and recrystallization from 10 cm 3 of isopropanol, the characteristic of which compound is as follows: melting point 142'C.
EXAMPLE 69 Preparation of (3aRS4SR9SR,9aRS)-4,9-ethano-2-r2-(2- -159methoxyphenvl)propenoyll-9-(3-methylphenyl)-2.3.3 a,4,9.9a-hexahydro- 1 Hbenzo rflisoindole-3 a-carboxylic acid- By carrying out the reaction as in Example 2, but from 2.2 g of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(3 methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylate, from 8.7 cm 3 of a normal aqueous sodium hydroxide solution and [lacuna] 22 cm' of ethanol, 1.75 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(3-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylic acid are obtained, after recrystallization from 50 cm 3 of isopropanol, the characteristic of which compound is as follows: melting point 252 0
C.
EXAMPLE Preparation of methyl (3aRS .4SR,9SR.9aRS)-9-( 1 3-benzodioxol-5-yl)-4,9-ethano-2r2-(2-methoxyphenyl)propenoyl] -2.3 .3a,4,9,9a-hexahydro-l1H-benzorflisoindole-3 acarboxylate *Stage A By carrying out the reaction as in Stage A of Example 3 1, but from 5.9 g of methyl (3 aRS ,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3 acarboxylate, from 2.5 cm 3 of veratrole and from 6.3 cm 3 of trifluoromethanesulfonic acid in 26 cm 3 of dichiorornethane, 1.8 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl- 9-(3,4-dimethoxyphenyl)-4,9-ethano-2 3a, 4,9 ,9a-hexahydro-1H-benzo[flisoindole- 3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (90/10 by volume) mixture, in the form of a colourless oil, used as is in the subsequent syntheses.
Stage B A solution of 1.8 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3,4dimethoxyphenyl)-4,9-ethano-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 acarboxylate in 20 cm 3 of dichloromethane is added to 22.3 cm 3 of boron tribromide cooled to a temperature in the region of-5O 0 C. The reaction mixture is stirred for one -160hour at a temperature in the region of -50°C and then 75 cm 3 of a saturated aqueous sodium hydrogencarbonate solution are added. The aqueous phase is separated by settling and extracted with two times 25 cm 3 of dichloromethane. The organic phases are combined, washed with three times 15 cm 3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol (97.5/2.5 by volume) mixture. 0.8 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3,4-dihydroxyphenyl)-4,9-ethano-2,3,3a,4,9,9ahexahydro-lH-benzo[fjisoindole-3a-carboxylate, in the form of an orange oil used as is in the subsequent syntheses, and 1.0 g of a mixture of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3-hydroxy-4-methoxyphenyl)- 2,3,3a,4,9,9a-hexahydro-lH-benzo[fjisoindole-3a-carboxylate and of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-hydroxy-3-methoxyphenyl)- 2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate, in the form of an 15 orange oil used as is in the subsequent syntheses, are thus obtained.
Stage C A solution of 1.8 g of potassium carbonate in 4 cm 3 of distilled water and then 60 mg of Adogen 464 are added to a solution of 0.58 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3,4-dihydroxyphenyl)-4,9-ethano-2,3,3a,4,9,9a- 20 hexahydro-1H-benzo[flisoindole-3a-carboxylate in 4 cm 3 ofdibromomethane. The reaction mixture is heated at reflux with stirring for 90 minutes, then cooled to a temperature in the region of 20°C and diluted with 25 cm3 of dichloromethane. The aqueous phase is separated by settling and extracted with two times 15 cm 3 of dichloromethane. The organic phases are combined, washed with three times 15 cm 3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. 0.8 g of a crude product is thus obtained, which product is combined with a second batch of 0.4 g originating from another experiment. The purification of this mixture by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (90/10 by volume) mixture, provides 0.45 g of Omethyl (3aRS,4SR,9SR,9aRS)-9-(1,3-benzodioxol-5-yl)-2-benzyl-4,9-ethano- -161- 2,3,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylate in the form of a white foam, used as is in the subsequent syntheses, the characteristics of which are as follows: 'H N.M.R. spectrum (400 MHz, CDCl 3 at a temperature of 333K, 6 in ppm): 1.43, 1.65 and 2.47 (3 mnts, respectively 1H, 1H and 2H, CH 2
CH
2 from 2.25 to .2.40 (mt, 1H, 1H of the CH 2 at 2.36 J 10 Hz, 1H, 1H of the CH 2 at 2.77 (broad d, J 9.5 Hz, 1H, the other H of the CH 2 at from 3.15 to 3.25 (mt, lH, CH at 9a), 3.21 J 10 Hz, I1H, the other H of the CH 2 at 3.3 9 (broad s, IlH, CH at 3.43 and 3.67 (2 d, J 13 Hz, each IlH, NCH 2 Ar), 3.55 3H, COOCH 3 ),5.98 (limit AB, 2H,
OCH
2 6.63 (broad d, J 7.5 Hz, lH, H at 6.85 and 6.91 (2 broad d, J 8.5 Hz, each 1H, H at 6 and H at 7 of the l,3-benzodioxol), 6.96 (broad s, lH, H at 4 of the 494 1,3-benzodioxol), from 7.00 to 7.35 (mnt, 8H, H at 5, H at 6, H at 7 and aromatic H of 000:.
41 the benzyl).
Stage D By carrying out the reaction as in Stage E of Example 1 but from 0.5 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(1I,3-benzodioxol-5 -yl)-2-benzyl-4,9-ethano- 2,3,3 a,4,9,9a-he xahydro- 1H-benzo [flisoindole-3 a-carboxylate, from 0.21 g of amrn oniumn formate and from 70 mg of 10% palladium-on-charcoal, 0.25 g of methyl (3aRS,4SR,9SR,9aRS)-9-( 1,3-benzodioxol-5-yl)-4,9-ethano-2,3 ,3a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate is obtained in the form of a white solid, used as is in the subsequent syntheses.
Stage E By carrying out the reaction as in Stage G of Example but from 0.25 g of methyl (3 aRS,4SR,9SR,9aRS)-9-( 1,3-benzodioxol-5-yl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3a-carboxylate, from 0.12 g of 2-(2- *methoxyphenyl)-propenoic acid, from 0.06 cm' of oxalyl chloride and from 0. 19 cm 3 of triethylamine, 0.26 g of methyl (3 aRS,4SR,9SR,9aRS)-9-( 1,3 -benzodioxol-5 -yl)- 4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate is obtained, after flash chromatography on silica (230-400 mesh), elution being carried out with a dichloromethane/methanol -162- (97.5/2.5 by volume) mixture, in the form of a white foam, used as is in the subsequent syntheses.
Stage F By carrying out the reaction as in Example 2, but from 0.26 g of (3aRS,4SR,9SR,9aRS)-9-(1 ,3-benzodioxol-5-yl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo(flisoindole-3 acarboxylate, from 2.4 cm 3 of a normal aqueous sodium hydroxide solution and [lacuna] 5 cm 3 of methanol, 80 mg of (3aRS,4SR,9SR,9aRS)-9-(1,3-benzodioxol-5yl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylic acid are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol (97.5/2.5 by volume) mixture, and crystallization from 2.5 cm 3 of diisopropyl ether, the characteristic of which compound is as follows: mligpoint =24C EXAMPLE 71 Preparation of methyl (3 aRS .4SR,9SR,9aRS)-9-(3 .4-dimethylphenyl)-4,9-ethano-2r2-(2-methoxyphenvl)propenoyl] -2,3.3 a,4,9,9a-hexahydro- 1H-benzo rflisoindole-3 acarboxylate Stage A By carrying out the reaction as in Stage A of Example 3 1, but from 10.34 g of methyl (3 aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3 acarboxylate in 40. cm 3 of dichloromethane, from 50 cm 3 of ortho-xylene, from 24 cm 3 of 99% trifluoromethanesulphonic acid and from 6.5 cm 3 of trifluoromethanesulphonic anhydride under an argon atmosphere for 23 hours at a temperature in the region of 20'C, 7.27 g of impure methyl (3aRS,4SR,9SR,9aRS)- 2-benzyl-9-(3 ,4-dimethylphenyl)-4,9-ethano-2,3 ,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate are obtained in the form of a colourless oil, which can be used as is in the following stage, the characteristic of which is as follows: mass spectrum (DCI): MIZ 452 Stage B -163- By carrying out the reaction as in Stage E of Example 1, but from 9.51 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3,4-dimethylphenyl)-4,9ethano-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate, obtained as in the preceding stage, from 4 g of ammonium formate, from 0.5 g of 10% (w/w) palladium-on-charcoal in 150 cm 3 of methanol and from 100 cm 3 of dioxane at a temperature in the region of 50'C for six hours, after flash chromatography on 500 g of silica gel, elution being carried out successively with one dinm of pure dichloromethane, then one dm' of the dichloromethane/ethanol (98/2 by volume) mixture, then one dm 3 of the dichloromethane/ethanol (95/5 by volume) mixture, then dm 3 litres of the dichloromethane/ ethanol (90/10 by volume) mixture and then the dichioromethane/ethanol (80/20 by volume) mixture, 5.79 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3,4-dimethylphenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3a-carboxylate are obtained in the form of a slightly foamy colourless lacquer, used as is in the following stage, the characteristic of which is as 15 follows: mass spectrum (DCI): VM/Z 361 Stage C ~By carrying out the reaction as in Stage G of Example 1, but from a solution of 2.67 g of 2-(2-methoxyphenyl)propenoic acid in 50 cm 3 of 20 dichloromethane containing 2 drops of N,N-dimethylformamide, from 1.31 cm 3 of *i oxalyl chloride, for 2 hours, and from a solution of 5.075 g of (3aRS,4SR,9SR,9aRS)-9-(3,4-dimethylphenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3a-carboxylate, obtained in the preceding stage, and from 4.4 cm 3 of triethylamine in 100 cm 3 of dichloromethane, and then running in 100 cm 3 of water after 1 hour, 3.4 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3,4dimethylphenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate are obtained in the form of a white powder, the characteristics of which are as follows: melting point 1630C (dec) mass spectrum M/Z =521 -164- EXAMPLE 72 Preparation of (3 aRS .4SR,9SR,9aRS)-4,9-ethano-9-(3 .4-dimethvlphenvl)-2-r2-(2methoxyphenyl)propenoyll-2.3 .3 a,4,99a-hexahydro-l1H-benzorflisoindole-3 acarboxylic acid By carrying out the reaction as in Example 2, but from 4.736 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylate, obtained in the preceding stage, and from 36 cm 3 Of a normal aqueous sodium hydroxide solution in 50 cm' of ethanol and 100 cm' of dioxane for sixteen hours at a temperature in the region of7 0 T, 3.375 g of (3aRS,4SR,9SR,9aRS)-9- (3 ,4-dimethylphenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylic acid are obtained in the form of a *white powder, the characteristics of which are as follows: melting point 200TC, then 245TC.
N.M.R. spectrum No. 127748 mass spectrum M/Z =507 (MW).
$00G.
-165- EXAMPLE 73 Preparation of methyl (3 aRS .4SR,9SR.9aRS)-4,9-ethano-9-(4-methoxyphenyfl-2- r2- (2-methoxyphenvl~hropenoyl]-2,3 .3 a,4,99a-hexahydro- 1H-benzo rflisoindole-3 acarboxylate Stage A By carrying out the reaction as in Stage A of Example 3 1, but from 11.5 g of methyl (3 aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3 acarboxylate, from 13.1 cm 3 of anisole and from 21.2 cm 3 Of trifluoromethanesuiphonic acid in 120 cm 3 of dichioromethane, 12 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-methoxyphenyl)-2 ,3 ,3a,4, 9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate are o btained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a 04 cyclohexane/ethyl acetate (70/30 by volume) mixture, the characteristic of which *0 406 O.L. 0compound is as follows: melting point 150'C.
Stage B canrying out the reaction as in Stage E of Example 1, but from 11.4 g of methyl (3 aRS ,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-methoxyphenyl)- 2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylate, from 4.76 g of 20 ammonium formate and from 1 g of 10% (wlw) palladium-on-charcoal, 9 g of methyl 00 (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2, 3,3 a,4 9a-hexahydrolH-benzo[flisoindole-3a-carboxylate are obtained, which product is used as is in the subsequent syntheses.
Stage C By carrying out the reaction as in Stage G of Example 1, but ftrm 8.9 g of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)- 2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3a-carboxylate, from 4.36 g of 2-(2-methoxyphenyl)propanoic acid, from 2.1 cm 3 of oxalyl chloride and ftrm 6.9 cm 3 of triethylamine, 0.47 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4methoxyphenyl)-2- [2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H- -166benzo[flisoindole-3a-carboxylate is obtained, after purification by flash chromatography on silica gel (230-400 mesh), eluting being carried out with a cyclohexane/ethyl acetate (50/50 by volume) mixture, in the form of a white foam, the characteristic of which is as follows: melting point EXAMPLE 74 Preparation of (3 aRS .4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenvl)-2-[2-(2methoxvphenyl~propenovll-2,3 .3 a,4,99a-hexahydro-l1H-benzo 1fl isoindole-3 acarboxylic acid By carrying out the reaction as in Example 2, but from 11 g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3 a- 0V carboxylate, from 42 cm 3 of a normal aqueous sodium hydroxide solution and from 3 of methanol, 2.15 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9- 15 (4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl] -2,3 ,3a,4,9,9a-hexahydro-l1Hbenzo[f.!isoindole-3a-carboxylic acid are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with dichioromethane/methanol (100/0 to 98/2 by volume) mixtures, the characteristic of which compound is as follows: melting point 165'C.
EXAMPLE Isolation of the dextrorotatory enantiomer of (3 aRS .4SR,9SR.9aRS)-4,9-ethano-9- (4-methoxyphenyl)-2- r2-(2-methoxyphenl)propenov1] -2.3 .3a,4,9,9a-hexahydro- 1H-, benzorflisoindole-3a-carboxylic acid 9.2 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2- [2-(2-rnethoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [f]isoindole-3 acarboxylic acid, obtained in Example 74, are resolved, on a chiral silica column carrying N-(3,5-dinitrobenzoyl)-(R)-phenylalanine grafts, in 5 successive injections and by eluting with an n-heptane/dichloromnethane/methanol (50/50/3 by volume) mixture. On collecting the first fractions eluted (retention time 42 min), 3.51 g of the -167dextrorotatory enantiomer of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9- (4-methoxyphenyl)-2- [2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro-l1Hbenzo[flisoindole-3a-carboxylic acid are obtained, after concentrating the solvent under reduced pressure, in the form of a white powder, the characteristics of which are as follows: melting point 203'C mass spectrum M/Z 509 optical rotation: [a]2 5 71.7 1.20 (c 0.5, methanol) EXAMPLE 76 Preparation of (3 aRS .4SR,9SR.9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-r2-(2methoxyphenyl)propenovl1 -2,3,3 a,4,9,9a-hexahydro- 1H-benzorflisoindole-3 a-N- (3-pyridvlmethvl)carboxamide By carrying out the reaction as in Example 42, but from 1 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3a-carboxylic acid, 0.24 cm 3 of 3-(aminomethyl)pyridine, 0.46 g of 1 -ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and 0. 16 g of N-1- hydroxybenzotriazole hydrate, *000i 0.72 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2- methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 a-N- 20 (3-pyridylmethyl)carboxamide is obtained, after crystallization from 11 cm 3 of an isopropanol/diisopropyl ether (10/90 by volume) mixture, the characteristic of which compound is as follows: melting point =121T 0 L u -168p p p
P
i 2 p.
EXAMPLE 77 Preparation of (3 aRS .4SR.9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2- r2-(2methoxyphenyl)propenoyl]-2 .3,3 a,4,9,9a-hexahydro- 1H-benzorfl]isoindole-3 a-N'phenylcarbohydrazide By carrying out the reaction as in Example 27, but from 1 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-carboxylic acid, 0.25 cm 3 of N-phenylhydrazine, 0.45 g of 1 -ethyl-3-[3 -(dimethylamino)propyl]carbodiimide hydrochloride and 0. 16 g of N- I -hydroxybenzotriazole hydrate, 0.9 g of (3aRS,4S R,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyl]-2 ,3,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-N'phenylcarbohydrazide is obtained, after crystallization from 11I cm 3 of an isopropanolldiisopropyl ether (10/90 by volume) mixture, the characteristic of which compound is as follows: 15 melting point 180'C.
EXAMPLE 78 Preparation of (3 aRS .4SR,9SR.9aRS)-4,9-ethano-9-(4-methoxvphenyl)-2-r2-(2methoxyphenvyl~propenoyl]-2,3 .3 a,4,99a-hexahydro- IH-benzorflisoindole-3 ahydroxamic acid 20 Stage A A solution of 0.83 g of O-benzylhydroxylamine and of 0.73 cm 3 of triethylamine in 10 cm 3 of dichloromethane is added to a solution of 2.2 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid, of 1 g of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and of 0.35 g of N-i -hydroxybenzotriazole hydrate in 10 cm 3 of dichioromethane. The reaction mixture is stirred for twenty-four hours at a temperature in the region of 200'C and then 15 cm 3 of distilled water are added. The organic phase is separated by settling, washed with 20 cm 3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is crystallized from 25 cm 3 of an Z4v q 0.
-169isopropanolldiisopropyl ether (20/80 by volume) mixture. 2.03 g of benzyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-i2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 hydroxamate are thus obtained in the form of a white solid, the characteristic of which is as follows: melting point 201' 0
C.
Stage B By carrying out the reaction as in Example 16, but from 1.84 g of benzyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 hydroxamate, from 1 g of aluminium chloride and from 0.98 cm 3 of anisole, 0.5 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 ahydroxamic acid is obtained, after flash chromatography on silica gel (230- :15 400 mesh), elution being carried out with a dichloromethane/methanol (90/10 by volume) mixture, in the form of an ecru solid, the characteristic of which is as follows: melting point 165'C.
EXAMPLE 79 Preparation of (3 aRS .4SR.9SR,9aRS)-4,9-ethano-9-(4-methoxyphenvyl)-2-r2-(2- ~methoxyphenylhpropenoyll-2,3 .3 a,4,99a-hexahydro- 1H-benzo [flisoindole-3 a-N'- (3 -pvridyl)carbohydrazide By carrying out the reaction as in Example 27, but from 1 g of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid, 0.26 g of N-(3 -pyridyl)hydrazine, 0.45 g of 1 -ethyl-3 -(dimethylamnino)propyl]carbodiimide hydrochloride and from 0. 16 g of N-1I-hydroxybenzotriazole hydrate, 0.6 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N'- (3-pyridyl)carbohydrazide is obtained, after purification by flash chromatography on u-I a a a a -170silica gel (230-400 mesh), elution being carried out with dichioromethane/methanol (95/5, then 90/10, by volume) mixtures, and recrystallization from isopropanol, the characteristic of which compound is as follows: melting point 180'C.
