AU628794B2

AU628794B2 - New labdane derivatives, a process for their preparation, and their use as a medicaments

Info

Publication number: AU628794B2
Application number: AU26368/88A
Authority: AU
Inventors: Vijay Atmaram Aroskar; Alihussein Nomanbhai Dohadwalla; Yatendra Khandelwal; Bansi Lal; Greta Moraes; Richard Helmut Rupp
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1987-12-01
Filing date: 1988-11-30
Publication date: 1992-09-24
Anticipated expiration: 2008-11-30
Also published as: AU2636888A; DK668788D0; HU203092B; PT89103B; ZA888937B; JPH01186877A; DE3740625A1; EP0318851A3; DK668788A; EP0318851A2; KR890009917A; HUT50807A; PT89103A

Description

&L ji5v0 1 I ri±fCjVLZALLUijn H AV Prokurist Authorized Signat ppa. Isenbruck i.V. Lapice PAT .510 628 79 4r1 COMMONWEALT14 OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Application Number: Lodged: Int. Class Complete Specification Lodged: Accepted, Published: Priority: 4 Ro'lated Art: 4r i Name of Applicant: Address of Applicant: Actual Inventor, Adidress for Service HOECHST AKTIENGESELLSCHAFT 3 unxigstrasso, D-6230 FrankfurL/Maln Fedcral RepubLic of Germany.

YATENDRA KHIANDELWAL, GRETA MOAES, VISHAL NAGAR BANSI LAL VIJAY ATMARAM AROSKAR, ALIHUSSETN NOMANBHAI DOHADWALLA RICHARD HELMUT RUPP, ,DIWD. wVA'rEItS SONS, 50 QU1 EN STIEET, MLIOUUNE AUSTRALtAt 3000.

Complete SpecificatIon for the Invention entitled: NEW LABDANE DERTVNVIVES FOR A PROCESS FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS Tho following statement is a full description of thIs Invention, lncliding the best method of perlormlng It known to u I r la HOECHST AKTIENGESELLSCHAFT HOE 87/F 360 Dr. KA/Je Specification New labdane derivatives, a process for their preparation, and their use as medicaments The present invention relates to new derivatives of polyhydroxylated Labdanes and their physiologically utilizable salts, to a process for their preparation, and to their use as medicaments.

Polyhydroxylated labdanes and their derivatives have already been described in: German Offenlegungsschriften Nos. 2,557,784, 2,640,275 and 2,654,796; Tetrahedron Letters No. 19, pages 1669-1672 (1977); J. Chem. Soc., Perkin Trans. 1, 767 (1982), and in European Patent 'Applications EP-A 0,217,372, EP-A 0,191,166 and EP-A 15 0,193,132.

I As a consequence of the pharm6cological properties of the polyhydroxylated labdanes and their derivatives they are suitable for the treatment of cardiovascular disorders, 20 high blood pressure, glaucoma, allergies and asthma, and they act as immunomodulators and act to stimulate adenylate cyclase.

im l The polyhydroxylated labdanes according to the invention 25 are neither described in the publications mentioned as state of the art nor are they obvious from the latter.

Coopounds of the state of the art, which in some cases are structurally related to the compounds according to the invention, are the derivatives which have an amlinoacyloxy group or hydroxyacyloxy group in the 7-position.

The essential difference between the compounds according to the invention and those of the state of the art is that, in the compounds according to the present invention, one of the bonds between the carbon atoms In the 5- and 6-positions or in the 6- and 7-positions is a dlouble bond, or both bonds are single bonds, in the Latter case the 6substituent being onLy hydrogen. Surprisingly, these structural changes alter the pharmacological profile of the compounds, resulting in these compounds being mor'e suitable for the treatment of diseases with heart failure, such as congestive cardiomyopathy and related indications, for the treatment of hypertension and for the treatment of elevated intraocular pressure.

Hence the present invention relates to new derivatives of poLyhydroxyLated Labdanes of the formula I [OR14 *4 4 4 4 *4 44 14 4 *4*4 4t 44 4 4 4 If 4 4 *4*4 4* 4 1 *4 4 44 4~ 4 4 44 44 44 4 4; in which Rl denotes OH, 0-aLkyL or a group of the formu~a II A RlS R3.

7 A i R21

R

16 RleR2

R

22 4*444* 4 4 *1444 4

I

4*44 44 4* 0 20 in which A and A' represent oxygenl or sulfur, 8 represents -CH 2 oxygen, sulfur or RIS-R 23 represent hydrogen, aLkyL, aryL, araLkyL, hydroxyL, acyL, alkoxy, iercapto, haLogen or a group of the formula NR24R25t in which R24 and R25 denote, if they are identical, hydrogen, aLkyL, substituted aLkyt, aryL or araLkyL, or, if R2 4 represents hydrogen, R25 denotes aLkyL, substituted atkyL, cycLoaLkyL, aratkyLp aryL, a heterocyctic radical, amino, diaLkyLaminot aLkyLamino, aryLamino, araLkylamino, hydroxyL, mercapto, acyLoxy, acyt, carbamoyl, carboxyatkyL, carbaLkoxyaLkyL or diaLkyLaininoatkyto or, if R24 represents alkyL, R25 denotes substituted atkylL, cyctoalkylt aryL, araLkyl or diaLkyLaminoatkyt, or R 24 and RaS represent, together with the nitrogen atom to which they are bonded, a heterocycLic radlical which can have one or more hetero atoms and be optionally substituted once or several times by alkyl, aryl, hydroxyalkyl, halogen, hydroxy, aLkoxy or other heterocyclic groups, with the proviso that the radlical of the formula II contains at Least three of the substituents R 15

-R

2 3, at Least one of the three substituents having a hetero atom of the group comprising N, 0 or S, and L, m, n, L'g, ml n' and p each denote 0 or an integer from 1 to 10, or Rl represents a radlical of the f r muLa e C* O- -C-R23 0 4 16 klB in which A, R 1 6-R 1 8 and R 2 3 have the same meaning as indicated above, if I R7 denotes OH, 0-aLkyL or a radical of the formula II A R3.S R,17 A'R9 R 2 1 O-C.(C)1(CH2)m(C)n (BC-C)j-(H2)m-)n p23

R

1 6 RiB R 20 R2 or of the formulae x 0 ~or 0 in which A, L. m, nt LI, il', n00 p and R 15 R2 have the some meaning as indicated above,

R

14 denotes vinyL, ethyl, cyclopropylL, CHOIICH 2 OU, CH 2 0H z or the rtadicalL -CuCH 2 in which I rep~resents halogeni such as Whorine, bromine or ftuorine, X represents pharmacoLogicatty utilitabLe sats thereof, 4 and the dotted Lines denote that a dloubLe bond can be present in either the 5,6- or the 6,7-position, with the proviso that Rl and R 7 are not both OH groups.

A preferred group of compounds of the present invention are compounds of the formula I in which: Rl denotes OH, R7 denotes a group contributing to the radlical of the formula Il described above, represented by the formuLa III 0 R15 0OR19

.OC-(C)

1 C)1'JpR 23 I in which L, B, R 15 R16, R19, R2 0 and R 2 3 have the abovementioned meaning, or a radical of the formula

I

110 0 0 -0 -C -C C -R2 16 LB1 in which R16, R18 and R 23 represent hydrogen,

R

14 denotes vinyto ethyL, cycLopropyL, CHOHCI 2 Oi, 15 CH 2 OH or -1ucliat in which Z represents haLogen such as chlorine, bromine or fluorine, and a double bond is Located in the 6 -positione with the proviso that in the radicak III 0 RJ5 0 R1 at least one of the substitueits RISP R160 Rj9, Rao, R23 or 8 contains an atom from the group compriging No O or S.

A second group of preferred compounds are those where R 1 and R 7 each denote OH, QAc or a radical of the formula 11" A Rls

II

Rio z

R

1 4 denotes vinyl, ethyl, cyclopropyl, 01-O1-01- 2 O11 or C-01-1 2 1 In which Z represents halogen such as chlorine, bromine or fluorine, and a double bond Is located In the 5,6.-position, with the proviso that at least one of the substituents R, and R 7 denote the radical IV" A Rio 0OC---(C) 1

R

23 fill 1 0 In which A, I, RIB, RIG and R 2 3 have the abovementioned meaning, but at least one of the substltuents RIS, Ft 16 and Ft 2 3 contains an atom from the group comprising N, 0 or S.

4FThe term "talkyl" 'tin the substituents RisR8 2 s Is to be understood to mean ii stralght-chaln or branched alkyl radicals having up to 6, and preferably up to 4, carbon atoms, for example methyl, ethyl, Isopropyl, t-butyi and n-butyl.

1Is The term "substituted alkyl groups" In the moaning of R 2 4 and Ft 2 6 Is to be understood to moan hydroxyC-C00alkyl such as hydroxyothyl, carboxyC-Ce- a 1k,1 such as carboxyothyl, and carb.C 1 *Ce-alkoxyaikyl such as carbethoxyothyl.

The term "cycloalkyl groups" In the moaning Of R 2 4 and Ft 2 5 Is to be understood to moan. Cx-C7.cycloalkyl groups, In particular cyclopontyl, cyclohexyl or cyclohoptyl.

The torm "araikyl groups" In the meaning of R24 and R126 Is to be understood to mean phenylalkyl groups, In particular phonyl-i.t.-alkyl, for example the benzyl group, In which the phenyl group can be substituted by one or more substituonts such as halogen. Cl-.C 3 aikyi, Ci 0 a *3alkoxy, nilro or trifluoromothyl.

The term *'aryl groups" In tho (neaning of P 2 4 antd P1 2 6 Is to be understood to mean 2 the phenyl group, which can be substituted by one or more substiiuents such as halogen, cl- C1-C-alkyl, Ci-C3-alkoxy, nitro or trifluoromethyl.

The term "acyl groups" in the meaning of R 1 i-R 23 and R 25 is to be understood to mean C 1

-C

6 -alkanoyl, C 2

.C

6 -alkenoyl, aroyl, aryl-C1-C 6 -alkanoyl or a heteroaroyl group having up to 10 carbon atoms, in which one or more carbon atoms can be replaced by oxygen, nitrogen and/or sulfur.