EXAMPLE Preparation of (3 aRS .4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyll -2,3,3 a,4,9,9a-hexahydro- 1H-benzo rflisoindole-3a-N- (3 -thienylmethyl)carboxamide By carrying out the reaction as in Example 42, but from 1 g of (3.aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid, 0.2 g of 3 -aminomethylthiophene, 0.45 g of 1 -ethyl-3-[3 -(dimethylamino)propyl]carbodiimide hydrochloride and 0. 16 g of N- 1 -hydroxybenzotriazole hydrate, 1 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2- 15 methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N- (3-thienylmethyl)carboxamide is obtained, after recrystallization from 11 cm 3 of an isopropanolldiisopropyl ether (10/90 by volume) mixture, the characteristic of which compound is as follows: melting point 130' C.
20 EXAMPLE 81 Preparation of (RZS)- and f3 aRS.4SR,9SR.9aRS)-4,9-ethano-9- (4 -methoxyphenyl)-2- r2-(2-methoxypheniyl)propenoyl1-2,3 .3 a,4,99a-hexahydro-lIHbenzorflisoindole-3 a-carbonylamino Iphenylacetic acids Stage A By carrying out the reaction as in Example 42, but from 1.27 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid, 0.61 g of methyl phenylglycinate hydrochloride, 0.59 g of l-ethyl-3- [3-(dimethylamino)propyl]carbodiimide hydrochloride, 0.42 cm 3 of triethylamine 0.2 g of N-1-hydroxybenzotriazole hydrate, 1 g of a mixture of methyl and
L
C)
-171- {(3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3acarbonylamino}phenylacetates is obtained, after flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol-(99/1 by volume) mixture, in the form of a foam, used as is in the subsequent syntheses.
Stage B By carrying out the reaction as in Example 2, but from 0.6 g of a mixture of methyl and {(3aRS,4SR,9SR,9aRS)-4,9-ethano-9- (4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carbonylamino}phenylacetates in 1.83 cm 3 of a normal aqueous sodium hydroxide solution and 20 cm 3 of ethanol, 0.5 g of crude product is obtained, which is combined with a second batch of 0.65 g originating from another **:experiment. The purification of this mixture, by recrystallization from 50 cm 3 of an isopropanol/diisopropyl ether (50/50 by volume) mixture, provides 1.05 g of an S 15 equimolar mixture of and {(3aRS,4SR,9SR,9aRS)-4,9-ethano-9- (4-methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carbonylamino}phenylacetic acids, the characteristics of which g are as follows: melting point 196 0
C
'H N.M.R. spectrum (250 MHz, d6-(CD 3 2 SO, at a temperature of 383 K, d in ppm). The mixture of the two diastereoisomers is observed in the proportions 50/50.
1.38, 1.60, 1.98 and 2.14 (4 mts, each 1H, CH 2
CH
2 from 3.15 to 3.80 (mt,
CH
2 at 1, IH of the CH 2 at 3, CH at 9a and CH at 3.64, 3.71 and 3.84 (3 s, 6H in all, the 2 ArOCH 3 from 4.20 to 4.45 (mt, 1H, the other H of the CH 2 at 5.19 (mt, 1H, NCHAr), 5.47, 5.51, 5.66 and 5.69 (4 broad s, 2H in all, =CH 2 6.42 (mt, 1H, H at from 6.80 to 7.50 (mt, 16H, H at 5, H at 6, H at 7, aromatic H of the 4-methoxyphenyl, aromatic H at the 2-methoxyphenyl and aromatic H of the phenyl), 7.98 and 8.02 (2 broad s, 1H in all, CONH).
EXAMPLE 82 Preparation of (3aRS.4SR,9SR,9aRS)-4,9-ethanokAw *E
C..
C
C
C.
-172- 2-F2-(2-methoxyph enylproenovl]-9-(4-trifluoromethoxyphenvl-2.33a,4.9.9ahexahydro-1H-benzorflisoindole-3a-carboxvlic acid Stage A By carrying out the reaction as in Stage C of Example 45, but from 1.51 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,a,4,5,7ahexahydroisoindole-3a-carboxylate, from 0.17 g of tetrakis(triphenylphosphine)palladium, from 0.73 g of 4-trifluoromethoxyphenylboronic acid, obtained in trimeric anhydride form by carrying out the reaction as in Patent D.E. 4,218,614, and [lacuna] 1.5 g of sodium carbonate at reflux for two hours in 15 cm 3 of toluene and 13 cm 3 of methanol, 1.2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-4-phenyl-7-(4-trifluoromethoxyphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (80/20 by volume), in the form of a pale-yellow oil, the characteristic of which is as follows: mass spectrum M/Z 507 (Me).
Stage B By carrying out the reaction as in Stage C of Example 38, but from 0.48 g of methyl (3aRS,4SR,7aRS)-2-benzyl-4-phenyl-7-(4-trifluoromethoxyphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate and from 1.18 cm of trifluoromethanesulphonic acid in 2 cm' of dichloromethane for two hours at room temperature, 0.43 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9- (4-trifluoromethoxyphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3acarboxylate is obtained, after purification by flash chromatography on silica gel (230- 40 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (90/10 by volume), in the form of a beige paste, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 507 Stage C By carrying out the reaction as in Stage B of Example 47, but from j/S~j Ii -173- 0.83 g of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-4,9-ethano-9-(4-trifluoromethoxyphenyl)-2,3,3a,4,9,9a-hexahydro-1H-isoindole-3a-carboxylate and from 0.29 cm 3 of vinyl chloroformate for eighteen hours at room temperature in 10 cm 3 of dichloromethane, and by then taking the concentrate up in 20 cm 3 of a normal solution of hydrogen chloride gas in isopropanol at reflux for one hour, 0.59 g of methyl (3aRS,4SR,9RS,9aRS)-4,9-ethano-9-(4-trifluoromethoxyphenyl)- 2,3,3a,4,9,9a-hexahydro- 1 H-benzo[fjisoindole-3a-carboxylate is obtained, after neutralization with a normal aqueous sodium hydroxide solution and then extraction with dichloromethane and concentration of the solvent under reduced pressure, in the form of a white foam, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 417 Stage D By carrying out the reaction as in Stage E of Example 5, but from 15 0.59 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-trifluoromethoxyphenyl)- 2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3a-carboxylate, from 0.25 g of2-(2methoxyphenyl)propanoic acid, from 0.2 g of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride and from 27 mg of N-i -hydroxybenzotriazole hydrate in 15 cm' of dichloromethane for eighteen hours 20 at room temperature, 0.41 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano- S: 2-[2-(2-methoxyphenyl)propenoyl]-9-(4-trifluoromethoxyphenyl)-2,3,3a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate is obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (60/40 by volume), in the form of a light-beige powder, the characteristics of which are as follows: melting point 86 0
C
mass spectrum M/Z 577 Stage E By carrying out the reaction as in Example 2, but from 0.38 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9- -174- (4-trifluoromethoxyphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3 acarboxylate at reflux for four hours in 13 cm 3 of a decinormal aqueous sodium hydroxide solution and 13 cm 3 of methanol, 200 mg of (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-trifluoromethoxyphenyl)-2 3a,4 9a-hexahydro-1H-benzo~flisoindole-3a-carboxylic acid are obtained, after purification by recrystallization from pentane, in the formn of a white solid, the characteristics of which are as follows: melting point 160'C mass spectrum M/Z 563 (MW).
EXAMPLE 83 Preparation of methyl (3 aRS .4SR,9SR,9aRS -bromophenvl)-4,9-ethano-2-r2-(2methoxynhenyl)propenoyl]-2,3 3 a.4,9,9a-hexahydro- 1H-benzo rflisoindole-3 acarboxylate Stage A By carrying out the reaction as in Stage C of Example 45, but from 11.61 g of methyl (3 aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3 ,a,4,5 ,7ahexahydroisoindole-3a-carboxylate, from 1.33 g of tetrakis(triphenylphosphine)palladium, from 5.46 g of 3 -bromophenylboronic acid, obtained in the trimeric anhydride form, and from 11.5 g of sodium carbonate at reflux for two hours in 70 c 3 of toluene and 50 cm 3 of methanol, 8.5 g of methyl (3 aRS,4SR,7aRS)-2-benzyl-7-(3 -bromophenyl)-4-phenyl-2,3 ,3 a,4,5 ,7ahexahydro- 1H-isoindole-3 a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (80/20 by volume), in the form of a paleyellow oil, the characteristic of which is as follows: mass spectrum M/Z 502 (We).
Stage B By carrying out the reaction as in Stage C of Example 38, but from 8.6 g of methyl (3 aRS,4SR,7aRS)-2-benzyl-7-(3-bromophenyl)-4-phenyl- 2,3,3a,4,5,7a-hexahydro-lH-isoindole-3a-carboxylate and from 25 cm 3 of -175trifluoromethanesulphonic acid in 25 cm 3 of dichloromethane for two hours at room temperature, 4.58 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9- (3-bromophenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3acarboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of a beige powder, the characteristics of which are as follows: melting point 74'C mass spectrum M/Z 502 Stage C By carrying out the reaction as in Stage B of Example 47, but from S1.88 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3-bromophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro- 1 H-benzo[fjisoindole-3a-carboxylate and from 0.6 cm 3 of vinyl chloroformate for two hours at room temperature in 15 cm of dichloromethane, and by then taking the concentrate up in 30 cm of a 2M solution of hydrogen chloride gas in methanol at reflux for three hours, 1.72 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3-bromophenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate hydrochloride are obtained, after crystallization from diisopropyl ether, in the form of white crystals, the characteristic of which is as 20 follows: mass spectrum M/Z 412 Stage D By carrying out the reaction as in Stage E of Example 5, but from 1.72 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3-bromophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro- 1 H-benzo[fjisoindole-3a-carboxylate hydrochloride, from 0.68 g of 2-(2-methoxyphenyl)propenoic acid, from 0.73 g of 1-ethyl-3-[3- (dimethylamino)propyl]carbodiimide hydrochloride, from 50 mg of N-1-hydroxybenzotriazole hydrate and from 0.54 cm 3 of triethylamine in 15 cm 3 of dichloromethane for eighteen hours at room temperature, 0.58 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3-bromophenyl)-4,9-ethano-2-[2-(2- -176methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 acarboxylate is obtained, after purification on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (70/30 by volume), in the form of a light-beige powder, the characteristics of which are as follows: melting point 184-5'C mass spectrum M/Z =572 *.4q -177- EXAMPLE 84 Preparation of (3 aRS,4SR,9SR,9aRS)-9-(3-bromophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyll-2,3 .3 a,4,9,99a-hexahydro-l1H--benzorflisoindole-3 a-.
carboxylic acid By carrying out the reaction as in Example 2, but from 0.50, g of methyl (3 aRS ,4SR,9SR,9aRS)-9-(3 -bromophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[f] isoindole-3 acarboxylate at reflux for four hours in 70 cm 3 of a decinormal aqueous sodium hydroxide solution and 70 cm 3 of methanol, 170 mg of (3aRS,4SR,9SR,9aRS)-9-(3-bromophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 acarboxylic acid are obtained, after purification by recrystallization from a mixture of *water and of ethanol (90/10 by volume), in the form of a white solid, the characteristics of which are as follows: 15 melting point: 164'C mass spectrum M/Z 558 (MW).
EXAMPLE Preparation of methyl (3 aRS .4SR,9SR.9aRS)-4,9-ethano-9-(3 -fluorop~henvl)-2-r2-(2methoxviphenyl)p2ropenoyl]-2,3 .3 a.4,99a-hexahydro-l1H-benzorflisoindole-3 acarboxylate Stage A By carrying out the reaction as in Stage C of Example 1, but from 2 g of magnesium turnings, from 9.1 cm' of 3-fluorobromobenzene, in 60 cm 3 of diethyl ether, then in 20 cm 3 of toluene, and then from 15 g of methyl (3aRS,4SR,7aRS)-2benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 60 cm 3 of toluene, 21.29 g of impure methyl. (3aRS,4SR,9RS,9aRS)-2-benzyl-7-(3-fluorophenyl)-7hydroxy-4-phenyloctahydroisoindole-3 a-carboxylate are obtained in the form of a brown oil, used as is in the following stage, the characteristic of which is as follows: mass spectrum (DCI): M/Z 460 Stage B -178- B y carrying out the reaction as in Stage D of Example 1, but from 21.29 g of methyl (3 aRS,4SR,9RS,9aRS)-2-benzyl-7-(3-fluorophenyl)-7-hydroxy-4 phenyloctahydroisoindole-3a-carboxylate and from 40 cm' of 99% trifluoromethanesuiphonic acid in 300 cm' of dichioromethane under an argon atmosphere for forty-three hours at a temperature in the region of 20' C, 14.38 g of impure methyl (3 aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethanio-9-(3 -fluorophenyl)- 2,3,3 a,4,9,9a-hexahydro-l1H-benzo isoindole-3 a-carboxylate are obtained in the form of a brown oil, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 441 Stage C By carrying out the reaction as in Stage E of Example 1, but from 14.38 g of methyl (3 aRS ,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3-fluorophenyl)- 2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-carboxylate, from 5.53 g of ammonium formate and from 1. 8 g of 10% palladium-on-charcoal in 200 cm 3 of methanol for sixteen hours at reflux, 10.36 g of impure methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -fluorophenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H- :benzo[flisoindole-3a-carboxyla te are obtained in the form of a brown oil, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z =351 Stage D By carrying out the reaction as in Stage G of Example 1, but from a solution of 5.66 g of 2-(2-methoxyphenyl)propenoic acid in 50 cm 3 of dicliloromethane containing 2 drops of N,N-dimethylformamide, from 2.75 cm 3 of oxalyl chloride, for two hours, from a solution of 10.36 g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -fluorophenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1Hbenzo[flisoindole-3a-carboxylate, obtained in the preceding stage, and from 7.3 cm 3 of triethylamine in 100 cm 3 of dichloromethane, 3.59 g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -fluorophenyl)- 2 -[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-lH-berizo[flisoindole- -179- 3a-carboxylate are then obtained, after crystallization from petroleum ether in the form of a beige powder, the characteristics of which are as follows: melting point 151 'C.
'H N.M.R. spectrum (250 MHz, (CD 3 2 S0, d in ppm): 1.43, 1.67, 2.00 and 2.14 (4 mts, 1H: CH 2
CH
2 from 3.30 to 3.45 (mt, 3H, CH 2 at 1 and CH at 9a), 3.46 (mt, I1H, CH at 3.54 3H, COOCH 3 3.61 and 4.09 (respectively d and d (broad), J 12.5 Hz, each IH, CH 2 at 3.71 3H, ArOCH 3 5.5 and 5.68 (2s, each 1H1, CH 2 [lacuna], 6.41 (broad d, J 7.5 Hz, 1H, H at from 6.90 to 7.40 (mt, H at 6, at 7 and aromatic H of the 3-fluorophenyl), 7.54 (broad q, J 7.5 Hz, 1H, H at 5 of the 3-fluorophenyl) mass spectrum M/Z 511 (MW).
EXAMPLE 86 Preparation of (3 aRS .4SR,9SR,9aRS)-4,9-ethano-9-(3 -fluorophenyl)-2-r2-(2methoxyvphenvl)propenoyl]-2.3,3 a,4,9,9a-hexahydro- 1H-benzorflisoindole-3 acarboxylic acid By carrying out the reaction as in Example 2, but from 1.02 g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-fluorophenyl)-2-[2-(2-methoxy- S phenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3a-carboxylate, obtained as in the preceding stage, and from 24 cm' of a normal aqueous sodium hydroxide solution in 30 cm 3 of dioxane for eighteen hours at reflux, 0.71 g of (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(3 -fluorophenyl)-2-[2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro-l1H-benzo [f]isoindole-3 a-carboxylic acid is obtained in the form of a white powder, the characteristics of which are as follows: melting point 161 'C.
mass spectrum M/Z 497 (MW).
EXAMPLE 87 Preparation of (3 aRS,4SR.9SR.9aRS)-4,9-ethano-9-(3 -fluorophenyl)-2-f2-(2methoxyphenyl~propenoyl]-2.3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N- (3 -pydvlmethyl)carboxamide By carrying out the reaction as in Example 42, but from 0.52 g of
\CZA
-1 (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -fluorophenyl)-2- [2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo isoindole-3 a-carboxylic acid, from 0.128 cm 3 of 3-(amninomethyl)pyridine, from 0.24 g of l-ethyl-3- [3-(dimethylamnino)propyl]carbodiimide hydrochloride and from 85 mg of N-1hydroxybenzotriazole hydrate in 30 cm 3 of dichioromethane, 183.6 mg of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -fluorophenyl)-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benizo(flisoindole-3 a-N- (3-pyridylmethyl)carboxamide are obtained, after sixteen hours at a temperature in the region of.20'C, in the form of an ecru powder, the characteristics of which are as follows: melting point 223'C.
mass spectrum M/Z =587 0 -181- EXAMPLE 88 Preparation of methyl (3aRS,.4SR,9SR,9aRS)-9-(3-chlorophenvl-4,9-ethano-2- methoxvphenvl)propenoyll-23 .3a.4.9,9a-hexahydro-1H-benzof flisoindole-3acarboxvlate Stage A By carrying out the reaction as in Stage C of Example 1, but from 2 g of magnesium turnings, from 9.75 cm 3 of 3-chlorobromobenzene, in 60 cm 3 of diethyl ether, then in 20 cm 3 of toluene, and then from 15 g of methyl (3aRs,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 60 cm' of toluene, 31.2 g of impure methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-(3chlorophenyl)-7-hydroxy-4-phenyloctahydroisoindole-3a-carboxylate, which are used as is in the following stage, are obtained in the form of an orange-coloured oil, the characteristic of which is as follows: mass spectrum (DCI): M/Z 476 15 Stage B By carrying out the reaction as in Stage D of Example 1, but from 31.2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(3-chlorophenyl)-7-hydroxy-4phenyloctahydroisoindole-3a-carboxylate, obtained in the preceding stage, and from cm of 99% trifluoromethanesulphonic acid in 300 cm 3 of dichloromethane under sees*: an argon atmosphere for four days at a temperature in the region of 20 0 C, 23.88 g of impure methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3-chlorophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3a-carboxylate are obtained in the form of an oil, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 457 Stage C By carrying out the reaction as in Stage B of Example 47, but from 23.88 g of impure methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3-chlorophenyl)-4,9ethano-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3a-carboxylate, from 5.4 cm 3 of vinyl chloroformate and from 11.5 g of potassium carbonate in 200 cm 3 of -182dichloromethane for sixteen hours at a temperature in the region of 20'C, 24.4 g of impure methyl (3aRS,4SR,9SR,9aRS)-9-(3-chlorophenyl)-4,9-ethano- 2-vinyloxycarbonyl-2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-carboxylate are obtained in the form of a brown oil, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 437 After taking this oil up again for eighteen hours in a 6N solution of hydrogen chloride gas in dioxane, 18.28 g of impure methyl (3aRS,4SR,9SR,9aRS)- 7-(3-chlorophenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3acarboxylate hydrochloride are obtained in the form of a thick brown oil, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 368 Stage D :5By carrying out the reaction as in Stage G of Example 1, but from a solution of 8.76 g of 2-(2-methoxyphenyl)propenoic acid in 50 cm 3 of dichloromethane containing 2 drops of N,N-dimethylformamide, from 4.21 cm of oxalyl chloride, for two hours thirty minutes, then from a solution of 18.5 g of methyl (3aRS,4SR,9SR,9aRS)-7-(3-chlorophenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate hydrochloride, obtained in the preceding stage, and from 11.5 cm 3 of triethylamine in 100 cm 3 of dichloromethane, then running in 100 cm 3 of water after forty-two hours, 0.95 g of methyl (3aRS,4SR,9SR,9aRS)-9- (3-chlorophenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9ahexahydro-1H-benzo[f]isoindole-3a-carboxylate is obtained in the form of a beige powder, the characteristics of which are as follows, the characteristics of which are as follows: melting point 159 0
C.