Examples of alkanoyl groups of this type are formyl, acetyl, propionyl, butyryl, Isobutyryl, valeryl, palmltyl or bromolsobutyryl, preferably lormyl, acetyl or propionyl. The alkanoyl groups can contain one or more double bonds, for example acryloyl, stearoyl or oleoyl. The alkanoyl groups can contain one or more triple bonds.

1 0 They can, in addition, contain one or more double bonds. An example of such alkynoyl groups Is propiolyl. Aroyl groups are represented by, for example, benzoyl, in which the phenyl group can be substituted by one or more substituents such as Ci-C 3 -alkyl,

C

1 -C3-alkoxy, halogen, nitro or trifluoromethyl. Examples of aralkanoyl and heteroaroyl groups are phenylacetyl and pyridine-3-carbonyl, respectively.

1 5 Dialkylamlnoalky groups are to be understood to be those in which each of the alkyl groups contains 1 to 6 carbon atoms, such as diethylaminoethyl.

Where R 24 and R 2 a, together with the nitrogen atom to which 9- 4. O s I1 -7 they are bonded, represent a heterocycle, preference is given to piperidine, pyrrolidine, morpholine, piperazine, thiomorpholine, imidazole or theophylline, each of which can be substituted once or several times by C 1

-C

4 -alkyl, Ci-C 4 -alkoxy, aryl, aryl-C 1

-C

4 -alkyL, hydroxyl, amino, or substituted alkyl or amino.

Suitable examples of salts of the compounds of the invention with inorganic or organic acids are hydrochloride, hydrobromide, sulfate, phosphate, acetate, oxalate, tartrate, citrate, maleate or fumarate.

In the formulae depicted here, the various substituents are shown as connected to the Labdane nucleus in one of two modes of representation: a full Line which t indicates a substituent in the $-oriontation above 15 the plane of the molecule), and a broken Line which S indicates a substituent in the a-orientation below the plane of the molecule). ALL the formulae are drawn in such a way that they depict the compounds in their absolute stereochemical configuration. Since the starting materials having a Labdane nucleus are naturally occurring or are derived from naturally occurring materials they have, as do the final products, a labdane nucleus existing in the single absolute configuration depicted here. However, the process of the present invention is also meant for application to the synthesis of labdalnes of the racemic series.

In addition to the optical centers of the Labdane nucleus, the substituents thereon may also have chitral centers which contribute to the optical properties of the compounds of the present invention and after a means for their separation by conventional methods, for example by the use of opticatly active acids, A wavy Line connecting a group to a Chiral center indicates that the stereochemtstry of the center is unknown, i.e. the group be present in any of the possible orientations. The present invention embraces alt the optialt isomers and rreemic forms of the

~_IIC~~

i i i- 8 compounds of the present invention when such compounds have chiral centers in addition to those of the Labdane nucleus.

Some of the new derivatives of polyoxygenated Labdanes according to the invention are listed in Table I.

Table I

HO

OC-(C) iCB-C(CH 2 )mp R 23 I la

R

1 6 1 R 1 5 R1 6 p B m' R 2 3 X M.P. (C) 2 H OH 0- 0 H 182 184 (R-config,) 0 0 0 CH 3 160-162 1 H H 1 0 0 H 116 118 1 H H 0 0 OH IS6 1 H H 1 0 1 ND 108 110 4 44 1 H H 1 0 1 HC1 2,17-219 t 1 HI R 1 0 1 N'O HCI 192 -194 (2) I H H 1 0 1 N(CH 3 2 HO 1 209 H H 1 0 N (C 11 HC1,14 0 130 133 Ii~~ NC1 5 2 tii 2 v 1' it 10 1H 0 rc 101 2IC 0H 138 1 H it 1 0 1 Ni NCH 3 2H It'H 2 0 177 180 1 II H 1 0 1 N KC 11 5 lc14tsy 2 O 157- 160 1 H H 1 0 2 N(0H 3 2 III01SHP 178 1 it it 1 0 2 N 0 1101 189-190 I H It 1 0 2 NQN'CIt 211C-11H 2 0 230 3 9- Compound of the formula [IOH1O Melting point 151-153 0

C

OCC-H (R configuration) Tables II and III List compounds corresponding to the second group of preferred compounds defined above having the formulae lb and Ic, respectively.

Table I I Sf S S I ft S 55 ii S 5,5* IS t~ t.~

S

511 s I, S

S

S SI

II

S St

S

*1 5 t *4 11*151

S

IS

1*

S

1 RIS R 16

R

23 M p. *C)

OCOCH

2

O

OHl

OH

OR

ont O H 3

NHCH

3

NH(CH

2 2 C.H3 NHC6HS

-N(CH

3 2 ~NG N-H HC. 0 15H 2 0 0,51120 0,5 H(20 JI12,R12 123 -125 233 -234 117 -118 240 217 113 -114 238 199 -200 192 2.93 19 202 -204 i i i It ii 'i i Table III 0 RIS1 00c-'()-R 23

R

1 6 x Ic M.p.

R

1 5 R16

R

2 3

S

4 .4

I,

Ii 1 *f i 455 NMe2 NEt 2

C

N

CO

N ~Me )Q11 HC1 HC1 HC1 HC1 HC1 HC1.H 2 0 2HCl.H20 HC1 HC1 HC1. 0, 5H20 243 210 211 220 221 227 228 215 216 193 195 220 223 203 20)4 228 230 219 220 R H WQD' Ph U H N 0 \-4CH3 HCI .120 194 195 191 192 A -1 11 Tab~e III, continuation

R

1 5

R

1 6

R

2 3 Mn.P. aC) 9 4 A *V

A

4 44*1 I

A

4 jet' C A 4 4 4* A I 4.

4 4 4 Al 'sAt 4 IA A NMe 2 NEt 2 N 0O N~4.Me NMe 2 NEt 2 d~.CH 3 163 164 153 154 169 170 168 169 154 155 177 178 149 150 185 186 183 186 196 197 0' 5 H 2 0

OH

H H CxPh H H t 132 133 172 173 166 169 12 Table III, continuation 1 RIS R 1 6 R 23 x (OC) 4 H H N 0 -168 -169 4 H H IN' -CH 3 6 16 1 H CH 3 NoHC1 225 -226 The invention also relates to a process for the prepara' tion of new derivatives of polyhydroxyLated Labdanes of the general formula 1.

The process comprises reaction of a compound of the formula 1 g ORO 14 ex C7 in which

R

1 represents H and R7 represents OH or the group 0

O-C.-CH

2 0H, or R 1 represents a protective group for a hydroxyL group, such as, for exampLe, the t'-butyLdimethytsiLyl group, and R7 represents OH o~r the group a) with a comspound of the formuta III A *lsRi A' Rjg R2 1 II hI

R

1 6 R 18 R0I2 in which RIS5 R2Zt A# Al, Bo to, mp no in', n' 'and p have the aboveinentiontcd meaning!, arnd R 2 3 represents a 13 halogen atom such as CL, Br or I, or the group OW, W representing aryL-Cj-C 6 -aLkyL or aryL, to give a compound of the formuLa I in which Rl and/or R 7 denotes a radlicaL of the formula 11 A R1i 5

R

17 A' R 19

R

21

I

0-C (C)1-(H2)m-(C)n-[BCCk)'ICH2)m'(C)n, ]r.R23 R16 ReR 20 R2 in which R15 R22, A, B, L1, m, 1O' m' n' andi p have the said meanings, and R 23 reprqsents a halogen atom or an O-aryl-C 1

-C

6 -aLkyL or aryl radical, and elimination by customary methods of Rif it represents a protective ~10 group, or b) with a compound of the formula 91 HOC CH -CH2 0* 0~ 0 4*x fit it to give a compound of the formula I in which one of the two substituents RI and R? represents the radical OC CH- CH 2 0 0 09 where appropriate 0) treatment of a compound of the formuLa i iA 4

IX

14 in which one of the substituents Rl and R 7 represents the OH group, and the other represents a radical of the formula OC CH CH 2 0 0 0 with an organic acid, resulting in a compound of the formula I in whi8 ejher R 1 or R 7 represents the radical -O-C-CH-c+4S~ Xand the other represents the OH group, or d) reaction of a compound of the formula I in which one 10 of the substituents R 1 and R 7 represents the radical

-OCCH

2 R2 3

R

23 denoting halogen, and the other represents the OH group, with sodium formate to give a compound of the formula I in which one of the substituents

R

1 and R 7 represents the radical -OCOCH2-O-CHO, e) where appropriate reaction of the compound obtained in step c) with aluminum oxide to give a compound of the formula I in which one of the substituents R I and P7 represents the radical -OCOCH 2

OH,

f) where appropriate initial acylation, by customary methods, of the compound of the formula I obtained in step and subsequent reaction of the resulting compound with an amine of the formula tH9 2 4R 2 5, in which R 2 4 and

R

25 have the abovementioned meanings, to give a compound of the formula la

Q'_

1 R 14 I 15 in which one of the substituents R 1 and R 7 denotes the OH group, and the other denotes a radical of the formula 0 0 W I1

OC-CH

2 -0-C-(CH2)m'R23 in which m' has the abovementioned meaning, and R 2 3 represents the group -NR 2 4 R2 5

R

24 and R 2 5 having the abovementioned meanings, g) where appropriate, initial reaction of a compound of the formula in which R 1 denotes a protective group for a hydroxyl group, and R 7 denotes OH, with a compound of the formula IV

IV

Tot i in which T denotes oxygen or sulfur, subsequent addition of an amine of the formula HNR24R25 to the reaction mixture, or by treatment of a compound of formula I' with potassium cyanate and trifluoroacetic acid and finally elimination of the protective group in the 1-position in a known manner, resulting in a compound of the formula I in which R denotes OH, and R denotes a radical of the formula

-OCONR

24 R25, in which R 24 and R 25 have the abovementioncd meanings i h) where appropriate acylation of a compound of the *t formula I in which R 'denotes a protective group for a hydroxyl group, and R 7 denotes OH, with a compound of the formulae Hal C (C)1 Hal V R16 or

H

1 5 ^17 HOOC C e C li

I

16 in which Hal denotes a halogen atom, and R 15

R

17 and R 18 each represent hydrogen, optionally substituted C 1

-C

6 alkyL, aryL or aryl-C 1

-C

6 -alkyl, reaction of the resulting reaction product with an amine of the formula

HNR

2 4

R

2 5 in which R 2 4 and R 2 5 have the abovementioned meanings, and finally elimination of the protective group in the 1-position, resulting in a compound of the formula I in which R 1 represents the OH group, and R7 represents a radical of the formula 0 R 1 0

-OC-(C)

1

NR

24

R

2 R16 in which R15 R 1 6, R24, R 25 and I have the abovementioned meanings.

4*

I(

a The acylation in steps a) and b) is carried out in organic solvents such as ethyl acetate or dichloromethane in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, and of a catalyst, such as a tertiary amine.