mass spectrum M/Z 527 EXAMPLE 89 Preparation of (3aRS,.4SR.9SR.,9aRS)-9-(3-chlorophenvl)-4,9-ethano-2-[2-(2methoxvphenvl)propenoll-2,3,3a,4,9,9a-hexahydro- 1H-benzorflisoindole-3a- -183carboxylic acid By carrying out the reaction as in Example 2, but from 795 mng of methyl (3 aRS ,4SR,9SR,9aRS)-9-(3 -chlorophenyl)-4,9-ethano-2- methoxyphenyl)propenoyl]-2 3a,4,9, 9a-hexahydro-1H-benzo[flisoindole-3acarboxylate, obtained as in the preceding stage, and from 30 cm 3 of a normal aqueous sodium hydroxide solution in 30 cm 3 of dioxane for eighteen hours at reflux, 0.77 g of (3 aRS,4SR,9SR,9aRS)-9-(3-chlorophenyl)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid is obtained in the form of a white powder, the characteristics of which are as follows: melting point 1700'C -mass spectrum M/Z 513 EXAMPLE Preparation of (3aRS .4SR,9SR. 9aRS)-9-(3-chlorophenyl)-4, 9-ethano-2- methoxyphenvl)propenoyll-2,3 .3 a,4,99a-hexahydro-l1H-benzof flisoindole-3 a-N- 15 (3-p3ridylmethyl)carboxamide By carrying out the reaction as in Example 42, but from 0.46 g of (3 aRS ,4SR,9SR,9aRS)-9-(3 -chlorophenyl)-4,9-ethano-2-12-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- IH-benzo[f]isoindole-3a-carboxylic acid, from .11cm 3 of 3 -(aminomethyl)pyridine, from 0.21 g of 1 -ethyl-3 [3 -(dimethylamino)propyl]carbodiimide hydrochloride and from 70 mg of N-i1- ':hydroxybenzotriazole hydrate in 30 c 3 of dichioromethane, 269.8 mg of (3 aRS ,4SR,9SR,9aRS)-9-(3 -chlorophenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[f]isoindole-3 a-N- (3-pyridylmethyl)carboxamide are obtained, after sixteen hours at a temperature in the region of 20TC, in the form of an off-white powder, the characteristics of which are as follows: -melting point 2440 C.
-mass spectrum M/Z 603 EXAMPLE 91 Preparation of methyl (3 aRS .4SR,9SR,9aRS)-9-(3-NN-dimethvlaminophenyl)Y4,9- -184ethano-2-[2-(2-methoxyphenvl)propenoyl -2,3,3 a,49,9,9a-hexahdro- 1 H-benzo isoindole-3a-carboxvlate Stage A By carrying out the reaction as in Stage C of Example 45, but from 2.5 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7ahexahydroisoindole-3a-carboxylate, from 0.30 g of tetrakis- (triphenylphosphine)palladium, from 0.77 g of 3-N,N-dimethylaminophenylboronic acid, obtained in the trimeric anhydride form, and from 20 cm 3 of a 2M aqueous sodium carbonate solution at reflux for seven hours in 20 cm 3 of toluene and 10 cm 3 of methanol, 2.09 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(3-N,N-dimethylaminophenyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of an orange-coloured pasty solid, used as is in the following 15 stage, the characteristic of which is as follows: mass spectrum M/Z 466 (M Stage B The reaction is carried out as in Stage B of Example 39, but from 2.09 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(3-N,N-dimethylaminophenyl)-4- 20 phenyl-2,3,3a,4,5,7a-hexahydro-lH-isoindole-3a-carboxylate and from 20 cm 3 of pure trifluoromethanesulphonic acid for four days at room temperature. After neutralization with a 30% aqueous sodium hydroxide solution in the presence of dichloromethane, the organic phase is separated by settling, then washed with water and dried over magnesium sulphate, and then stirred for one hour with 20 g of silica gel (230-400 mesh). After concentrating the solvent under reduced pressure, 1.74 g (83 of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3-N,N-dimethylaminophenyl)- 4,9-ethano-2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate are then obtained in the form of a yellow pasty solid, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 466
RA
-185- Stage C The reaction is carried out as in Stage B of Example 47, but from 2.21 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3-N,N-dimethylaminophenyl)-4,9ethano-2,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3a-carboxylate, from 3 cm 3 of vinyl chloroformate and from 4.6 cm 3 of triethylamine for seven hours at room temperature in 20 cm' of dichloromethane. After hydrolysis, the organic phase is separated by settling and then concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (85/15 by volume), 0.27 g (27 of methyl (3aRS,4SR,7aRS)-9-(3-N,N-dimethylaminophenyl)-4,9-ethano-2vinyloxycarbonyl-2,3,3a,4,9,9a-hexahydro- 1H-isoindole-3a-carboxylate is then gee.
.obtained, which product is dissolved in methanol and heated at reflux for five hours @606 in the presence of 5 cm 3 of a 5M solution of hydrogen chloride gas in dioxane. After ;;crystallization from diisopropyl ether, 0.68 g (98 of methyl (3aRS,4SR,7aRS)-9- S* 15 (3-N,N-dimethylaminophenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro-1H-isoindole-3acarboxylate dihydrochloride is thus obtained in the form of a white solid, the characteristic of which is as follows: mass spectrum M/Z 376 gee.
g ~Stage D 20 By carrying out the reaction as in Stage E of Example 5, but from 0.68 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3-N,N-dimethylaminophenyl)-4,9ethano-2,3,3a,4,9,9a-hexahydro- 1H-benzo[f]isoindole-3a-carboxylate dihydrochloride, from 0.29 g of 2-(2-methoxyphenyl)propenoic acid, from 0.38 g of l-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride, from 20 mg of N- 1-hydroxybenzotriazole hydrate and from 0.42 cm 3 of triethylamine in 15 cm 3 of dichloromethane for twenty-four hours at room temperature, 0.27 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3-N,N-dimethylaminophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3acarboxylate is obtained, after purification by flash chromatography on silica gel (230- 400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl -186acetate (70/30 by volume), and then recrystallization from pentane, in the form of a white powder, the characteristics of which are as follows: melting point mass spectrum M/Z 536 EXAMPLE 92 Preparation of (3 aRS,4SR,9SR9aRS)-9-(3 -N.N-dimethvlaminophenl)-49-ethano- 2-r2-(2-methoxvphenvl)propenoyl]-2,3 3 a4,9,9a-hexahydro-1 H-benzoflisoindole- 3a-carboxylic acid By carrying out the reaction as in Example 2, but from 0.23 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(3-N,N-dimethylaminophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3a,4,9,9a-hexahydro- 1H-benzotflisoindole-3acarboxylate at reflux for five hours in 2 cm 3 of a normal aqueous sodium hydroxide solution and 5 cm 3 of ethanol, 120 mg of (3aRS,4SR,9SR,9aRS)-9-(3-N,Ndimethylaminophenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9ahexahydro-lH-benzo[flisoindole-3a-carboxylic acid are obtained, after purification by recrystallization from a mixture of dichloromethane and of pentane (50/50 by volume), in the form of a white solid, the characteristics of which are as follows: r: melting point 194C 2 mass spectrum M/Z 522 EXAMPLE 93 Preparation of methyl (3 aRS.4SR,9SR.9aRS)-9-(3-aminophenyl)-4.9-ethano-2-f2-(2oo i 0 methoxythenylvropenovll-2,3 3 a,4.9,99a-hexahydro-1H-benzorflisoindole-3acarboxylate hydrochloride Stage
A
'0.0 25 By carrying out the reaction as in Stage C of Example 45, but from g of methyl (3aRS,4SR,7RS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7ahexahydroisoindole-3a-carboxylate, from 0.30 g of tetrakis- (triphenylphosphine)palladium, from 0.72 g of 3-aminophenylboronic acid and from cm 3 of a 2M aqueous sodium carbonate solution at reflux for seven hours in 0Aj 0 20 cm 3 of toluene and 10 cm 3 of methanol, 1.60 g of methyl -187- (3aRS,4SR,7aRS)-7-(3-aminophenyl)-2-benzyl-4-phenyl-2,3,3a,4,5,7a-hexahydro- 1H-isoindole-3a-carboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (80/20 by volume), in the form of an orange-coloured solid, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 438 Stage B The reaction is carried out as in Stage B of Example 39, but from 0.20 g (0.4 mmol) of methyl (3aRS,4SR,7aRS)-7-(3-aminophenyl)-2-benzyl-4phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate and from 5 cm 3 of pure trifluoromethanesulphonic acid for three days at room temperature. After neutralization with a 30% aqueous sodium hydroxide solution in the presence of dichloromethane, the organic phase is separated by settling, then washed with water and dried over magnesium sulphate, and then stirred for one hour with 20 g of silica gel (230-400 mesh). After concentrating the solvent under reduced pressure, 0.16 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3-aminophenyl)-2-benzyl-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate is then obtained in the form of a brown oil, used as is in the following stage, the characteristic of which is as follows: 20 mass spectrum M/Z 438 Stage C By carrying out the reaction as in Stage E of Example 45, but from 1.5 g of methyl (3aRS,4SR,9RS,9aRS)-9-(3-aminophenyl)-2-benzyl-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-isoindole-3a-carboxylate and from 0.6 g of 10% (w/w) palladium-on-charcoal in 100 cm 3 of methanol and 3.5 cm 3 of hydrogen chloride gas as a 1M solution in methanol for eight hours at 50 0 C under a hydrogen atmosphere, 1.27 g of methyl (3aRS,4SR,9RS,9aRS)-9-(3-aminophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-isoindole-3a-carboxylate dihydrochloride are obtained, after crystallization from diisopropyl ether, in the form of a white solid, the characteristics of which are as follows: rA~, -oiL -18 8mass spectrum M/Z 348 (MW).
Stage D By carrying out the reaction as in Stage G of Example 1, but from 0.74 g of methyl (3 aRS ,4SR,9SR,9aRS)-9-(3-aminophenyl)-4,9-ethano- 2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylate dihydrochioride, from 0.41 g of 2-(2-methoxyphenyl)propenoic acid, from 0.22 cm' of oxalyl chloride and from 0.76 cm 3 of triethylamine in 10 cm' of dichioromethane for twenty hours at room temperature, 0.20 g (2 of methyl (3 aRS,4SR,9SR,9aRS)-9-(3 -aminophenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3a-carboxylate hydrochloride are obtained, after purification by flash chromatography on silica gel (23 0-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (50/50 by volume), and then recrystallization from diisopropyl ether, in the form of a white powder, the characteristics of which are as follows: melting point =186TC mass spectrum M/Z 508 (MW).
EXAMPLE 94 Preparation of methyl (3aRS .4SR,9SR.9aRS)-9-(4-NN-dimethylaminophenyl)-4,9- 20 ethano-2- r2-(2-methoxyphenyl)propenoyl] -2.3,3 a,4,9,9,9a-hexahydro- 1 H-benzo rfl 20isoindole-3a-carboxylate Stage A By carrying out the reaction as in Stage C of Example 45, but from 1.15 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,a,4,5,7ahexahydroisoindole-3a-carboxylate, from 0.12 g of tetrakis- 25 (triphenylphosphine)palladium, from 0.44 g of 4-N,N-dimethylamrinophenylboronic acid and from 15 cm 3 of a 2M aqueous sodium carbonate solution at reflux for four hours in 20 cm 3 of toluene and 10 cm 3 of methanol, 0.93 g of methyl (3 aks,4SR,7aRS)-2-benzyl-7-(4-N,N-dimethylaminophenyl)-4-phenyl-2,3 ,3 a,4,5 ,7ahexahydro-1H-isoindole-3a-carboxylate is obtained, after purification by flash chromatography on silica gel (23 0-400 mesh), elution being carried out with a 0r -189mixture of cyclohexane and of ethyl acetate (80/20 by volume), in the form of an orange-coloured oil, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 466 Stage B The reaction is carried out as in Stage B of Example 39, but from 0.53 g of methyl (3aRs,4SR,7aRS)-2-benzyl-7-(4-N,N-dimethylaminophenyl)-4phenyl-2,3,3a,4,5,7a-hexahydro-lH-isoindole-3a-carboxylate and from 10 cm 3 of pure trifluoromethanesulphonic acid for two days at room temperature. After neutralization with a 30% aqueous sodium hydroxide solution in the presence of dichloromethane, the organic phase is separated by settling, then washed with water and dried over magnesium sulphate. After concentrating the solvent under reduced pressure, the residue is purified by flash chromatography on silica gel (230- 400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume). 0.34 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl- 9-(4-N,N-dimethylaminophenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carboxylate is then obtained in the form of a colourless oil, the characteristic of which is as follows: mass spectrum M/Z 466 Stage C By carrying out the reaction as in Stage E of Example 45, but from 0.34 g of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-9-(4-N,N-dimethylaminophenyl)- 4,9-ethano-2,3,3a,4,9,9a-hexahydro-1H-isoindole-3a-carboxylate and from 0.15 g of 10% palladium-on-charcoal in 20 cm 3 of methanol, 10 cm 3 of chloroform and 25 1.5 cm 3 of a 1M solution of hydrogen chloride gas in methanol for 5 hours at under a hydrogen atmosphere, 0.31 g of methyl (3aRS,4SR,9RS,9aRS)-9-(4- N,N-dimethylaminophenyl)-4,9-ethano-2,3,3 a,4,9,9a-hexahydro- 1 H-isoindole- 3a-carboxylate dihydrochloride is obtained, after crystallization from diisopropyl ether, in the form of a light-green solid, the characteristic of which is as follows: mass spectrum M/Z 376 a. a a o o o a a a a a o* a a a a a a o *oooo* oooo o oe oo *o* Ij~FL9~1 3 3;.
I L -190- Stage D By carrying out the reaction as in Stage G of Example 1, but from 0.30 g of methyl (3 aRS,4SR,9SR,9aRS)-9-(4-N,N-dimethylaminophenyl)-4,9 ethano-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylate dihydrochioride, from 0.13 g of 2-(2-methoxyphenyl)propenoic acid, from 0.07 cm 3 of oxalyl chloride and from 0.3 cm 3 of triethylamine in 5 cm 3 of dichioromethane for eighteen hours at room temperature, 0. 18 g (5 of methyl (3aRS,4SR,9SR,9aRS)- 9-4NNdmtyaiohnl-,-tan--2(-ehxpey~rpny] 2,3,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylate is obtained, after purification on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate and of a 28% ammonia solution (60/40/0.2 by volume), in the form of a white powder, the characteristics of which are as follows: -melting point 86-90'C mass spectrum M/Z =536 -191- EXAMPLE Preparation of (3aRS,4SR.9SR,9aRS)-9-(4-cvanophenyl)-4,9-ethano-2-[2-(2methoxvphenvl)propenovl]-2,3,3a,4,9,9a-hexahdro- 1H-benzorflisoindole-3acarboxvlic acid Stage A 1.15 g of tetrakis(triphenylphosphine)palladium and 5.84 g of zinc cyanide are added to a solution, maintained under an argon atmosphere, of 5.02 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(4-bromophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate, obtained in Stage B of Example 49, in 50 cm 3 of dimethylformamide, the mixture is brought to reflux for five hours and is then stirred for an additional eighteen hours at room temperature, still under an argon atmosphere. After addition of water and of ethyl acetate, the organic phase is separated by settling, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (95/5 by volume). 3.09 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(4-cyanophenyl)-4,9-ethano-2,3,3a,4,9,9ahexahydro-lH-benzo[flisoindole-3a-carboxylate are thus obtained in the form of a white powder, the characteristics of which are as follows: 20 melting point 158 0
C
'H N.M.R. spectrum (300 MHz, CDC1 3 d in ppm): 1.46, 1.70 and 2.49 (3 mts, respectively 1H, 1H and 2H, CH 2
CH
2 from 2.25 to 2.40 and 2.63 (respectively mt and d, J 10 Hz, each 1H, CH 2 at 2.31 and 3.21 (2 d, J 10 Hz, each 1H, CH 2 at 3.23 (mt, 1H, CH at 9a), 3.41 and 3.63 (2 d, J 12.5 Hz, each 1H, NCH 2 Ar), 25 3.45 (broad s, 1H, CH at 3.55 3H, COOCH 3 6.43 J 7.5 Hz, 1H, H at 8), from 6.95 to 7.80 (mts, 12H, H at 5, H at 6, H at 7, aromatic H of the 4-cyanophenyl and aromatic H of the benzyl).