I 4 1*~t 14 Examples of tertiary amines which may be mentioned are 4-dimethylaminopyridine or N,N-dimethylaniline, preference being given to 4-dimethylaminopyridine. The temperature at which the acylation is carried out is not critical, but it is preferable to carry out the reaction at a temperature in th2 range 0-50°C. It is most preferable to carry out the acylation reaction at 27 0 C 30 0

C.

The reaction is carried out for a period of 16 24 hours.

The most preferred period is 16 hours. The compounds of the formula I are isolated from the reaction mixture in a known manner. For example, the reaction mixture is filtered and the filtrate is washed with bicarbonate solution and water, dried over anhydrous sodium sulfate and then concentrated. The resulting residue is purified by flash chromatography and then recrystalltted from organic solvents such as petroleum ether/ethyl acetate mixture.

17 17 The derivatization of compounds of the formula I in which one of R 1 and R7 represents hydroxyl, and the other of

R

1 and R 7 represents a group of the formula

HH

I I

O-C-C-C-H

11 1 I 000

X

is carried out in a manner known to the expert, by treatment with organic acids such as p-toluenesulfonic acid or acetic acid in alkanols, such as methanol, as solvent and at room temperature, in order to obtain the corresponding derivatives of the formula I in which R 1 or R 7 is a radical of the formula O- CH- nII I L* f O0 OH Fe the derivatization of compounds of the formula I in 4 'which one of the substituents RI and R7 is -0 CH2R2j and 0 R23 represents halogen, they are treated with sodium Si" 15 formate in an organic solvent such as hexamethylphosphor- *n amide at room temperature, in order to obtain the corresponding formyl derivative of the formula I in which R 1 0 or R 7 represents -0-I-CH 2

-O.CH

The Latter compound is further reacted by treatment with aluminum oxide to give a compound of the formula I in which R 1 or R7 represents the hydroxyacetoxy group 0-CO-CH 2 OH. The Latter compound is further reacted by acylation with carboxyltc acids of the formula V 0 0 IC II 2 )m9R 23

V

and subsequent treatment with an amine of the formula -18

HNR

2 4

R

2 5 in which R2 4 and R 2 5 are as defined above, to give a compound of the formula I.

The process for the preparation of compounds of the formula Ib (Table II) comprises initial reaction of a compound of the formula I' with a compound of the formula

IV

T

11 I in which T is oxygen or sulfur, and then addition of an amine of the formula HNR 24

R

2 5 in which R24 and R 2 are as defined above, to the reaction mixture, in organic solvents such as ethyl acetate, at room temperature and with maintenance of an inert atmosphere by, for example, So nitrogen gas, and stirring for a total period of 26 to

I,

36 hours, or by the treatment of a compound of formula I' 15 with potassium cyanate and trifluoroacetic acid. The removal of the protective group, for example alkylsilyl, in the 1-position and the isolation and purification of the compound of the formula I from the reaction mixture are carried out in a known manner.

•20 '9r The process for the preparation of compounds of the Q t ft formula Ic in which R 7 represents the radical ,9 S -OCO-( l-R 2 3 (Tab. III) comprises two stages. The 16 first stage comprises the acylation of compounds of the formula I using an equimolar aAount of a haloalkanoyt halide of the formula V A I 1 Hal C Hal V in which R 1 5 R1i6 and IL are as defined above, and Hal represents halogen such as chlorine or bromine, in the presence of a base such as pyridine or triethylamine, or acylatlon using a carboxyLt acid of the formula VI 19

R

15

R

17 I I HOOC C C RI 8 in which R15 R 16 and R 18 represent hydrogen, alkyl, substituted alkyl, aryL or aralkyL, in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine in organic solvents. The second stage comprises reaction of the acylated product with amines of the formula

HNR

24

R

25 in which R 24 and R25 have the same meaning as described above.

The reaction in the first stage can be carried out at temperatures of 0 C to room temperature and in solvents such as aromatic hydrocarbons, such as benzene or toluene, or ethers, such as dioxane or tetrahydrofurar, or halogenated hydrocarbons, such as chloroform or methylene chloride, ethylacetate, dimethylformamide. The reaction 99 .on 15 is carried out for 0.5 to 24 hours. The product which is o o- formed is isolated by dilution of the reaction mixture with the 2 solvent which is used, washing successively with water, dilute hydrochloric acid,water, sodium bicarbonate and water, and Sdrying over anhydrous sodium sulfate and, finally, concentration in vacuo. The resulting residue is a mixture of compounds and is, where appropriate, used without o to purification in the second stage of the reaction with amines of the formula HNR2 4 9 25 The second stage of the process is carried out at temperatures in the range between room temperature and 150°C, for 0.5 to 6 hours, with or without solvents.