mass spectrum M/Z 448 Stage B The reaction is carried out as in Stage B of Example 47, but from (iC i:; -192- 0.80 g of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-9-(4-cyanophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-isoindole-3a-carboxylate and from 1 cm 3 of vinyl chloroformate for twenty-four hours at room temperature in 20 cm 3 of dichloromethane. After hydrolysis, the organic phase is separated by settling and then concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), 0.69 g of methyl (3aRS,4SR,7aRS)-9- (4-cyanophenyl)-4,9-ethano-2-vinyloxycarbonyl-2,3,3 a,4,9,9a-hexahydro-1Hisoindole-3a-carboxylate is then obtained, which compound is dissolved in 20 cm 3 of methanol and heated at reflux for five hours in the presence of 5 cm 3 of a solution of hydrogen chloride gas in dioxane. After crystallization from diisopropyl ether, 0.62 g of methyl (3aRS,4SR,9RS,9aRS)-9-(4-cyanophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro-1H-isoindole-3a-carboxylate hydrochloride is thus obtained in the form of a white solid, the characteristic of which is as follows: mass spectrum M/Z 358 (M Stage C By carrying out the reaction as in Stage G of Example 1, but from 0.72 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4-cyanophenyl)-4,9-ethano-2,3,3a,4,9,9ahexahydro-1H-benzo[f]isoindole-3a-carboxylate hydrochloride, from 0.32 g of 20 2-(2-methoxyphenyl)propenoic acid, from 0.175 cm 3 of oxalyl chloride and from 0.55 cm 3 of triethylamine in 20 cm 3 of dichloromethane for eighteen hours at room temperature, 0.52 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4-cyanophenyl)-4,9ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carboxylate is obtained, after purification on silica gel (230- 25 400 mesh), elution being carried out with a mixture of cyclohexane and of ethyl acetate (70/30 by volume), in the form of a white powder, the characteristics of which are as follows: melting point 90-2°C mass spectrum M/Z 518 Stage D -193- By carrying out the reaction as in Example 2, but from 0.50 g of methyl (3aRS,4SR,9SR,9aRS)-9-(4-cyanophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fjisoindole-3acarboxylate at reflux for five hours in 1.1 cm of a normal aqueous sodium hydroxide solution and 20 cm 3 of ethanol, 220 mg of (3aRS,4SR,9SR,9aRS)-9-(4cyanophenyl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-2,3,3a,4,9,9ahexahydro-1H-benzo[f]isoindole-3a-carboxylic acid are obtained, after purification by flash chromatography on silica gel, elution being carried out with a gradient of mixtures of cyclohexane and of ethyl acetate (from 95/5 to 50/50 by volume), in the form of a white solid, the characteristics of which are as follows: melting point 182 0
C
mass spectrum M/Z 504 EXAMPLE 96 Preparation of methyl (3aRS,4SR.9SR.,9aRS)-9-(3-cyanophenvl)-4,9-ethano-2-r2-(2methoxvphenvl)propenovll-2,3,3a,4,99a-hexahydro- 1H-henzoFflisoindole-3acarboxylate Stage A By carrying out the reaction as in Stage A of Example 95, but from 2.69 g of methyl (3aRS,4SR9SSR,9aRS)-2-benzyl-9-(3-bromophenyl)-4,9-ethano- 20 2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3a-carboxylate, obtained in Stage B of Example 83, from 0.62 g of tetrakis(triphenylphosphine)palladium and from 3.14 g of zinc cyanide in 50 cm 3 of dimethylformamide at reflux for five hours and then for an additional eighteen hours at room temperature under an argon *9 atmosphere, 2.0 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-9-(3- 25 cyanophenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro-1H-benzo[fjisoindole-3acarboxylate are obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a mixture of cyclohexane and ethyl acetate (90/10 by volume), in the form of a white powder, the characteristics of which are as follows: melting point 88 0
C
-194mass spectrum M/Z 448 Stage B By carrying out the reaction as in Stage B of Example 47, but from g of methyl (3aRS,4SR,9RS,9aRS)-2-benzyl-9-(3-cyanophenyl)-4,9-ethano- 2,3,3a,4,9,9a-hexahydro- 1H-isoindole-3a-carboxylate and from 0.6 cm 3 of vinyl chloroformate for 4 hours at room temperature in 20 cm 3 of dichloromethane, and by then taking the concentrate up in 20 cm 3 of methanol and 10 cm 3 of a normal solution of hydrogen chloride gas in isopropanol at reflux for 2 hours, 1.22 g of methyl (3aRS,4SR,9RS,9aRS)-9-(3-cyanophenyl)-4,9-ethano-2,3,3a,4,9,9a-hexahydro-
IH-
isoindole-3a-carboxylate are obtained, after neutralization with a 5N aqueous sodium hydroxide solution and extraction with diethyl ether, in the form of a white foam, used as is in the following stage, the characteristic of which is as follows: mass spectrum M/Z 358 Stage C By carrying out the reaction as in Stage G of Example 1, but from 1.22 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3-cyanophenyl)-4,9-ethano-2,3,3a,4,9,9ahexahydro-1 H-benzo[fjisoindole-3a-carboxylate hydrochloride, from 0.61 g of 2-(2methoxyphenyl)propenoic acid, from 0.3 cm 3 of oxalyl chloride and from 0.96 cm of triethylamine in 25 cm 3 of dichloromethane for 2 hours at room temperature, 0.75 g of methyl (3aRS,4SR,9SR,9aRS)-9-(3-cyanophenyl)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-2,3,3a,4,9,9a-hexahydro- 1H-benzo[fJisoindole-3acarboxylate is obtained, after purification on silica gel (230-400 mesh), elution being carried out with mixtures of cyclohexane and of ethyl acetate (95/5, then 80/20, by volume), in the form of a white powder, the characteristics of which are as follows: melting point= 176-8 0
C
mass spectrum M/Z 518 EXAMPLE 97 Preparation of (3aRS,.4SR.9SR9aRS)-4,9-ethano-9-(3-hydroxy-4-methoxyphenl)-2r2-(2-methoxvphenvl)propenol]-23, 3a,4.9,9a-hexahydro- 1H-benzorflisoindole-3acarboxvlic acid 3~~JAik -195- Stage A By carrying out the reaction as in Stage E of Example 1, but from 3.1 g of a mixture of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(3hydroxy-4-methoxyphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 acarboxylate and of methyl (3 aRS ,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4hydroxy-3 -methoxyphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [fjisoindole-3 acarboxylate, obtained in Stage B of Example 70, from 1.25 g of ammonium formate and from 0.4 g of 10% palladium-on-charcoal, 2.1 g of a mixture of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(3-hydroxy-4-methoxyphenyl)-2,3 ,3 a,4,9,9ahexahydro-l1H-benzo [flisoindole-3 a-carboxylate and of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-hydroxy-3 -methoxyphenyl)-2,3 ,3 a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylate are obtained in the form of a colourless oil, used as is in the subsequent syntheses.
Stage B By carrying out the reaction as in Stage G of Example 1, but from 2.1 g of a mixture of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-9-(3 -hydroxy-4methoxyphenyl)-2,3 ,3a,4,9,9a-hexahydro- 1H-benzo(flisoindole-3 a-carboxylate and of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-hydroxy-3 -methoxyphenyl)- 20 2,3,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylate, from 1.0 g of 2-(2methoxyphenyl)propenoic acid, from 0.47 cm' of oxalyl chloride and from 1.5 cm of triethylamine, 0.4 g of methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-hydroxy-4methoxyphenyl)-.2-[2-(2-methoxyphenyl)propenoyll-2,3 ,3 a,4,9,9a-hexahydro- 1Hbenzo[flisoindole-3 a-carboxylate, containing 5% of methyl. (3 aRS,4SR,9SR,9aRS)- 4,9-ethano-9-(4-hydroxy-3 -methoxyphenyl)-2-[2-(2-methoxyphenyl)propenoyl]- 25 2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylate, is obtained, after three flash chromatography operations on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol (96.5/3.5 by volume) mixture for the first, a dichloromethane/methanol (99/1 by volume) mixture for the second and a dichioromethane/methanol (99.5/0.5 by volume) mixture for the third, and after ~L 20recrystallization from 25 cm' of acetonitrile, the characteristic of which compound is -196as follows: melting point 242 C.
Stage C By carrying out the reaction as in Example 2, but from 0.35 g of methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(3 -hydroxy-4-methoxyphenyl)-2-[2-(2methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 acarboxylate, from 3.25 cm 3 of a normal aqueous sodium hydroxide solution and [lacuna] 5 cm 3 of methanol, 0.24 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3hydroxy-4-methoxyphenyl)-2- [2-(2-methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9ahexahydro-1H-benzo[flisoindole-3a-carboxylic acid is obtained, after recrystallization from 6 cm 3 of isopropanol, the characteristics of which compound are as follows: melting point 278 0
C.
'H N.M.R. spectrum (250 M4Hz, d6-(CD 3 2 S0, at a temperature of 383 K, d in ppm): 1. 38, 1.5 6, 1.96 and 2.12 (4 mits, each 1 H, CH 2 CHA) from 3.20 to 3.50 (mt, 3H, CH 2 at 1 and CH at 9a), 3.42 (mt, 1H: CH at 3.59 and 4.06 (respectively d and d (broad), J 12.5 Hz, each 1H, CH 2 at 3.73 and 3.86 (2 s, each 3H, the two ArOCH 3 5.54 and 5.69 (respectively d and s (broad), J 1 Hz, each 1H, =CH 2 6.52 ::(broad d, J 7.5 Hz, 1H, H at 6.73 (dd, J 8 and 2 Hz, IlH, H at the 6 position of 20 the 3-hydroxy-4-methoxyphenyl), 6.86 J 2 Hz, 1H, H at the 2 position of the 3hydroxy-4-methoxyphenyl), from 6.90 to 7.40 (mt, 8H, H at 5, H at 6, H at 7, H at the 5 position of the 3-hydroxy-4-methoxyphenyl and aromatic H of the 2methoxyphenyl), from 8.20 to 8.90 (broad unresolved peak, 1H, ArOH).
EXAMPLE 98 25 Preparation of methyl. (3aRS,4SR,9SR.9aRS)-4,9-ethano-5-methoxv-2-r2-(2methoxyphenyl)-2-propenoyl] -9-(4-methvlphenyl)-2,3 .3 a.4,99a-hexahydro- 1Hbenzorflisoindole-3 a-carboxylate Stage A 77.5 g (1.1I mol) of methyl vinyl ketone and 1. 1 din 3 of a normal aqueous sodium hydroxide solution are successively added to a solution, cooled to -197- 0 C, of 178 g (0.917 mol) of(2-methoxyphenyl)pyruvic acid, which can be obtained according to Org. Synth., 1939, 19, 1-3, in 970 cm 3 of methanol and then the mixture is stirred at a temperature in the region of 20 0 C for two hours. After neutralization with 1.1 dm 3 of a normal aqueous hydrochloric acid solution and concentration of the methanol, the precipitate formed is filtered off, washed with water and then dried at C. 189.7 g of 6-(2-methoxyphenyl)-3-oxocyclohexan-l-ol-l-carboxylic acid are thus obtained in the form of a yellow powder, the characteristics of which are as follows: melting point 204°C 'H N.M.R. spectrum (250 MHz, CDCl 3 d in ppm): 1.20 J 7 Hz, 3H, CH 3 of the ethyl), 1.47 J 7 Hz, 3H, CH 3 4.17 J 7 Hz, 2H, OCH 2 of the ethyl), 4.49 J 7 Hz, 1H, ArCH), from 7.15 to 7.45 (mt, 5H, aromatic H).
Stage B 396.7 g (1.5 mol) of 6-(2-methoxyphenyl)-3-oxocyclohexan-l-ol-1carboxylic acid are heated at reflux for two hours in 13.3 dm 3 of toluene in the presence of 39.7 g ofpara-toluenesulphonic acid. The reaction mixture is subsequently concentrated under reduced pressure and the precipitate formed is filtered off, washed with isopropyl ether and then dried at 50 0 C. 288 g of (RS)-6-(2-methoxyphenyl)-3-oxocyclohexene-1-carboxylic acid are thus obtained in 20 the form of a brown solid, the characteristics of which are as follows: melting point 177'C mass spectrum M/Z 246 'H N.M.R. spectrum (300 MHz, CDC1 3 d in ppm): from 2.10 to 2.50 (mt, 4H,
CH
2
CH
2 3.70 3H, COOCH 3 3.90 3H, ArOCH 3 4.61 (mt, 1H, ArCH), from 25 6.80 to 7.00 and 7.25 (2 mts, 5H in whole, =CH and aromatic H).
Stage C 235 g (1.66 mol) of methyl iodide and 212 g (1.39 mol) of 1,8diazabicyclo[5.4.0]undec-7-ene, dropwise, are successively added to a solution of 288 g (1.17 mol) of (RS)-6-(2-methoxyphenyl)-3-oxocyclohexene- -carboxylic acid in 2.5 dm 3 of acetone and then the mixture is brought to reflux for one hour. The -198acetone is subsequently concentrated and then the residue is stirred with 1 dm 3 of water. After cooling to 10 0 C, the precipitate formed is filtered off, washed with petroleum ether and then dried at 50 0 C. 289 g of methyl methoxyphenyl)-3-oxocyclohexene-1-carboxylate are thus obtained in the form of a mustard-coloured powder, the characteristics of which are as follows: melting point 76°C mass spectrum M/Z 260 Stage D A solution of 6 g (0.023 mol) of methyl (RS)-6-(2-methoxyphenyl)-3oxocyclohexene-1-carboxylate and of 0.3 cm 3 of trifluoroacetic acid in 185 cm 3 of dichloromethane is brought to reflux. 7.7 g (0.0275 mol) ofN-n-butoxymethyl-N- (trimethylsilylmethyl)benzylamine, which can be obtained according to Chem.
Pharm. Bull., 1985, 276, are then added dropwise and the mixture is brought to reflux for three hours. The reaction mixture is then cooled to 20°C. After stirring for one hour with approximately 5 g of potassium carbonate, the organic phase is concentrated and the yellow oil obtained is purified by chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture. 6.1 g of methyl (3aRS,4SR,7aRS)-2-benzyl-4-(2- S methoxyphenyl)-7-oxooctahydroisoindole-3a-carboxylate are then obtained in the 20 form of a yellow oil, the characteristics of which are as follows: mass spectrum M/Z 393 Stage E A solution of 166.6 g (0.424 mol) of methyl (3aRS,4SR,7aRS)-2benzyl-4-(2-methoxyphenyl)-7-oxo-octahydroisoindole-3a-carboxylate and of 84.5 g 25 (1.69 mol) of hydrazine hydrate in 2.8 dm 3 of methanol is brought to reflux for two hours. After concentrating the methanol under reduced pressure, the residue is taken up in 2 dm 3 of dichloromethane, washed with four times 1 dm 3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure.
175.2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-(2methoxyphenyl)octahydroisoindole-3a-carboxylate are thus obtained in the form of a ^si -199yellow oil, the characteristics of which are as follows: mass spectrum M/Z 407 Stage F 106.1 g (0.418 mol) of iodine in 1.1 dm 3 of tetrahydrofuran are added dropwise to a solution of 85 g (0.209 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7hydrazono-4-(2-methoxyphenyl)octahydroisoindole-3a-carboxylate in 2 dm 3 of tetrahydrofuran. After addition of 2 dm 3 of ethyl acetate, the organic phases are washed with two times 1 dm 3 of a saturated aqueous sodium hydrogencarbonate solution, washed with two times 1 dm 3 of a saturated aqueous sodium thiosulphate solution, then dried over magnesium sulphate and concentrated under reduced pressure. After purification by chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture, 51 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-(2-methoxyphenyl)- 1,2,3,4,5,7a-hexahydro-isoindole-3a-carboxylate are obtained in the form of a brown oil, the characteristics of which are as follows: mass spectrum M/Z 503 Stage G A solution of 0.41 g (2.99 mmol) of 4-methylphenylboronic acid in 13 cm 3 of methanol and 30 cm 3 of a 2N aqueous sodium carbonate solution are successively added to a solution of 1.37 g (2.7 mmol) of methyl (3aRS,4SR,7aRS)-2benzyl-7-iodo-4-(2-methoxyphenyl)-1,2,3,4,5,7a-hexahydro-isoindole-3acarboxylate and of 0.15 g (0.13 mmol) of tetrakis(triphenylphosphine)palladium in 30 cm 3 of toluene and then the mixture is brought to reflux for two hours. After returning to a temperature in the region of 20C, the reaction mixture is extracted 25 with 100 cm 3 of ethyl acetate, washed with two times 50 cm 3 of distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The brown residue obtained is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture. 1.2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-4-(2-methoxyphenyl)-7- (4-methylphenyl)-1,2,3,4,5,7a-hexahydro-isoindole-3a-carboxylate are thus obtained
SC-
-0 7 -200in the form of a yellow oil, the characteristics of which are as follows: mass spectrum M/Z 467 Stage H 94 cm 3 of trifluoromethanesulphonic acid are added dropwise to a solution of 66.4 g (0.142 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-4-(2methoxyphenyl)-7-(4-methylphenyl)- 1,2,3,4,5,7a-hexahydro-isoindole-3acarboxylate in 750 cm 3 of dichloromethane maintained at a temperature in the region of 0C. The reaction mixture is stirred for three hours at a temperature in the region of 20 0 C and then cooled to a temperature in the region of OC. 700 cm 3 of a saturated aqueous potassium carbonate solution are then added. The organic phase is separated by settling, washed successively with three times 150 cm 3 of distilled water and with two times 100 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After washing with diisopropyl ether, 54.9 g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9- 15 ethano-5-methoxy-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carboxylate are thus obtained in the form of an off-white solid, the characteristics of which are as follows: melting point 129 0
C
'H N.M.R. spectrum (250 MHz, CDC1 3 d in ppm): 1.41, 1.73 and from 2.40 20 to 2.60 (3 mts, respectively 1H, 1H and 2H, CH 2
CH
2 from 2.30 to 2.40 (mt, 2H, 1H of the CH 2 at 1 and 1H of the CH 2 at 2.39 3H, ArCH 3 2.75 (broad d, J= Hz, 1H, the other H of the CH 2 at 3.23 J 9.5 Hz, 1H, the other H of the
CH
2 at 3.26 (mt, 1H, CH at 9a), 3.41 and 3.65 (2 d, J 12.5 Hz, each 1H,
NCH
2 Ar), 3.55 3H, COOCH 3 3.81 3H, ArOCH 3 3.96 (mt, 1H, CH at 4), 6.21 J 7.5 Hz, 1H, H at 6.71 J 7.5 Hz, 1H, H at 6.99 J 7.5 Hz, 1H, H at from 7.15 to 7.40 (mt, 9H, aromatic H of the 4-methylphenyl and aromatic H of the benzyl).
Stage I From 0.54 g (1.1 mmol) of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl- 4,9-ethano-5-methoxy-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H- -201benzo[f]isoindole-3a-carboxylate in solution in 100 cm 3 of methanol and in the presence of 54 mg of 10% palladium-on-charcoal, 0.5 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-5-methoxy-9-(4-methylphenyl)-2,3,3a,4,9,9ahexahydro-1H-benzo[fjisoindole-3a-carboxylate hydrochioride is obtained, after stirring for one hour under hydrogen at atmospheric pressure and at 40 0 C, filtering off the catalyst and concentrating to dryness under reduced pressure, in the form of a beige solid, the characteristics of which are as follows: melting point 260°C IR spectrum (KBr): 3050-2250 cm-' n N'H n CH, aromatic and aliphatic 2833 cm-' n CH, OCH 3 1738 cm-' n C=O, methyl ester 1603, 1584, 1514, 1477 cm' breathing of the aromatic nuclei 1258 cm-' n O-C=O, methyl ester, na C-O, ether 15 824 cm-' g CH, para-disubstituted phenyl aromatic 776, 755 cm-' g CH, trisubstituted phenyl aromatic Stage J A solution of 0.058 cm 3 of oxalyl chloride in 5 cm 3 of 20 dichloromethane is added dropwise to a solution of 0.12 g of :2-(2-methoxyphenyl)propenoic acid in 5 cm 3 of dichloromethane containing 3 drops of N,N-dimethylformamide. The reaction mixture is stirred for a further two hours at a temperature in the region of 20 0 C, then cooled to a temperature in the region of 0°C and run dropwise into a solution of 0.25 g of methyl (3aRS,4SR,9SR,9aRS)-4,9ethano-5-methoxy-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate hydrochloride in 7 cm 3 of dichloromethane and 0.19 cm 3 of triethylamine, the temperature being maintained in the region of 0°C. The reaction mixture is stirred for a further one hour at a temperature in the region of 00C and then at 20 0 C overnight, and poured into 15 cm 3 of distilled water. The organic phase is separated by settling, washed with two times 15 cm 3 of distilled water and then
/AVAI
r 1- -202cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (70/30 by volume) mixture, 0.17 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-5-methoxy-2-[2-(2-methoxyphenyl)propenoyl]-9- (4-methylphenyl)-2,3,3a,4,9,9a-hexahydro- 1H-benzo[f]isoindole-3a-carboxylate is obtained in the form of a white solid, the characteristics of which are as follows: melting point 185 0
C
mass spectrum M/Z 537 EXAMPLE 99 :Preparation of (3aRS,4SR.9SR.9aRS)-4,9-ethano-5-methoxy-2-r2-(2methoxvphenvl)propenovl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-lH- :benzo[flisoindole-3a-carboxylic acid 0.365 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-5-methoxy-2-[2- 15 (2-methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-lHbenzo[f]isoindole-3a-carboxylate are heated at reflux for three hours in 30 cm 3 of ethanol in the presence of 0.82 cm 3 of a normal aqueous sodium hydroxide solution.
The reaction mixture is subsequently concentrated under reduced pressure and the residue dissolved in 10 cm 3 of distilled water. The aqueous phase is washed with two 20 times 10 cm 3 of dichloromethane, acidified with a normal aqueous hydrochloric acid Ssolution to a pH in the region of 2, extracted with 30 cm 3 of dichloromethane, washed with distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The orange solid obtained is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a dichloromethane/methanol/acetic acid (98/1.5/0.5 by volume) mixture. 0.09 g (26%) of (3aRS,4SR,9SR,9aRS)-4,9-ethano-5-methoxy-2-[2-(2methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3,3a,4,9,9a-hexahydro-1Hbenzo[fjisoindole-3a-carboxylic acid is thus obtained in the form of a white solid, the characteristics of which are as follows: 9 melting point 260°C -203- 1 H N.M.R. spectrum (250 MHz, d6-(CD 3 2 S0, at a temperature of 383 K, d in ppm): 1.32, 1.60 and from 1.85 to 2.20 (3 mnts, respectively 1H, 1H and 2H1,
CH
2
CH
2 2.38 3H, ArCHA) 3.34 (mnt, 3H, CH 2 at 1 and CH at 9a), 3.62 and 4.04 (2 d, J 12.5 Hz, each 1H, CH 2 at 3.72 and 3.81 (2 s, each 3H, ArOCH 3 3.93 (mt, I1H, CH at 5.5 2 and 5.66 (2 broad s, each IlH, =CH 2 6.06 J 7.5 Hz, I1H, H at 6.82 J 7.5 Hz, 1H, H at from 6.90 to 7.10 (mnt, 3H1, H at 7 and 2 aromatic H of the 2-methoxyphenyl), from 7.20 to 7.40 (mnt, 6H, 2 aromatic H of the 2-methoxyphenyl and aromatic H of the 4-methoxyphenyl).
EXAMPLE 100 Isolation of the dextrorotatory enantiomer of (3 aRS .4SR,9SR.9aRS)-4,9-ethano- 5-methoxy-2- r2-(2-methoxyphenyl)-2-propenoyl]-9-(4-methylphenlyl)-2.3,3 a,4.9.9a- OVhexahydro- 1H-benzorflisoindole-3a-carboxylic acid :00: 6.5 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-5-methoxy-2-[2-(2methoxyphenyl)propenoyl]-9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H- :15 benzo[flisoindole-3a-carboxylic acid, obtained in Example 99, are resolved, on a chiral silica colun carrying N-(3 ,5 -dinitrobenzoyl)-(R)-phenylalanine grafts, in 4 successive injections and by eluting with an n-heptane/dichloromethane/ethanol (50/50/1 by volume) mixture. On collecting the first fractions eluted (retention time min), 2.81 g of the dextrorotatory enantiomer of (3aRS,4SR,9SR,9aRS)-4,9- 20 ethano-5 -methoxy-2-[2-(2-methoxyphenyl)propenoyl] -9-(4-methylphenyl)- 2,3,3 a,4,9,9a-hexahydro- IH-benzo[flisoindole-3 a-carboxylic acid are obtained, after concentrating the. solvent under reduced pressure, in the form of a white powder, the characteristics of which are as follows: mass spectrum M/Z 523 optical rotation: [a]'0 5 36.5 1 (c 0.5, dichloromethane) EXAMPLE 101 Preparation of (3 aRS .4SR.9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenvl)-2prop enoyl] -9-(4-methoxyphenvyl)-4-methyl-2,33 3a,4,9,9a-hexahydro- 1 Hbenzorflisoindole-3a-carboxylic acid Stage A -204- A 1.6 N solution ofn-butyllithium in hexane is run dropwise into a solution, cooled to the region of-70 0 C, of 33 g (0.220 mol) of(RS)-2phenylpropionic acid in 220 cm 3 of tetrahydrofuran and of 44 cm 3 of N,N'-tetramethylethylenediamine. After having stirred the reaction mixture for three hours at -70 0 C, the reaction mixture is returned to a temperature in the region of 0 C and the solution obtained is run into a solution of 75 cm 3 (0.55 mol) of ethyl oxalate in 110 cm 3 of tetrahydrofuran, the temperature being maintained at -75 C, for 1 hour. The reaction mixture is hydrolysed with 800 cm 3 of a saturated aqueous sodium hydrogencarbonate solution, extracted with three times 100 cm 3 of ethyl acetate, washed with three times 50 cm 3 of a normal aqueous hydrochloric acid solution, dried over sodium sulphate and concentrated under reduced pressure. 44 g of ethyl (RS)-2-oxo-3-phenylbutyrate are then obtained in the form of an orange oil, the characteristics of which are as follows: 'H N.M.R. spectrum (250 MHz, CDC1 3 d in ppm): 1.20 J 7 Hz, 3H, CH 3 S: 15 of the ethyl), 1.47 J 7 Hz, 3H, CH 3 4.17 J 7 Hz, 2H, OCH 2 of the ethyl), 4.49 J 7 Hz, 1H, ArCH), from 7.15 to 7.45 (mt, 5H, aromatic H).
Stage B 3.5 cm 3 (39 mmol) of methyl vinyl ketone and 72 cm 3 (71.5 mmol) of a normal aqueous sodium hydroxide solution are successively added to a solution, cooled to the region of 7°C, of 6.7 g (32.5 mmol) of ethyl (RS)-2-oxo-3phenylbutyrate in 68 cm 3 of ethanol and then the reaction mixture is stirred at a temperature in the region of 20 C for two hours. The reaction mixture is cooled to C and 72 cm 3 of a normal aqueous hydrochloric acid solution are added. After concentrating the ethanol, the precipitate formed is filtered off, washed with water and then dried at 50°C. 4.4 g of(1RS,2RS)-2-methyl-5-oxo- 2-phenylcyclohexan-1 -ol-1 -carboxylic acid are thus obtained in the form of a beige powder, the characteristics of which are as follows: 'H N.M.R. spectrum (300 MHz, CDC1 3 d in ppm): 1.79 3H, CH 3 from 2.00 to 2.25 and from 2.25 to 2.55 (2 mts, each 2H, CH 2
CH
2 3.59 3H,
COOCH
3 6.72 1H, from 7.15 to 7.35 (mt, 5H, aromatic H).
iT\ 3^/i~ -205- Stage C 4.4 g (17.6 mmol) of(1RS,2RS)-2-methyl-5-oxo- 2-phenylcyclohexan-l-ol-l-carboxylic acid are heated at reflux for one hour in 100 cm 3 of toluene in the presence of 0.34 g of para-toluenesulphonic acid. The reaction mixture is cooled to 0 0 C and the precipitate formed is filtered off, washed with ethyl ether and then dried at 50 0 C. 2.8 g of (RS)-2-methyl-5-oxo-2phenylcyclohexene- 1-carboxylic acid are thus obtained in the form of a pink solid, the characteristics of which are as follows: melting point 206°C mass spectrum M/Z 230 Stage D 0.88 cm 3 (14 mmol) of methyl iodide and 1.8 cm 3 (12 mmol) of 1,8diazabicyclo[5.4.0]undec-7-ene, dropwise, are successively added to a solution of 2.3 g (10 mmol) of (RS)-2-methyl-5-oxo-2-phenylcyclohexene-1-carboxylic acid in
CM.
15 20 cm 3 of acetone. The reaction mixture is subsequently heated at reflux for two hours. The acetone is subsequently concentrated, the residue is then stirred with 100 cm 3 of water and then extracted with three times 30 cm 3 of ethyl acetate. After drying over magnesium sulphate and concentrating under reduced pressure, 2.3 g of methyl (RS)-2-methyl-5-oxo-2-phenylcyclohexene- -carboxylate are obtained in the form of an orange oil, the characteristic of which is as follows: mass spectrum M/Z 244 Stage E A solution of 18.3 g (0.075 mol) of methyl 2-phenylcyclohexene-l-carboxylate and of 0.57 cm 3 of trifluoroacetic acid in 145 cm 3 of dichloromethane is brought to reflux. 31.4 g (0.112 mol) of N-n-butoxymethyl-N-(trimethylsilylmethyl)benzylamine, which can be obtained according to Chem. Pharm. Bull., 1985, 276, are then added dropwise and the reaction mixture is brought to reflux for four hours. The reaction mixture is then cooled to 20 0 C. After stirring for one hour with approximately 15 g of potassium carbonate, the organic phase is concentrated and the oil obtained is crystallized from $T ^C) -206pentane. After filtration, 19 g of methyl (3aRS,4SR,7aRS)-2-benzyl-4-methyl- 7-oxo-4-phenyloctahydroisoindole-3a-carboxylate are obtained in the form of a yellow solid, the characteristics of which are as follows: melting point 115 C mass spectrum M/Z 377 Stage F A solution of 3 g (7.95 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl- 4-methyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate and of 1.55 cm 3 (31.8 mmol) of hydrazine hydrate in 30 cm 3 of methanol is brought to reflux for two hours. After concentrating the methanol under reduced pressure, the residue is taken up in dichloromethane, washed with three times 30 cm 3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. 2.8 g of methyl o (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-methyl-4-phenyloctahydroisoindole-3a- :o carboxylate are thus obtained in the form of a brown oil, the characteristics of which 15 are as follows: S 'H N.M.R. spectrum (300 MHz, CDCI 3 d in ppm): 1.33 3H, CH 3 1.86, 2.24, 2.48 and 2.84 (4 mts, each 1H, CH 2 at 5 and CH 2 at 2.43 and 3.47 (2 d, :J 9 Hz, each 1H, CH 2 at 2.67 and 3.19 (2 t, J 8.5 Hz, each 1H, CH 2 at 3.10 3H, COOCH 3 3.53 and 3.71 (2 d, J 13 Hz, each 1H, NCH 2 Ar), 3.78 J 20 8.5 Hz, 1H, H at 7a), 4.98 (broad s, 2H, NH 2 from 7.10 to 7.35 (mt, 10H, aromatic H of the phenyl and aromatic H of the benzyl).
Stage G 2.95 cm 3 of triethylamine are added to a solution of 2.8 g (7 mmol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-methyl- 4-phenyloctahydroisoindole-3a-carboxylate in 80 cm 3 of tetrahydrofuran and a solution of 3.6 g (14.1 mmol) of iodine in 40 cm 3 of tetrahydrofuran is run in dropwise. After addition of ethyl acetate, the organic phases are washed with two times 50 cm 3 of a saturated aqueous sodium hydrogencarbonate solution, washed with two times 50 cm 3 of a saturated aqueous sodium thiosulphate solution, then dried over magnesium sulphate and concentrated under reduced pressure. After -207purification by chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (85/15 by volume) mixture, 2.4 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-(2-methoxyphenyl)-1,2,3,4,5,7ahexahydro-isoindole-3a-carboxylate are obtained in the form of a yellow oil, the characteristic of which is as follows: mass spectrum M/Z 487 Stage H A solution of 20.1 g (0.132 mol) of 4-methoxyphenylboronic acid in 580 cm 3 of methanol and 1170 cm 3 of a 2N aqueous sodium carbonate solution are successively added to a solution of 58.6 g (0.12 mol) of methyl (3aRS,4SR,7aRS)-2benzyl-7-iodo-4-(2-methoxy-phenyl)-1,2,3,4,5,7a-hexahydro-isoindole-3acarboxylate and of 7 g of tetrakis(triphenylphosphine)palladium in 30 cm 3 of toluene *o and then the mixture is brought to reflux for twenty-four hours. After returning to a temperature in the region of 20 0 C, the reaction mixture is extracted with ethyl 15 acetate, washed with distilled water, dried over magnesium sulphate and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (98/02 by volume) mixture. 29 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4-methoxyphenyl)-4-methyl-4-phenyl- 1,2,3,4,5,7a- 20 hexahydro-isoindole-3a-carboxylate are thus obtained in the form of a brown *0 powder, the characteristics of which are as follows: melting point 132°C 'H N.M.R. spectrum (250 MHz, CDC1 3 d in ppm): 1.60 3H, CH 3 at 4), 2.03 (dd, J 9 and 5 Hz, 1H, 1H of the CH 2 at from 2.40 to 2.90 (mt, 1H, the other H of the CH 2 at 3.56 3H, COOCH,), from 3.40 to 3.95 (mt, 2H,
NCH
2 Ar), 3.79 (mt, 1H, CH at 7a), 3.83 3H, ArOCH 3 6.08 (mt, 1H, =CH at 6), from 6.75 to 7.45 (mt, 14H, aromatic H of the 4-methoxyphenyl, aromatic H of the benzyl and aromatic H of the phenyl).
Stage I 105 cm 3 of trifluoromethanesulphonic acid are added dropwise to a -208solution of 54.7 g (0.117 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4methoxyphenyl)-4-methyl-4-phenyl- 1,2,3,4,5,7a-hexahydro-isoindole-3a-carboxylate in 700 cm 3 of dichloromethane maintained at a temperature in the region of 5 C. The reaction mixture is stirred for three hours at a temperature in the region of 20 0 C and then cooled to a temperature in the region of OC. 100 cm 3 of a 10N aqueous sodium hydroxide solution are then added. The organic phase is separated, washed successively with three times 100 cm 3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. After washing in petroleum ether, g of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl-4,9-ethano-9-(4-methoxyphenyl)-4-methyl-2,3,3a,4,9,9a-hexahydro-lH-benzo[f]isoindole-3a-carboxylate are thus obtained in the form of a grey solid, the characteristics of which are as follows: melting point 143°C 'H N.M.R. spectrum (400 MHz, CDC13, d in ppm): 1.21, 1.79, 2.36 and 2.53 (4 mts, each 1H, CH 2
CH
2 1.41 3H, CH 3 2.37 and 2.55 (2 mts, each 1H, CH 2 at 15 2.74 and 3.14 (2 d, J 10Hz, each 1H, CH 2 at 3.19 (mt, 1H, CH at 9a), 3.44 3H, COOCH 3 3.47 and 3.61 (2 d, J 13 Hz, each 1H, NCH 2 Ar), 3.86 3H, ArOCH 3 6.59 J 7.5 Hz, 1H, H at 6.96 (broad d, J 7.5 Hz, 2H, aromatic H at the ortho positions with respect to the OCH 3 from 7.05 to 7.25 (mt, 3H, H at 5, H at 6 and H at from 7.25 to 7.45 (mt, 7H, aromatic H at the meta positions with 20 respect to the OCH 3 and aromatic H of the benzyl).
Stage J From 13 g (0.028 mol) of methyl (3aRS,4SR,9SR,9aRS)-2-benzyl- 4,9-ethano-9-(4-methoxyphenyl)-4-methyl-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate in solution in 260 cm 3 of methanol, and in the presence of 1.7 g of 10% palladium-on-charcoal, 10.2 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-4-methyl-2,3,3a,4,9,9ahexahydro-lH-benzo[f]isoindole-3a-carboxylate hydrochloride are obtained, after stirring for four hours under hydrogen at atmospheric pressure and at 40'C, filtering off the catalyst and concentrating to dryness under reduced pressure, in the form of a yellow solid, the characteristics of which are as follows: -209- IR spectrum (KBr) 3050-2250 cm n N'H n CH, aromatic and aliphatic 2842 cm-' n CH, OCH 3 1737 cm-' n C=O, methyl ester 1611, 1571, 1516, 1460 cm-' breathing of the aromatic nuclei 1253 cm-' n O-C=O, methyl ester, na C-O, ether 825 cm-' g CH, para-disubstituted phenyl aromatic 768 cm-' g CH, ortho-disubstituted phenyl aromatic Stage K A solution of 3.1 cm 3 of oxalyl chloride in 50 cm 3 of dichloromethane is added dropwise to a solution of 4.62 g (0.026 mol) of 2-(2-methoxyphenyl)propenoic acid in 100 cm 3 of dichloromethane containing 2 drops of N,N- 15 dimethylformamide. The reaction mixture is stirred for a further two hours at a temperature in the region of 20°C, then cooled to a temperature in the region of 0OC and run dropwise into a solution of 8.3 g (0.024 mol) of methyl :::(3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-4-methyl-2,3,a,4,9,9ahexahydro-lH-benzo[f]isoindole-3a-carboxylate hydrochloride in 100 cm 3 of 20 dichloromethane and 6.1 cm 3 of triethylamine, the temperature being maintained in the region of 0°C. The reaction mixture is stirred for a further one hour at a temperature in the region of 0C and then overnight at 20°C. After washing with two times 100 cm 3 of distilled water, the organic phase is separated by settling, washed successively with two times 100 cm 3 of a normal aqueous hydrochloric acid solution and with two times 100 cm 3 of a normal aqueous sodium hydroxide solution, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (70/30 by volume) mixture, 9.1 g of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[ 2 2 -methoxyphenyl)propenoyl]-4-methyl-9- 4 -methoxyphenyl)-2,3,3a,4,9,9a-hexahydro-1H-benzo[f]isoindole-3a-carboxylate -210are obtained in the form of an orange-coloured solid, the characteristics of which are as follows: melting point 141°C H N.M.R. spectrum (300 MHz, d6-(CD 3 2 SO, d in ppm [lacuna]: from 0.95 to 1.25 and from 1.55 to 2.10 (2 mts, 4H in all, CH 2
CH
2 1.38 and 1.46 (2 s, 3H in all, CH 3 from 3.05 to 3.35 (mt, 3H, CH 2 at 1 and CH at 9a), from 3.30 to 3.40 and 3.41 (respectively mt and s, 3H in all, COOCH 3 3.62, 3.72, 3.80 and 3.83 (4 s, 6H in all, ArOCH 3 from 3.80 to 4.20 (mt, 2H, CH, at 5.43, 5.56, 5.60 and 5.78 (4 s, 2H in all, =CH 2 6.39 and 6.42 (2 d, J 7.5 Hz, 1H in all, H at from 6.85 to 7.45 (mts, 11H, H at 5, H at 6, H at 7, aromatic H of the 4-methoxyphenyl and aromatic H of the 2-methoxyphenyl).