The solvents which are used are aromatic hydrocarbons, such as benzene or toluene, ethers, such as tetrahydrofuran or dioxane, or halogenated hydrocarbons, such as chloroform or methylene chloride. The product is isolated from the reaction mixture by concentration of the reaction mixture, followed by extraction using an organic solvent, washing of the extract with water, drying of the organic layer over anhydrous sodium sulfate, concentration of the extract, and purification of the resulting residue by either crystallization or chromatography.

The starting material for the preparation of the compounds of the invention is, for example, 8,13-epoxyla,9a,7a-trihydroxyLabda-5,14-dien-11-one, of the formula 1 in which R 1 and R 7 each denotes the OH group, and R14 denotes the vinyl group. It can be prepared by methods already described in the literature. It can also be prepared starting from forskolin, in which initially the 1-hydroxyl group is protected by acetyl or t-butyldimethylsilyl by customary processes, and which is then treated with thionyl chloride and pyridine in an anhydrous solvent, for example dichloromethane, at OOC. The reaction mixture is stirred at room temperature for 18 hours, f*f and then the product of the formula VIII I *h VII I **0 in which RI represents a protective group for the OH group, for example -OAc or -OSI(CH 3 )2C(CH 3 3 is isolated. Treatment of the compound with non-aqueous alkali, for example NaOH in methanol, at room temperature with stirring and for a period of 3 hours results in a compound ol the formula IX

IX

'.0 I OH which can be used as starting compound for further reactions.

The compounds of the invention obtained as free bases can if desired, be converteo into an Inorganic acid addition salt such as hydrochoridae, hydrobromide, sulfate or phosphateh or into an organic acid addition salt 1 21 such as the salt of formic acid, acetic acid, fumaric acid, maleic acid, citric acid, tartaric acid, lactic acid or methane-sulfonic acid.

The compounds of the present invention and their salts have the pharmacological properties attributed in the literature to the class of polyhydroxylahed labdanes and their derivatives. However, they exhibit in a more specific manner a selective positive inotropic activity, antihypertensive activity and reduction of the intraocular pressure. This is shown by the following pharmacological experiments.

Positive inotropic activity The following method was used: Guineapigs of both sexes and weighing 400 g were sacrificed, and the heart was removed and placed in Ringer's solution at room temperature. Both the left and the right atria were then isolated and fixed in an organ holder, and the preparation was placed in an organ bath containing Ringer's solution and maintained at a temperature of 32 0

C.

Carbogen (95% 02 and 5% C0 2 was then bubbled through the 20 organ bath. The compound to be tested is dissolved directly in water together with a stoichiometric amount of 0.1 N HCI S' or a salt thereof to give a solution of known concentration and the latter is added to the bath. The contracti- ,p lity of the atrium is recorded for 7 to 10 minutes on a 25 Nihon Kohden 4-channel pen recorder with an isometric Sstrain gage. The activity is expressed on the basis of the resulting data as the ECSo.

The results obtained for representative compounds of the invention are given in the table which follows.

aza Compound

H~

R

7

COCH

3

COCH

2 0CHO Guineapig atrium

EC

50 pg/mi 0,028 0,024 *4 41 4 4 *4 I 44 14 4*44 54 4* I S t *4 4 4,44 4* 4 4i

S

1 44 4 4 4* 44 4 4 4* 4 I S4~ ~t 4 4 is 4 4 *4 *4 4

R

7 COCH- CH 2 0H

OH

CONHCH

3 CON4 N-CH 3 \-j Compound 0, 0008 0 *051 0,3 044 HC1 Gu'fneapig atPiuM Ecs 0 Pg/Mt ,b Co

COCH

2 A4'" 0,079 -23- Continuation Compound Guineapig atrium EcSO iig/mL

R

7 C0(CH2)2O 0,28 CO (:CH 2 t~-Me 0,30 CO(CH2) 3 NEt 2 0,037

CO(CH

2 3 14 NMe 01

CO(CH

2 )4NMO2075

CO(CH

2 4

NMO

2 0,615 C0(c-H 2 4 a 01 Compound Gufn#4lg AtU

ECS

0 UIimL

HQI

OXX

cOCH240 HOC3 0.,072 C0C1l2N4( C2S) 2 MCI 0.72 MCI 0*14 COCH2t COCfl2-w MCI 0,3 C6)13 rC0(C12)afl(CH3)2 0,1058 23a Continuation compound Guinocaping atrium R7x

EQ

50 pg/ni

COCH

2 OCOC1H 2 NMe 2 1HC1 0.8 COCfl 2 OC0CH 2 NEt 2 1101-11 2 0 0.018

COCH

2 0COC 2 N$D IIC) COC11 2 COC112 QO f~cX C0CR 2 OCOCfI 2 W-P<%O 11Cl, 1120 0,72 COCII 0C0C1~N, -u 211C3.H2 0.44 COCII000 (Cllz 2IK.jCn3 2110H '120 I i~ V it

V

#1 ft ft

V

-24 Reduction in intraocular pressure Measurement of the intraocuLar pressure in conscious rabb its For this experiment rabbits of both sexes and weighing 2 to 3 kg are used. The intraocular pressure (10P) is measured with a Schioetz tonorneter after corneal. anesthesia with 2% strength novocaine soLution. A compound according to the invention, or a saLt thereof, is suspended in a concentration of 2% in 0.5%4 CMC. After the baseline value has been determined, 100 piL of the suspension of the test compound are instilled in a concentration of 2%4 into one of the eyes, while the other receives vehicle.