Stage L 13.4 g (0.025 mol) of methyl (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2- (2-methoxyphenyl)propenoyl]-4-methyl-9-(4-methoxyphenyl)-2,3,3a,4,9,9ahexahydro-1H-benzo[f]isoindole-3a-carboxylate are heated at reflux for three hours in 250 cm 3 of ethanol in the presence of 52 cm 3 of a normal aqueous sodium hydroxide solution. The reaction mixture is subsequently concentrated under reduced pressure and the residue is dissolved in 250 cm 3 of distilled water. The aqueous phase is washed with two times 100 cm 3 of ethyl ether, acidified with 60 cm 3 of a normal 20 aqueous hydrochloric acid solution, extracted with two times 150 cm 3 of dichloromethane, dried over magnesium sulphate and then concentrated under reduced pressure. The white solid obtained is purified by washing in 100 cm 3 of pentane. 10.8 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(4-methoxyphenyl)-4-methyl-2,3,3a,4,9,9ahexahydro-1H-benzo[f]isoindole-3a-carboxylic acid are thus obtained in the form of a white solid, the characteristics of which are as follows: melting point= 157 0
C
mass spectrum M/Z 523 (M Isolation of the dextrorotatory enantiomer of (3aRS,4SR,9SR.9aRS)-4.9-ethano-2- [2-(2-methoxvphenvl)propenovl-9-(4-methoxypheny)-4-methyl-2,3,3a.49,99a-
ITI'
-211hexahydro- H-benzo [fisoindole-3a-carboxylic acid 17.6 g of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methoxyphenyl)-4-methyl-2,3,3a,4,9,9a-hexahydro-1Hbenzo[f]isoindole-3a-carboxylic acid are resolved, in 4 injections, on a Whelk 01 (SS) chiral silica column, elution being carried out with an n-heptane/dichloromethane/propanol (50/48/2 by volume) mixture containing 0.05% of trifluoroacetic acid. On collecting the first fraction eluted (retention time 38 min), 7.01 g of the dextrorotatory enantiomer of (3aRS,4SR,9SR,9aRS)-4,9-ethano- 2-[2-(2-methoxyphenyl)propenoyl]-9-(4-methoxyphenyl)-4-methyl-2,3,3a,4,9,9ahexahydro-1H-benzo[f]isoindole-3a-carboxylic acid are obtained, after concentrating under reduced pressure, in the form of a white powder, the characteristics of which are as follows: melting point 238°C mass spectrum M/Z 523 (M S 15 optical rotation: [a] 5 74.4 1.30 (c methanol) EXAMPLE 102 Evaluation of the famesvl transferase activity of compounds according to the invention The famesyl transferase activity is measured by the amount 20 farnesylated of K-ras substrate or of substrate derived from the peptide corresponding to its C-terminal part, the faresyl group being introduced by famesyl pyrophosphate
(FPP).
Specifically, the biotinylated substrate used, representative of K-ras: BIOT-(pA) 3 6 is 3 H]-faresylated on its cysteine C by famesyl transferase in the presence of 3 H]-FPP. It is then brought into contact with PVT'-streptavidin (Amersham)® beads and is quantified by proximity scintillation (SPA assay) between the tritium and the PVT beads, by virtue of the streptavidin/biotin interaction.
Experimentally, farnesyl transferase purified according to the appended protocol is diluted, for this assay, to a concentration such that a -212consumption of substrates of less than 30% is obtained. The final molar concentrations of each substrate are adjusted to their respective Km: 50 nM for the biotinylated K ras peptide and 120 nM for FPP, introduced at 20 gl into a final volume of 100 pl of the reaction mixture based on 50 mM pH 7.5 Hepes buffer, 5 mM MgCl 2 40 mM KC1, 5 mM dithiothreitol, 0.01% Triton X100.
The inhibitors to be tested, initially dissolved at 1 mM in an appropriate solvent (DMF or DMSO), are diluted in the assay buffer and are added in the form of 10 l, in triplicate, to the reaction mixture at a concentration 10 times greater than their final concentration.
The reaction, carried out in Optiplates 96® microtitration plates, is initiated by the enzyme and lasts sixty minutes at 37 0 C. It is stopped by addition of 150 gl of mixture of a blocking buffer at pH 4 composed of 0.2M H 3
PO
4 1.5 mM *MgCl 2 0.5% BSA, 0.05% sodium azide containing 200 gg of PVTstreptavidin beads.
15 After slow agitation for thirty minutes (in order to remove the chemiluminescence), the plates are read as 3 H]CPM in a Top Count® (Packard) scintillation counter for microplates, where they are converted into 3 H]DPM from a range of coloured agent attenuating the scintillation (quenching).
The percentages of inhibition are calculated with respect to an 20 inhibitor-free control after subtraction from all the values of that of a blank which only contains the substrates and the buffer.
The IC 50 values are calculated or measured, from the inhibitions obtained at nine different concentrations, with Enzfitter® or Grafit® software. The
IC
50 values which appear in the results are the mean of measurements and calculations of two IC 5 0 values. The results obtained are collated in Table I.
0
S
S
S .5*
S
6S -213- TABLE I Product [lacuna] vitro inhibitory activity (KiRas) IC 50 (jiM) Example 1 0.305 Example 2 0.045 Example 3 0.028 Example 4 1.80 Example 5 0.050 Example 6 0.0575 Example 7 0.050 Example 8 0.100 Example 9 0.055 Example 10 0.160 Example 11 0.345 Example 12 0.045 Example 13 0.140 Example 14 0.210 Example 15 0.170 Example 16 0.360 Example 17 0.235 -2 14-
S
*5
S
S S
S**
S
S.
S S
S
S
*5S*
S
555.
*5S5
S
S
S. S S
S.
Example 18 0.050 Example 19 0.181 Example 20 0.140 Example 21 0.111 Example 22 0.131 Example 23 0.277 Example 24 0.084 Example 25 0.193 Example 26 0.145 Example 27 0.009 Example 28 0.054 Example 29 0.140 Example 30 0.074 Example 31 0.101 Example 32 0.106 Ex ample 33 0.242 Example 34 0.02 Example 35 0.084 -215-
S
4S *S .54.
4 S S
S
4 .4
S.
Example 36 0.120 Example 37 0.088 Example 38 0.099 Example 39 0.273 Example 40 0.083 Example 41 0.009 Example 42 0.083 Example 43 0.590 Example 44 0.369 Example 45 0.181 Example 46 0.132 Example 47 0.207 Example 48 0.095 Example 49 0.229 Example 50 0.059 Example 51 0.068 Example 52 0.181 I Example 53 0.020 RA4, -216-
S
*SS*
S.
S
*5
S
S
*5*S
S
S
S
S
Example 54 0.078 Example 55 0.558 Example 56 0.589 Example 57 0.280 Example 58 0.138 Example 59 0.408 Example 60 0.12 4 Example 61 0.178 Example 62 0.036 Example 63 0.020 Example 64 0.325 Example 65 0.040 Example 66 0.379 Example 67 0.101 Example 68 0.431 Example 69 0.053 Example 70 0.067 Example 71 0.335 Li 0 -2 17-
S
S
S S S S *5
S
S
*5*S
S
S
S
S
Example 72 0.098 Example 73 0.460 Example 74 0.048 Example 75 0.008 Example 76 0.244 Example 77 0.204 Example 78 0.048 Example 79 0.045 Example 80 0.067 Example 81 0.018 Example 82 0.097 Example 83 0.319 Example 84 0.008 Example 85 0.508 Example 86 0.005 Example 87 0.064 Example 88 0.404 Example 89 0.005
LL!
-218- Example 90 0.068 Example 91 0.183 Example 92 0.028 Example 93 0.786 Example 94 0.557 Example 95 0.177 Example 96 0.955 Example 97 0.040 Example 98 0.663 Example 99 0.018 Example 100 0.019 Example 101 0.019 0*
S
S 55 55
S
**SS
S
S
5555
S
S
S
S S -219- EXAMPLE 103 The activity of the compounds according to the invention can also be evaluated by the ability of the said compounds to inhibit the growth in agar of clones resulting from human tumour lines. For example, cells from the HCT116 human colic carcinoma line, supplied by the ATCC, are grown as a monolayer in a culture medium, Dulbecco's modified Eagle, containing 2 mM of L-glutamine, 200.U/ml of penicillin, 200 ug/ml of streptomycin complemented by 10% by volume of heat inactivated foetal calf serum. The cells in exponential growth are trypsinized, washed with PBS and diluted to a final concentration of 5000 cells/ml in the complete culture medium. The inhibitors to be tested, or the control solvent, are then added, at a volume of 50 ul, to 2.5 ml of cell suspension, prepared above. 0.4 ml of an agar solution, Noble Difco, maintained at 45 C, is subsequently added and mixing is then carried out. The medium thus obtained is immediately placed in Petri dishes, maintained for five minutes at 4'C and then incubated at 37 0 C under an atmosphere containing 5% of CO 2 The number of cell clones 50 cells) is counted after incubating for twelve days at 37 0 C under an atmosphere containing 5% of CO 2 Each inhibitor is tested in duplicate at the final concentrations in agar of 10, 1, 0.1, 0.01 ooo and 0.001 pg/ml. The results are expressed as percentage of inhibition of clonogenicity with respect to the untreated controls. The inhibitory doses IC 50 are 20 determined graphically from the semi-logarithmic means of the values obtained for each concentration.
The products according to the invention inhibit farnesylation of the Ras protein by 50% at concentrations of between 0.1 nM and 100 pM.
EXAMPLE 104 The antitumour activity of the compounds according to the invention can also be demonstrated by an in vivo test in mice, according to the tests and methodologies conventionally used (Corbett et al., Cancer Research 42, 1707-1715 (1982), Corbett et al., Cancer Treatment Report, 66, 1187-1200 (1982), Corbett et al., 2660-2680 (1977)).
The influence of the compounds according to the invention, 41s -220administered to mice, on the growth of carcinomas of human origin grafted subcutaneously into these mice is studied.
On day 0 of the experiment, the mice receive a tumour fragment mg) bilaterally under the skin using a trocar. The bilateral implantation of the tumours ensures a more uniform tumour weight per mouse and thus makes it possible to reduce the number of animals per group. The mice are then divided into the different treated and untreated groups.
The product is suspended in an aqueous solution at concentrations ranging from 0.01 to 1200 mg/ml, corresponding to doses of 0.1 to 10,000 mg/kg.
The treatments or their possible excipient are administered every day orally, at a maximum volume of 0.2 ml, the duration of administration depending on the doubling time of the tumour.
I• The tumours are measured 2 to 3 times per week, using a calliper rule, according to two measurements in mm, which are subsequently converted into 15 tumour weight according to the following formula: Length (nun) x width 2 (mm 2 tumour weight (mg) An active product is a product which makes it possible to limit the growth of the tumour 20 after it has been administered.
o The following example may be mentioned by way of illustration and without implied limitation of the present invention: Tumour stabilization was obtained at a dose of 400 mg/kg/adm. of the product of Example 3, administered orally to mice grafted subcutaneously with the HCT1 16 human colic carcinoma line supplied by the ATCC (Brattain et al., Cancer Research, 41, 1751-1756 (1981)).
EXAMPLE 105 EXAMPLE A Hard gelatin capsules containing 50 mg of active product are prepared, according to the usual technique, which have the following composition: -221- Active product Lactose Colloidal silica Sodium carboxymethylstarch Magnesium stearate EXAMPLE B 50 mg 18 mg 55 mg 1 mg 10 mg 10 mg 1 mng
S
S .5 Sb S S S S 55*5*5
S
*5*5
S
S
*555 5*55
S
S
S
S
S *5
S
Tablets containing 50.mg of active product are prepared, according to the usual technique, wh ich have the following composition: Active product 50 mg 104 mg 40 mg Polyvidone 10 mng 15 Sodium 22 mg Magnesium 2 mg Colloidal 2 mg Mixture of hydroxymethylcellulose, glycerol 20 and titanium oxide (72/3.5/24.5) q.s. for 1 coated tablet completed 245 mg EXAMPLE C An injectable solution containing 50 mg of active product is prepared which has the following composition: Active product 50 mg Benzoic acid 80 mg Benzyl 0.06 ml Sodium benzoate 80 mg 95% Ethanol 0.4 ml -222- Sodium hydroxide 24 mg Propylene glycol 1.6 m l Water q.s. for 4 ml Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that the prior art forms part of the common general knowledge in Australia.
*P
.000
*O~
*•go *•in
Claims (48)
1. Compounds of general formula I Ar R3 H R /P l (R2 Y R 1 in which: Ar represents 5 a phenyl radical substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and the following radicals: *0 alkyl containing 1 to 4 carbon atoms, alkenyl containing 2 to 4 carbon atoms, hydroxyl, mercapto, alkylthio, alkylsulphonyl or alkyl-sulphinyl, amino, o: "alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, 10 carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, cyano or trifluoromethyl, or alkoxy containing 1 to 4 carbon atoms, the alkyl portion of which is optionally perhalogenated, or a phenyl radical condensed with a 4- to 7-membered heterocycle containing one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms, an aromatic or non-aromatic polycyclic radical, a 5- to 12-membered aromatic or non-aromatic heterocyclic radical incorporating one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms, bonded to the condensed ring via a carbon-carbon bond, the said 0 -224- radical being substituted, if appropriate, by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and the following radicals: alkyl, alkenyl containing 2 to 4 carbon atoms, hydroxyl, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino or dialkylamino, formyl, alkylcarbonyl, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, cyano or trifluoromethyl, with, for all of these radicals, alkyl containing 1 to 4 carbon atoms, R represents a radical of general formula 1 0 -(CH 2 )m-X -(CH 2 )n-Z S. in which X, represents a single bond or an oxygen or sulphur atom, m represents an integer equal to 0 or 1, n represents an integer equal to 0, 1 or 2, S 15 one or more methylene radicals can be substituted by a carboxyl, o. o Calkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, amino, alkylamino or dialkylamino radical with, for all of these radicals, alkyl containing 1 to 4 carbon atoms, Z represents a carboxyl radical, a COOR 6 radical, in which R 6 represents a straight or branched alkyl radical containing 1 to 3 carbon atoms, or -225- a radical of formula CON(R 7 )(R 8 in which R 7 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms and R 8 represents a hydrogen atom, a hydroxyl radical, an arylsulphonyl radical, optionally substituted by one or more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl or alkyloxy radicals with, for these radicals, 0 o• 10 alkyl containing 1 to 4 carbon atoms, a 5- to 7-membered heterocycle incorporating one or more heteroatoms chosen from nitrogen, oxygen or sulphur atoms, it being possible for the said heterocycle to be bonded via a heteroatom, an amino radical optionally substituted by one or two radicals, Sj 15 which are identical or different, chosen from the following radicals: alkyl containing 1 to 4 carbon atoms, aryl, optionally substituted by one or more radicals, which are identical or different, chosen from alkyl or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms,
5- to 7-membered heterocyclyl containing one or more heteroatoms chosen from nitrogen, oxygen and sulphur atoms, arylcarbonyl, optionally substituted by one or more radicals, s b 1 -226- which are identical or different, chosen from alkyl or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms, an alkyloxy radical containing 1 to 6 straight- or branched-chain carbon atoms optionally substituted by a phenyl radical, a straight or branched alkyl radical containing 1 to 6 carbon atoms, optionally substituted by an amino, alkylamino, dialkylamino, hydroxyl, alkoxy containing 1 to 4 carbon atoms, mercapto, alkylthio, alkyloxycarbonyl, carboxyl or cyano radical, an optionally substituted 10 mono- or polycyclic aromatic radical having from 5 to 12 ring members which may or may not incorporate one or more heteroatoms •chosen from oxygen, nitrogen and sulphur atoms, or also being able to be a phenyl radical optionally substituted by one or more halogen atoms or by one or more hydroxyl, amino or trifluoromethyl groups or 15 by one or more alkyl or alkenyl, alkoxy, alkylthio, alkylamino, alkylcarbonyl or C 2 to C 4 alkoxycarbonyl, carbamoyl, alkylcarbamoyl I or dialkylcarbamoyl, the alkyl part of which contains 1 to 8 carbon atoms, or formyl radicals, or alternatively a 1- or 2-naphthyl radical, or Z represents a PO(OR 9 2 radical in which R 9 represents a hydrogen atom or a-straight or branched alkyl radical containing 1 to 6 carbon atoms, or R,4^\ t }Z .lu -227- an -NH-CO-T radical in which T represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms optionally substituted by an amino, carboxyl, alkyloxycarbonyl, hydroxyl, alkyloxy, mercapto or alkylthio radical, or alternatively -a -CH2- radical 5 having an anion as counterion, with, for all of the radicals possessing an alkyl group provided in the definition of Z, alkyl containing 1 to 4 carbon atoms, oo R, and R 2 which are identical or different, represent a hydrogen atom, a halogen atom or an alkyl radical, an alkyloxy radical, each optionally substituted by a 10 dialkylamino radical, each alkyl part of which contains 1 to 4 carbon atoms or forms, with the nitrogen atom, a saturated heterocycle containing 5 or 6 ring members, an J: alkylthio radical or an alkyloxycarbonyl radical, or alternatively situated at the ortho position with respect to one another, R, and R 2 form a saturated or unsaturated heterocycle containing 1 or 2 heteroatoms chosen from nitrogen and oxygen, optionally substituted by a halogen atom or by an alkyl or alkyloxy radical, with, for all of the radicals possessing an alkyl group provided in the definition of R, and R 2 alkyl containing 1 to 4 carbon atoms, 0 r z -228- R 3 and R 4 which are identical or different, represent a hydrogen or halogen atom or an alkyl, hydroxyl, alkyloxy, alkylcarbonyloxy, mercapto, alkylthio, alkylsulphonyl or alkylsulphinyl, amino, alkylamino or dialkylamino, alkyloxycarbonylamino, carboxyl, alkyloxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, formyl, alkylcarbonyl, cyano or trifluoromethyl radical, with, for all of the radicals possessing an alkyl group provided in the definition of R 3 and R 4 alkyl containing 1 to 4 carbon atoms, R 5 represents a hydrogen atom or an alkyl radical or an alkylthio radical, with, for the definition ofR,, alkyl containing 1 to 4 carbon atoms; 10 X represents an oxygen or sulphur atom or one of the following groups: -NH- methylene, alken-1,1-diyl, or cycloalkan-1,l-diyl containing 3 to 6 carbon atoms, and .Y represents an oxygen or sulphur atom, 15 in the racemic form or their optical isomers, as well as the salts of the product of general formula 2. Compounds according to claim 1, in which, when Ar represents a substituted phenyl radical, the alkyl radical is the methyl radical. 3. Compounds according to claim 1, in which, when Ar 2 0 represents a substituted phenyl radical, the alkoxy radical is the methoxy radical. 4. Compounds according to claim 1, in which, when Ar represents a substituted phenyl radical, the alkoxy radical, the alkyl part of which is -229- optionally perhalogenated, is the trifluoromethoxy radical. Compounds according to claim 1, in which R 6 represents the methyl radical.