The IOP is measured at defined time intervals, i.e. after 1, 4 and 5 hours. The percentage reduction in the IOP is calculated using the baseline vatue.

9 goo* The results obtained for representative compounds of the invent ion tested in this model are given in the table which folows; Compound Reduction of IOD SDose X decrease Duration percentage in IOD (mini) 9H R7R

(R)

.Co. H-CH20H025 30> 0

OH

c0aItL, 10U#>36 UAONllCll 23 24 to 360 II U Continuation Compound Activity of decreasing I00 Dose 2 decrease Duration percentage in 100 (mins) R7 X

CONH(CH

2 3

CH

3 -1.00 27.0 360 C0N37 1,00 26,0 240 f-

COCH

2 N 0 -2,00 20.3 360

COCH

2 fN -CH 3 H] .02. 6 a e t Antihypertensive effect Stood pressure in tats., Cats of both sexes and weighing 3 to 4 kg were anosthetized with ether and maintained under chLoraLose anesthesia (70 mglkg Cannutas were placed in the femoraL artery and in the femorat vein to recoed the blood prossure and to administer the medicament, respectively. The t Itt blood pressure in the lemotaL artery was recorded using a Statham P 23 Ob pressure transducer on a Nihon-Kohden pen recorder for physioLogical 'purposes. The compound to be 4 tested was dissoLved.. If a salt, in distilled water,, otherwise in propylene glycoL and administered introvenously.

The fall in blood pressure and tta duration of the hypotensive activity were determined.

The results obtained for representative compounds of the invention are givtn in the table which fotlowst 26 Compound Dose Decrease in SP Duration (mm Hg) (Mins) lieP ho RRr X rfr- CON 0 -132 Of it COCH 3 HCI 1 30 4#i it COCCa NO -cH3 H CZ1 30 120 COCH2N HCI 1 40 1 40 9 COCHIN (Cs He aHC 1 36 44411 The invention is illustrated, but not restricted by the exampLes which folLow.

EXAMPLE I 1 6,78 -oiac toly-8e, 1 3-ep o xy-e9a hyd r oxKy~larbd a-514- dien-i1one Freshly distilled thionyt chloride (1.2 Wl) was added at 0 0 C to a stirred mixture of i.17diactoxY=60,.9casdihydroxyM8, 13-poxyLabdami4-en-1 tone (5.0 g: 11.06 mmoL) dry dichlorowethane, (200 ml) and dry pyridine (2.5 mL, 30.9 mmol), The stirring vas continued at 0OC for a further half hour and at room temperaturt for 18 hours.

-2T' The reaction mixture was poured onto ice. The organic Layer was separated off and washed with water, strength HCl and 1% strength aqueous sodium bicarbonate solution, followed by water, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in a mixture of ethyl acetate:acetonitrile and filtered through florosiL (60-100 mesh). The filtrate was concentrated, and tfle residue was crystallized from ethyl acetate/petroLeuto ether. YieL,_ 80.2%. Melting point 190- 192 0 C EXAMPLE 2 8,13-Epoxy-1ca,9c,7-trihydroxyLabda-5,14-dien-11-one 6 Sodium hydroxide (1.03 g, 25.75 mmIoi) in water (30 ml) was added at room temperature tr, a stirred solution of 1a,78-diacetoxy-8, 13-epoxy-9cz-hydroxyLabda-5, 14-dien-1 1one (3.13 gt 7.21 mmol) in methanol (150 ml). The stirring was maintained for a further 3 hours, and the reaction mixture was cooled in an ice/saLt bath. The crystal- Line compound separated out. The crystals were filtered 20 off and dissolved in ethyL acetate. The organic Layer was washed with 10% strength aqueous HCI followed by water, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate/ petroleum ether. Yield 95.78%. Melting point 182-183 0

C.

I425 EXAMPLE 3 ?(;-ChLoroaceto, y-l1,9a-dihydroxy-8,13-epoxyLabda-5, 14en-I I-one Chloroacetyt chloride (0.38 ml.. mmol) was added to a cooled, stirred solution of 8,13-epoxy-1l,7B,9a-trihydroxyLabda-5,14-dien-11-one (1.5 g, 4.29 mmoL) in dry dichtoromethone (200 ml) and dry pyridine (1.0 ml). The stirring was continued at 0 0 C for one hour and then at room temperature for a further hour. A second aliquot of chLoroacety( chloride (0.1 ml, 1.26 mmol) was added to the reaction MixtUre, and the stirring was continued 28, for an additional 2 hours. The reaction mixture was diluted with chloroform, and the organic Layer was separated off, washed with 10% strength HCL followed by water, dried over anhydrous sodium sulfate and concentrated. The residue was used without purification in the next stage. Yield 97.38%.