6. Compounds according to claim 1, in which, when R, represents the arylsulphonyl radical, it is the phenylsulphonyl radical.
7. Compounds according to claim 1, in which, when R 8 represents an amino radical optionally substituted by an aryl radical, it is the phenyl radical.
8. Compounds according to claim 1, in which, when R 8 represents an amino radical optionally substituted by an arylcarbonyl radical, it is the benzoyl radical. Compounds according to claim 1, in which, when R 8 represents an alkyl radical, it is the methyl radical. Compounds according to claim 1, in which, when Z represents a radical -CH 2 the anion is the
11. Compounds according to claim 1, in which, in the definition ofR and/or R2, the alkyloxy radical is a methoxy radical.
12. Compounds according to claim 1, in which, in the definition of X, the alken-1,1-diyl radical is the vinyldiyl radical. a a a a. a a o -230-
13. Compounds according to claim 1, characterized in that Ar represents a 2,3-dihydro-1,4-benzodioxin-6-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzopyran-6-yl, 1- or 2-naphthyl, 5-indanyl or 1,2,3,4-tetrahydronaphth- 6-yl radical or a phenyl radical substituted at the 4 position by a methyl, trifluoromethyl or methoxy radical.
14. Compounds according to any one of the preceding claims, characterized in that R represents a carboxyl radical or a -COOMe radical or alternatively a -CON(R 7 )(R 8 radical in which, when R 7 represents a hydrogen atom, R 8 represents a methyl radical substituted by a 3- or 4-pyridyl radical or the N-oxide of pyridine.
15. Compounds according to any one of the preceding claims, characterized in that Ar represents a 2,3-dihydro-1,4-benzodioxin-6-yl or 2,3-dihydrobenzofuran-5-yl radical or a phenyl radical substituted at the 4 position by a methyl, trifluoromethyl or methoxy radical. 15 16. Compounds according to any one of the preceding claims, characterized in that R represents a carboxyl radical or a -COOMe radical or alternatively a -CON(R 7 )(R 8 radical in which, when R 7 represents a hydrogen atom, R 8 represents a methyl radical substituted by the 3-pyridyl radical.
17. Compounds according to any one of the preceding claims, 2 0 characterized in that one of the R, or R 2 symbols represents a hydrogen atom and the other of the symbols represents a methoxy radical.
18. Compounds according to any one of the preceding claims, -23 1- characterized in that either R 3 and R 4 each represent a hydrogen atom or one of the R 3 or R 4 symbols represents a hydrogen atom and the other of the R 3 or R 4 symbols represents a methoxy radical.
19. Compounds according to any one of the preceding claims, characterized in that R 5 represents a hydrogen atom or a methyl radical. Compounds according to any one of the preceding claims, characterized in that X represents a methylene or vinyldiyl group.
21. Compounds according to any one of the preceding claims, characterized in that Y represents an oxygen atom.
22. Compound according to claim 1, characterized in that it is a :compound chosen individually from methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxy-phenyl)propenoyl]-9-(4- methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-(2-methoxyphenyl)-propenoyl-9-(4- methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [(2-methoxyphenyl)-acetyl]-9-(4- methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[(2- methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo~flisoindole-3 a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [(2-methoxyphenyl)-acetyl]-9-(4- methylsulphanylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [fjisoindole-3 a- -232- carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2-[(2-methoxyphenyl)acetyl] 2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [(2-methoxyphenyl)-acetyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -methoxyphenyl)-2-[(2- methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[(2- methoxyphenyl)acetyl] -2,3,3 a,4,9,9a-hexahydro-l1H-benzo[f] isoindole-3 a- :carboxylate (3 aRS,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[(2- methoxyphenyl)acetyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-3 a-N-benzylcarbamoyl-4,9-ethano-2- methoxyphenyl)propenoyl]-9-(4-methylphenyl)2 3a, 4,9, 9a-hexahydro-1H- benzo[flisoindole (3 aRS,4SR,9SR,9aRS)-3 a-carbamoyl-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-9-(4-methylphenyl)2 ,3,3 a, 4,9, 9a-hexahydro-l1H- 2 0 benzo[flisoindole benzyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxy-phenyl)propenoyl]-9-(4- inethylphenyl)-2 ,3 ,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-hydroxamate -233- (3 aRS ,4SR,9SR,9aRS)-4,9-ethano--2-[2-(2-methoxyphenyl)-propenoyl] methylphenyl)-,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-hydroxamic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4- methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-N-(3 pyridylmethyl)-carboxamide (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [fjisoindole-3 a-N-(4- pyridylmethyl)-carboxamide methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] 10 methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-hydroxamate (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] *0 metylphenyl-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [fjisoindole-3 a-N',N'-dimethyI- *ehlhnl 00 carbohydrazide (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoylj-9-(4- methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N'-phenylcarbo- hydrazide 0: (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2methoxyphenyl)propenoyl]-9-(4- methylphenyl)-3 a-phenylsulphonylaminocarbonyl-2,3 ,3 a,4,9,9a-hexahydro- 1H- benzo[flisoindole -234- (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4- methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [fjjisoindole-3 a-N-(N-oxo-3 pyridyl)methylcarboxamide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N'- (4-methoxyphenyl)- carbohydrazide (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl]-9-(4- methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N'-methyl-N'- phenylcarbohydrazide 10 (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] methylphenyl)-2 ,3 ,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N'-(2-methyl- phenyl)carbohydrazide methyl (3 aRS,4SR,9SR,9aRS)-9-(2,3 -dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2- ~[2-(2-methoxyphenyl)-propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a- carboxylate (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [fjisoindole-3 a- carboxylic acid (3 aRS,4SR,9SR,9aRS)-9-(2,3 -dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-N-(3- pyridylmethyl)carboxamide (3 aRS,4SR,9SR,9aRS)-9-(2,3 -dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2- -23 methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [fl isoindole-3 a-N-(2- thienylmethyl)carboxamide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[(2-methoxyphenyl)-acetyl]-9-(3 ,4,5 trimethylphenyl)-2 3a, 4,9, 9a-hexahydr6-1H-benzo[flisoindole-3a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)-propenoyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] trifluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[fjisoindole-3 a- carboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl]-9-(4- trifluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)-propenoyl] trifluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 pyriylmetbhycrboaide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)-propenoyl]-9-(4- trifluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N'-phnl beycarbohydrazide (3h (aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl] a.1 -236- naphthyl)-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3 a-carboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl] naphthyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a-carboxylic acid methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] methyl-2-thienyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3a-carboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)-propenoyl]-9-(5 -methyl- 2-thienyl)-2 ,3 ,3a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-(4-bromophenyl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a- carboxylate (3 aRS,4SR,9SR,9aRS)-9-(4-bromophenyl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a- carboxylic acid (3 aRS ,4SR,9SR,9aRS)-9-(3 ,4-dichlorophenyl)-4,9-ethano-2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a- carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] chlorophenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylate (3 aRS,4SR,9SR,9aRS)-9-(4-chlorophenyl)-4,9-ethano-2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahiydro-l1H-benizo[flisoindole-3 a- carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyll-9-(4- -237- rnethoxy-3-methylphenyl)-2 3a,4, 9, 9a-hexahydro-1IH-benzo[flisoindole-3a- carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl] indolyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylate (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)-2-[(2-methoxyphenyl)- acetyl] -2,3,3 a,4,9,9a-hexahydro-l1H-benzo(flisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-isopropylphenyl)-2-[2-(2- methoxyphenyl)propenoyl] -2,3 ,3a,4, 9,9a-hexahydro- 1H-benzo [flisoindole-3 a- carboxylic acid 10 methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(3- thienyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylate methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-ethylphenyl)-2- methoxyphenyl)propenoyl] -2,3,3a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3 a- carboxylate (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-ethylphenyl)-2-[2-(2- methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a- 20 carboxylicacid methyl (3 aRS,4SR,9SR,9aRS)-9-(2,3 -dihydrobenzofuran-5-yl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-2,3 ,3a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a- -23 8- carboxylate acid (3 aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5-yl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-2,3 ,3a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N-(3 pyridylmethyl)- carboxamide methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2- methoxyphenyl)propenoyl]-2,3 ,3a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a- carboxylate (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-fluorophenyl)-2-[2-(2- methoxyphenyl)propenoyl2 3a,4, 9,9 a-hexahydro-1H-benzo[flisoindole-3a- carboxylic acid methyl (3 aRS ,4SR,9SR,9aRS)-9-(4-chloro-3 -fluorophenyl)-4,9-ethano-2-[2-(2- Ob methoxyphenyl)propenoyl-2 ,3,3a,4,9,9a-hexahydro-1H-benzo[flisoindole-3a- *carboxylate (3 aRS,4SR,9SR,9aRS)-9-(4-chloro-3 -fluorophenyl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [lisoindole-3 a- carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)propenoyl]-9-(3 methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylate (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2.-methoxyphenyl)propenoyl]-9-(3 methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo(flisoindole-3 a-carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-( 1,3 -benzodioxol-5 -yl)-4,9-ethano-2- methoxyphenyl)propenoyl] -2,3 ,3a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a- -0A -239- carboxylate methyl (3 aRS ,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a- carboxylate (3 aRS ,4SR,9SR,9aRS)-9-(3 ,4-dimethylphenyl)-4,9-ethano-2-[2-(2-methoxy- phenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benizo [flisoindole-3 a-carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxy-phenyl)-2-[2-(2- methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-beizo [flisoindole-3 a- carboxylate 0 -a.10 (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2- [2-(2-methoxy- ~phenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylic acid 15(3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2- [2-(2-methoxy- phenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3 pyridylmetbhydcrbamide 15(3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxy- phenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N'-(3 -240- pyridyl)carbohydrazide (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxy- phenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1 H-benzo [flisoindole-3a-N-(3 thienyhmethyl)carboxamide and aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-. methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1 H-benzo[flisoindole-3 a- carbonylamino }phenylacetic acids (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] trifluoromethoxyphenyl)-2,3 ,3a, 4,9,9, 9a-hexahydro-1H-benzo[flisoindole-3a- 10 carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-(3-bromophenyl)-4,9-ethano-2- ~methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [fi isoindole-3 a- carboxylate C (3 aRS,4SR,9SR,9aRS)-9-(3-bromophenyl)-4,9-ethano-2-[2-(2-methoxy- phenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid methyl (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(3 -fluoro-phenyl)-2-[2-(2- .methoxyphenyl)prop eno yl] -2,3 ,3 a, 4,9,9 a-hexahydro- 1 H-b enzo [f iso indole- 3 a- carboxylate (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(3 -fluorophenyl)-2-[2-(2-methoxy- phenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo [fjisoindole-3 a-carboxylic acid (3 aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3-fluorophenyl)-2-[2-(2-methoxy- phenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-N-(3 -241- pyridylmethyl)carboxamide methyl (3 aRS,4SR,9SR,9aRS)-9-(3-chlorophenyl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo Wlisoindole-3 a- carboxylate (3 aRS ,48R,9SR,9aRS)-9-(3 -chlorophenyl)-4,9-ethano-2-[2-(2-methoxy- phenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-9-(3-chlorophenyl)-4,9-ethano-2-t2-(2-methoxy- phenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- IH-benzo [flisoindole-3 a-N-(3- pyridylmethyl)carboxamide methyl (3 aRS,4SR,9SR,9aRS)-9-(3-N,N-dimethylaminophenyl)-4,9-ethano-2- ~methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9,9a-hexahydro- 1H-benzo isoindole-3 a- carboxylate (3 aRS,4SR,9SR,9aRS)-9-(3-N,N-dimethylaminophenyl)-4,9-ethano-2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9,9a-hexahydro- 1 H-benzo [flisoindole-3 a- carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-9-(3 -aminophenyl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-2 ,3 ,3a,4,9,9,9a-hexahydro- 1H-benzo(flisoindole-3 a- carboxylate hydrochloride methyl (3 aRS,4SR,9SR,9aRS)-9-(4-N,N-dimethylamninophenyl)-4,9-ethano-2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9,9a-hexahydro- 1H-benzo[flisoindole-3 a- carboxylate (3 aRS,4SR,9SR,9aRS)-9-(4-cyanophenyl)-4,9-ethano-2- [2-(2-methoxy- -242- phenyl)propenoyl] -2,3,3 a,4,9,9,9a-hexahydro- 1 H-benzo [flisoindole-3 a-carboxylic acid methyl (3 aRS ,4SR,9SR,9aRS)-9-(3-cyanophenyl)-4,9-ethano-2- methoxyphenyl)propenoyl] -2,3,3 a,4,9,9,9a-hexahydro- 1H-benzo [flisoindole-3 a- carboxylate (3aRS,4SR,9SR,9aRS)-4,9-ethano-9-(3 -hydroxy-4-methoxyphenyl)-2- methoxyphenyl)propenoyl]-2 ,3 ,3a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a- carboxylic acid methyl (3 aRS,4SR,9SR,9aRS)-4,9-ethano-5 -methoxy-2-[2-(2- 10 methoxyphenyl)propenoyl] -9-(4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H- benzo[flisoindole-3a-carboxylate (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-5-methoxy-2- [2-(2-methoxyphenyl)propenoyl]-9- (4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-2-propenoyl]-4-methyl- 9-(4-methoxyphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[flisoindole-3-a-carboxylic acid in the racemic form or their optical isomers, as well as their salts.
23. Compound according to claim 1, characterized in that it is (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)-propenoyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo[flisoindole-3 a-carboxylic acid in the racemic form or its optical isomers, as well as its salts.
24. Compound according to claim 1, characterized in that it is -243- (3 aRS ,4SR ,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzolisoindole-3 a-N-(3 pyridylmethyl)carboxamide in the racemic form or its optical isomers, as well as its salts.
25. Compound according to claim 1, characterized in that it is (3 aRS,4SR,9SR,9aRS)-9-(2,3 -dihydro- 1,4-benzodioxin-6-yl)-4,9-ethano-2-[2-(2- methoxyphenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-N- (3 -pyridylmethyl)carboxamide in the racemic form or its optical isomers, as well as its salts.
26. Compound according to claim 1, characterized in that it is (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] trifluoromethylphenyl)-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid in the racemic form or its optical isomers, as well as its salts.
27. Compound according to claim 1, characterized in that it is (3aRS,4SR,9SR,9aRS)-9-(2,3-dihydrobenzofuran-5-yl)-4,9-ethano-2-[2-(2-methoxy- phenyl)propenoyl]-2,3 ,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-N-(3 pyridylmethyl)carboxamide in the racemic form or its optical isomers, as well as its salts.
28. Compound according to claim 1, characterized in that it is (3 aRS ,4SR,9SR,9aRS)-4,9-ethano-9-(4-methoxyphenyl)-2-[2-(2-methoxy- phenyl)propenoyl] -2,3,3 a,4,9,9a-hexahydro- 1H-benzo [flisoindole-3 a-carboxylic acid jRA4/ -2 44- in the racemic form or its optical isomers, as well as its salts.
29. Compound according to claim 1, characterized in that it is (3 aRS,4SR,9SR,9aRS)-4,9-ethano-5 -methoxy-2-[2-(2-methoxyphenyl)propenoyl]-9- (4-methylphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo[fjisoindole-3 a-carboxylic acid in the racemnic form or its optical isomers, as well as its salts. Compound according to claim 1, characterized in that it is (3 aRS,4SR,9SR,9aRS)-4,9-ethano-2- [2-(2-methoxyphenyl)-2-propenoyl]-4-methyl- 9-(4-methoxyphenyl)-2,3 ,3 a,4,9,9a-hexahydro-l1H-benzo [flisoindole-3 a-carboxylic acid in the racemic form or its optical isomers, as well as its salts.
31. Compounds according to any one of the preceding claims, characterized in that they are provided in the dextrorotatory form. :32. Compound according to claim 1, characterized in that it is the dextrorotatory enantiomer of (3aRS,4SR,9SR,9aRS)-4,9-ethano-2-[2-(2- u~~~hox11Jypy11.ly)propenod1ylJ lpheyl)-2,,3a,-,9,a-liexahiydro-lH benzo[flisoindole-3a-carboxylic acid.
33. Compound according to claim 1, characterized in that it is the dextrorotatory enantiomer of (3 aRS,4SR,9SR,9aRS)-9-(2,3 -dihydro- 1,4- benzodioxin-6-yl)-4,9-ethano-2-[2-(2-methoxyphenyl)propenoyl] -2,3,3 a,4,9,9a- hexahydro- 1H-benzo [flisoindole-3 a-N-(3-pyridylmethyl)carboxamnide.
34. Process for the preparation of a compound of general formula -245- according to any one of claims 1 to 33, in which Y represents an oxygen or sulphur atom and X represents one of the following groups: methylene, alken- 1,1-diyl, such as vinyldiyl, or cycloalkan-1,1-diyl containing 3 to 6 carbon atoms, characterized in that an acid of general formula: HO- X =R2 Y RI .44 4 4 4** *44* 4 in which R, and R 2 are defined according to claim 1, X such as defined above and Y represents an oxygen or sulphur atom, of its methyl ester or of a derivative of this acid, such as a halide or the anhydride, is reacted with a product of general formula: (III) in which Ar, R, R 3 R 4 and R 5 are defined according to claim 1 and G, represents a hydrogen atom. Process for the preparation of a compound of general formula according to any one of claims 1 to 33, in which Y represents an oxygen or sulphur atom and X represents an oxygen atom, characterized in that a haloformate or FLz4 -246- of a halothioformate of general formula (IV): 0 (IV) Hal O R2 Y R1 in which Y represents an oxygen or sulphur atom, R, and R 2 are defined according to claim 1 and Hal represents a halogen atom, is reacted with a product of general formula (III) as defined in claim 34.
36. Process for the preparation of a compound of general formula according to any one of claims 1 to 33, in which Y represents an oxygen or S.sulphur atom and X represents an NH group, characterized in that an isocyanate or of an isothiocyanate of general formula :R2 RI in which Y represents an oxygen or sulphur atom and R, and R 2 are defined S* 10 according to claim 1, is reacted with a product of general formula (III) as defined in claim 34.
37. Process for the preparation of a compound of general formula according to any one of claims 1 to 33, in which R represents a radical of general formula -(CH 2 )m-X,-(CH 2 -Z in which: -247- m and n are defined as above and Z represents a -CON(R 7 radical in which: R 7 represents a hydrogen atom or a straight or branched alkyl radical containing 1 to 6 carbon atoms and Rg represents a hydrogen atom, a hydroxyl radical, an arylsulphonyl radical, such as phenylsulphonyl, optionally substituted by one or 10 more atoms or radicals, which are identical or different, chosen from halogen atoms and alkyl or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon S. atoms, a 5- to 7-membered heterocycle incorporating one or more heteroatoms chosen from nitrogen, oxygen or sulphur atoms, it being possible for the said heterocycle to 15 be bonded via a heteroatom, an amino radical optionally substituted by one or two radicals, which are identical or different, chosen from the following radicals: alkyl containing 1 to 4 carbon atoms, aryl, such as phenyl, optionally substituted by one or more radicals, which are identical or different, chosen from alkyl or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms, 5- to 7-membered heterocyclyl containing one or more heteroatoms chosen -248- from nitrogen, oxygen and sulphur atoms, arylcarbonyl, such as benzoyl, optionally substituted by one or more radicals, which are identical or different, chosen from alkyl or alkyloxy radicals with, for these radicals, alkyl containing 1 to 4 carbon atoms, an alkyloxy radical containing 1 to 6 straight- or branched-chain carbon atoms optionally substituted by a phenyl radical, a straight or branched alkyl radical containing 1 to 6 carbon atoms, such as methyl, optionally substituted by an amino, alkylamino, dialkylamino, hydroxyl, alkoxy .containing 1 to 4 carbon atoms, mercapto, alkylthio, alkyloxycarbonyl, carboxyl or 10 cyano radical, an optionally substituted mono- or polycyclic aromatic radical having from 5 to 12 ring members which may or may not incorporate one or more heteroatoms chosen from oxygen, nitrogen and sulphur atoms, or also being able to be a phenyl radical optionally substituted by one or more halogen atoms or by one or more hydroxyl, amino or trifluoromethyl groups or by one or more alkyl or alkenyl, 15 alkoxy, alkylthio, alkylamino, alkylcarbonyl or C 2 to C 4 alkoxycarbonyl, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl, the alkyl part of which contains 1 to 8 carbon atoms, or formyl radicals, or alternatively a 1- or 2-naphthyl radical, characterized in that a product of general formula: HN(R 7 )(Rs) in which R 7 and R 8 are defined as above is reacted with a product of general formula in which Z represents a carboxyl radical. ^t -249-
38. Process for the preparation of a compound of general formula (I) according to any one of claims 1 to 33, in which R represents a radical of general formula -NHCO-T in which T represents a hydrogen atom or an alkyl radical (1 to 6 carbon atoms) optionally substituted by an amino, carboxyl, alkyloxycarbonyl, hydroxyl, alkyloxy, mercapto or alkylthio radical, characterized in that an acid of general formula T-CO-OH, in which T is defined as above, is reacted with a product of general formula (VI): R3 H X (VI) R4- R2 Y R N *R *o in which Ar, R 2 R R 4 R 5 X and Y are defined according to claim 1.
39. Process for the preparation of a compound of general formula (I) 10 according to any one of claims 1 to 33, in which which R represents -a -CH2 radical characterized in that an excess of pyridine and of a strong acid or of a derivative of this acid are reacted with a product of general formula: -250- (ViI) a *S*S S *5 0 a a a a. a a a a a. a S a. in which Ar, R 2 R 3 R 4 R 5 X and Y are defined according to claim 1. Process for the preparation of a compound of general formula 5 in which R 3 R 4 Ar and R are as defined in claim 1 and G1 represents a benzyl radical, from compounds of general formula (IX): 0 H 'N-Gj(IX) -251- in which R 3 R 4 R 6 and G, are as defined above, characterized in that an intermediate of general formula (XV) (XV) a a in which R 3 R 4 R 5 R 6 Ar and G, are as defined above, is formed and the conversion of which by intramolecular cyclization of Friedel-Crafts type results in the product 5 (III) as defined in claim 34.
41. Compound, characterized in that it is represented by the general formula XV (XV) -252- in which R 3 R 4 R 5 and Ar are as defined in claim 1, G, represents a benzyl radical and R 6 represents an alkyl radical containing 1 to 3 carbon atoms, in the racemic form, as well as its optical isomers.
42. Process for the preparation of a compound of general formula (XV) according to claim 40, characterized in that a compound of general formula (IX) 0 H (IX) COOR 6 R3 R4 o* Sin which R 3 R 4 R 5 and Ar are as defined in claim 1, G, represents a benzyl radical 0 and R 6 represents an alkyl radical containing 1 to 3 carbon atoms, is converted at the 7 position, either into an iodoethylene derivative, by a Barton reaction, or into an enol triflate, and is then subjected to a palladium coupling reaction, the so-called Suzuki reaction with an arylboronic acid or the so-called Stille reaction with an arylstannane.
43. Process for the preparation of a compound of general formula (III) according to claim 34, in which Ar preferably represents -253- a phenyl nucleus substituted at the para, meta-para or meta-para-meta' position by electron-donating groups, an electron-rich heterocyclic radical or a heterocyclic radical suitably substituted by electron-donating groups, characterized in that an aromatic or heterocyclic hydrocarbon Ar-H is reacted, according to intermolecular and then intramolecular cyclization reactions of Friedel- Crafts type, with a compound of general formula in which R 3 R 4 R 5 and Ar are as defined in claim 1, G, represents a benzyl radical and R 6 represents an alkyl radical containing 1 to 3 carbon atoms, in an organic solvent in the presence of an 10 excess of strong acid or of a Lewis acid.
44. Process for the preparation of a product of general formula (III) *0 H *G -254- in which R 3 R 4 R 5 and Ar are as defined in claim 1, Gl represents a benzyl radical and R represents a carboxyl radical or a radical of general formula COOR 6 and R 6 represents an alkyl radical containing 1 to 3 carbon atoms, characterized in that intramolecular cyclization of Friedel-Crafts type is carried out by the action of trifluoromethanesulphonic acid on a product of general formula (VIII): OH Ar H 0W N-Gi (VIII) R 5 COOR 6 R4 R3 R4 in which: Ar, R 3 R 4 and R 5 are as defined in claim 1, G, represents a benzyl radical and R 6 represents an alkyl radical containing 1 to 3 carbon atoms, followed by replacement of the G, group by a hydrogen atom, either by hydrogenolysis and then optionally by replacement of the hydrogen atom by a tert- butoxycarbonyl radical, by reaction with tert-butoxycarbonyl anhydride in an organic solvent, or by a benzyloxycarbonyl radical, by reaction with benzyloxycarbonyl chloride; or by reaction with an alkyl chloroformate, followed by acid hydrolysis of the carbamate formed as an intermediate, optionally followed by saponification of the product obtained. -255- Process for the preparation of a compound of general formula (VIII), in which Ar, R 3 R 4 R 5 R 6 and G, are as defined in claim 44, characterized in that it is carried out from a compound of general formula (IX) 0 H -G (IX) R 5 COOR 6 i ooR4 o in which R 3 R 4 R 5 R 6 and G, are as defined in claim 43, S 5 either by reaction with an organomagnesium derivative of general formula Ar-Mg-X, in which Ar is as defined above and X represents a halogen atom, in the presence of anhydrous cerium(III) chloride in an organic solvent at a temperature of between 0 0 C and the reflux temperature of the reaction mixture, or by reaction with an organolithium derivative of general formula Ar-Li, in which Ar is as defined in claim 1, the reaction being carried out in an organic solvent at a temperature of between -78' and -20 0 C.
46. Process for the preparation of a compound of general formula (IX) as defined in claim 42 or 45, in which in which R 3 R 4 R, and Ar are as defined in claim 1, G represents a benzyl radical and R 6 represents an alkyl radical containing 1 K :y& nyru eimII)clrd na rancsleta epeaueo ewe -256- to 3 carbon atoms, characterized in that an N-trialkylsilylmethyl-N- (alkoxymethyl)amine, carrying a protective group for the amine functional group, is reacted with a derivative of a cyclohexenone of general formula: O (X) SCOOR 6 R R3 R S S in which R 3 R 4 and R 5 are as defined in claim 1 and R 6 represents an alkyl radical containing 1 to 3 carbon atoms.
47. Pharmaceutical composition, characterized in that it contains at least one product according to one of the preceding claims 1 to 33 in combination with one or more pharmaceutically acceptable diluents or adjuvants, whether inert or biologically active.
48. Use of the compounds according to one of the preceding claims 1 to 33 in the preparation of pharmaceutical compositions useful in inhibiting farnesyl transferase. -257-
49. Use of the compounds according to one of claims 1 to 33 in the preparation of pharmaceutical compositions for the treatment of diseases related to cell proliferations, malignant or benign, of cells of various tissues and/or organs, comprising muscle, bone or connective tissues, the skin, the brain, the lungs, the sexual organs, the lymphatic or renal systems, mammary or blood cells, the liver, the digestive system, the colon, the pancreas and the thyroid or adrenal glands, and including the following pathologies: psoriasis, restenosis, solid tumours, Kaposi's sarcoma, carcinomas, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumour, Hodgkin's disease, melanomas, teratocarcinomas, gliomas, multiple 10 myelomas, chronic lymphocytic leukaemias, acute or chronic granulocytic v lymphomas, and cancers, such as cancers of the pancreas, colon, lung, ovary, breast, o; brain, prostate, liver, stomach, bladder or testicles.
50. Use of the compounds of general formula according to one of claims 1 to 33 in the preparation of pharmaceutical compositions useful in the 15 treatment of diseases related to cell proliferations by inhibition of famesyl transferase.
51. Use of the compounds of general formula according to one of claims 1 to 33 in the preparation of pharmaceutical compositions for the treatment of cancers.
52. Use of the compound of claim 32 in the preparation of 2 0 pharmaceutical compositions for the treatment of cancers.
53. Use of the compounds of general formula according to one of claims 1 to 33 in the preparation of pharmaceutical compositions for the treatment of %LI: /T -258- cancer of the colon.
54. Use of the compounds of general formula according to one of claims 1 to 33 in the preparation of pharmaceutical compositions for the treatment of cancer of the pancreas.
55. Use of the compound of claim 32 in the preparation of pharmaceutical compositions for the treatment of cancer of the colon.
56. Use of the compound of claim 32 in the preparation of pharmaceutical compositions for the treatment of cancer of the pancreas.
57. Synergic therapeutic combinations of a product according to one of the preceding claims 1 to 33 with one or more compatible and pharmacologically active compounds and/or with a radiotherapy treatment.
58. A method of inhibiting famesyl transferase in a subject in need of such inhibition, said method comprising the administration to the subject of an effective amount of a compound according to any one of claims 1 to 33. 15 59. A method of treating diseases related to cell proliferations, malignant or benign, of cells of various tissues and/or organs, comprising muscle, bone or connective tissues, the skin, the brain, the lungs, the sexual organs, the lymphatic or renal systems, mammary or blood cells, the liver, the digestive system, the colon, the pancreas and the thyroid or adrenal glands, and including the following pathologies: psoriasis, restenosis, solid tumours, Kaposi's sarcoma, carcinomas, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumour, Hodgkin's disease, melanomas, teratocarcinomas, gliomas, multiple myelomas, chronic T9$) -259- lymphocytic leukaemias, acute or chronic granulocytic lymphomas, and cancers, such as cancers of the pancreas, colon, lung, ovary, breast, brain, prostate, liver, stomach, bladder or testicles in a subject in need of such treatment, said method comprising the administration to the subject of an effective amount of a compound of general formula according to any one of claims I to 33. A method of treating diseases related to cell proliferations by inhibition of famnesyl transferase, said method comprising the administration to a subject in need of such treatment of an effective amount of a compound of general 4:0V formula according to any one of claims 1 to 33. Wes: P
61. A method of treating cancers in a subject in need of such treatment, said method comprising the administration to the subject of an effective *efcv amount of a compound of general formula 1) according to any one of claims3. A method of treating cancer o h ces in a subject in need of c sctramsaid hd comprising t administration to the subject of anctv -260- effective amount of a compound of general formula according to any one of claims 1 to 33. A method of treating cancer of the colon in a subject in need of such treatment, said method comprising the administration to the subject of an effective amount of a compound according to claim 32.
66. A method of treating cancer of the pancreas in a subject in need of such treatment, said method comprising the administration to the subject of an effective amount of a compound according to claim 32. SRhone-Poulenc Rorer S.A. By DAVIES COLLISON CAVE Patent Attorneys for the Applicants 0e S* Patent Attorneys for the Applicants S. S
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR96/16206 | 1996-12-30 | ||
| FR9616206A FR2757855B1 (en) | 1996-12-30 | 1996-12-30 | NOVEL FARNESYL TRANSFERASE INHIBITORS, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| PCT/FR1997/002407 WO1998029390A1 (en) | 1996-12-30 | 1997-12-23 | Farnesyl transferase inhibitors |
Publications (2)
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| AU5669498A AU5669498A (en) | 1998-07-31 |
| AU741921B2 true AU741921B2 (en) | 2001-12-13 |
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| AU56694/98A Ceased AU741921B2 (en) | 1996-12-30 | 1997-12-23 | Farnesyl transferase inhibitors |
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| HU (1) | HUP0001747A3 (en) |
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| PL (1) | PL334345A1 (en) |
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| FR2787327B1 (en) * | 1998-12-21 | 2003-01-17 | Aventis Pharma Sa | COMPOSITIONS CONTAINING FARNESYL TRANSFERASE INHIBITORS |
| FR2796640A1 (en) * | 1999-07-22 | 2001-01-26 | Aventis Pharma Sa | New 3,9-ethano-2,3,3a,4,9,9a-hexahydro-1H-benzo (f) isoindole derivatives, are farnesyl transferase inhibitors useful for treating hyperproliferative disorders, e.g. psoriasis, restenosis or especially cancer |
| FR2796641B1 (en) * | 1999-07-22 | 2001-09-21 | Aventis Pharma Sa | NOVEL PROCESS FOR THE PREPARATION OF BENZOPERHYDROISOINDOLE COMPOUNDS |
| FR2845994B1 (en) * | 2002-10-18 | 2006-05-19 | Servier Lab | NOVEL SUBSTITUTED BENZO [E] [1,4] OXAZINO [3,2-G] ISOINDOLE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| US20060106060A1 (en) * | 2004-03-18 | 2006-05-18 | The Brigham And Women's Hospital, Inc. | Methods for the treatment of synucleinopathies (Lansbury) |
| TW202508595A (en) | 2023-05-04 | 2025-03-01 | 美商銳新醫藥公司 | Combination therapy for a ras related disease or disorder |
| AU2024360465A1 (en) | 2023-10-12 | 2026-04-09 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
| WO2025171296A1 (en) | 2024-02-09 | 2025-08-14 | Revolution Medicines, Inc. | Ras inhibitors |
| TW202547461A (en) | 2024-05-17 | 2025-12-16 | 美商銳新醫藥公司 | Ras inhibitors |
| WO2025255438A1 (en) | 2024-06-07 | 2025-12-11 | Revolution Medicines, Inc. | Methods of treating a ras protein-related disease or disorder |
| WO2025265060A1 (en) | 2024-06-21 | 2025-12-26 | Revolution Medicines, Inc. | Therapeutic compositions and methods for managing treatment-related effects |
| WO2026006747A1 (en) | 2024-06-28 | 2026-01-02 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026015801A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015790A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015796A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
| WO2026015825A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Use of ras inhibitor for treating pancreatic cancer |
| WO2026050446A1 (en) | 2024-08-29 | 2026-03-05 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026072904A2 (en) | 2024-09-26 | 2026-04-02 | Revolution Medicines, Inc. | Compositions and methods for treating lung cancer |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2170766A1 (en) * | 1993-11-05 | 1995-05-11 | Gary Louis Bolton | Substituted di- and tripeptide inhibitors of protein:farnesyl transferase |
| FR2736641B1 (en) * | 1995-07-10 | 1997-08-22 | Rhone Poulenc Rorer Sa | NOVEL FARNESYL TRANSFERASE INHIBITORS, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
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1996
- 1996-12-30 FR FR9616206A patent/FR2757855B1/en not_active Expired - Fee Related
-
1997
- 1997-12-03 PE PE1997001089A patent/PE28199A1/en not_active Application Discontinuation
- 1997-12-23 SK SK883-99A patent/SK88399A3/en unknown
- 1997-12-23 HU HU0001747A patent/HUP0001747A3/en unknown
- 1997-12-23 PL PL97334345A patent/PL334345A1/en unknown
- 1997-12-23 WO PCT/FR1997/002407 patent/WO1998029390A1/en not_active Ceased
- 1997-12-23 AU AU56694/98A patent/AU741921B2/en not_active Ceased
- 1997-12-23 ES ES97953000T patent/ES2172033T3/en not_active Expired - Lifetime
- 1997-12-23 BR BR9714498A patent/BR9714498A/en not_active IP Right Cessation
- 1997-12-23 AT AT97953000T patent/ATE214367T1/en not_active IP Right Cessation
- 1997-12-23 YU YU30299A patent/YU30299A/en unknown
- 1997-12-23 DK DK97953000T patent/DK0948483T3/en active
- 1997-12-23 CZ CZ992335A patent/CZ233599A3/en unknown
- 1997-12-23 KR KR1019997005966A patent/KR20000062391A/en not_active Ceased
- 1997-12-23 PT PT97953000T patent/PT948483E/en unknown
- 1997-12-23 EA EA199900608A patent/EA002114B1/en not_active IP Right Cessation
- 1997-12-23 EP EP97953000A patent/EP0948483B1/en not_active Expired - Lifetime
- 1997-12-23 JP JP52968698A patent/JP2001509147A/en not_active Ceased
- 1997-12-23 ID IDW990618A patent/ID22922A/id unknown
- 1997-12-23 CA CA002275943A patent/CA2275943A1/en not_active Abandoned
- 1997-12-23 IL IL13045397A patent/IL130453A0/en unknown
- 1997-12-23 DE DE69711081T patent/DE69711081T2/en not_active Expired - Fee Related
- 1997-12-23 TR TR1999/01502T patent/TR199901502T2/en unknown
- 1997-12-23 NZ NZ336042A patent/NZ336042A/en unknown
- 1997-12-26 MA MA24915A patent/MA26460A1/en unknown
- 1997-12-26 TN TNTNSN97214A patent/TNSN97214A1/en unknown
- 1997-12-27 DZ DZ970239A patent/DZ2389A1/en active
- 1997-12-29 CO CO97075391A patent/CO4920252A1/en unknown
- 1997-12-30 AR ARP970106263A patent/AR008950A1/en unknown
- 1997-12-30 ZA ZA9711734A patent/ZA9711734B/en unknown
- 1997-12-30 UY UY24832A patent/UY24832A1/en not_active Application Discontinuation
-
1999
- 1999-06-29 NO NO993225A patent/NO993225L/en not_active Application Discontinuation
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