EXAMPLE 4 1,la?-Di-2-bromopropionyLoxy-8el3-epoxy-9a-hyd,,oxyLabda- 2-8BromopropionyL bromide (0.56 ml. 5.35 mmoL) was added to an ice-cooled, stirred mixture of 8,13-epoxy-lcz,70,9ce trihydroxyLabda-5,14-dien-11-one (0.85 g, 2.43 mmoL), pyridline (0.5 ml, 6.18 mmoL) and dlichLoromethane (50 Wl.

The reaction mixture was stirred at room temperature for half an hour. A second aliquot of 2-bromopropionyL bromide (0.56 ml, 5.35 mmoL) was added to the reaction miXtLteo and the stirring was continued at room temperature for a further 6 hours. The reaction mixture was concentrated in vacuo. The residue was extracted with dichloromethane. The organic Layer was separated off, washed with 10% strength HL and water, followed by brine, and concentrated, and the residue was used without further purification in the next stage.

EXAMPLE lc,,9c-Dihydroxy-813-epoy-7B-morphoLinoacetoxyLabda- 5,14-dien-il-one A mixture of 70-chtoroacetoxy-1c*,9ct-dihydroxy-8,13-epoxy- Labda-5,14-dien-1,1-one (0.85 go, 2.0 mmoL) and morphoLine mL) was sti;rred at room temperature for 10 min. The reaction mixture was concentrated in vacuo, and the residue was extracted with ethyL acetate. The organic Layer was wahed with brine and dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from chloroform/peitroleum ether, yieLd 56.3%.

Melting point 164-166 0

C.

-29, The following compounds were prepared in a similar manner.

The first eLeven compounds were converted by treatment with ethereaL HCL into the corresponding hydrochLoridles.

1. lc*,9c-D ihydroxy-78-dimethyLaminoacetoxy-8, 13-epoxy- Labda-5,14-dien-11-one, m.p. 208 210 0

C.

2. 7B-D iethyLaminoacetoxy-l*,9cz-dihydroxy-8, 13-epoxy- Labda-5,14-dien-11-one, rn.p. 169 170*C.

3. 1c*,9cx-O ihydroxy-8, 13-epoxy-7a-pyrroL idinoacetoxy- Labda-5,14-dien.-11-one, rn.p. 206 2W)8C.

4. lte9t-L)ihydroxy-8,13-epoxy-7$-piperidinoacetoxy- 14-d len-il-one.

S. 1c,9c-Dihydroxy-813-epoxy-78-homopiperidinoacetoxy- Labdla-S,14-dien-l1-one, in.p. 154 155 0

C.

*IV*

6. iQt,9ci-Dihydroxy-8,13-epoxy-70-morphoLinoacetoxy- Labda-5,14-dien-11-one, 164 166*C.

7. lci,9c-Dhydroxy-8,13-epoxy-7Q-N-methyLpiporozinoacetoxyLabda-5,14-dien-ll-oner m-p. 219 220 0

C.

8. 1Qt9c-Dihydroxy-8,13-epoxy-78-thiomorphoLinoacetoxy- Labda-5,14-dien-11-ono, ni-p. 157 41 %20 9, 1ci9c-ihydroxy-8,13-epoxy-70-(4-inthytpiperidinoacetoxy)tabda-5,14-dlien-11-onst m.p. 204 205*C.

1a,9*-Dihydroxy-8,13-epoxy-70-(3- methyLptperidinoacetoxy)Labda-5014-dien-11-one, Mn.P. 179 110 11, 1cx9a-bihydroxy-8, i3'epoxy=?'.(4-( -hydroxy-4- 'henyl)as piperidinoscetoxy)Labda-5#14-dien-l1uone, M.P. 165 -166*C.

12. lo~-iyrx-8(,6dmtyaioopoio actooy)-8, 13-.poxytabda-5, 14-.con-1 1-onet flbP. 191-192C- 13. lcz,9*-D ihydroxy-70-(4-N,N-dimethyLarninobutyryLoxy)- 8,13-epoxyLabda-5,14-dien-11-one, m.p. 177 178-C.

14. 1o,9ca-Dihydroxy-70-(4-diethy,aminobutyryLox')-8, 13epoxyLabda-5,14-dien-11-one, rn.p. 149 150'C.

15. lc*,9ceO ihydroxy-8, 13-epoxy-7B-(4-piper idinobutyryL.oxy)Labda-5,14-dien-11-one, M.P. 185 186*C, 16. 1a,9ca-Dihydroxy-8,13-epoxy-7-(4-mo~rphoL inobutyryLoxy)Labda-5,14-dien-11-one I m.p. 183 184'C.

17. 1ot,9cz-D ihydroxy-8,13-epoxy-70-(4-N-methyLpiperazinobutyryLoxy)Labda-5,14-dien-11-one, m.p. 196 197 0

C.

18. lt,9c-Dihydroxy-8,13-epoxy-70-C4-(4-hydroxy-4-.nhenyl)piper idino)butyrytoxyJtabda-S, 14-dien-11-one,m-p- 132-133*C.

19. 1ca,9c-ihydroxy-7$-(5-dinethyLaminovateryLoxy)-8 13epoxy~abda-S,14-dion-1i-onel m.p. 172 -173 0

C.

20. lci,9cx-o ihydroxy-8,13-epoxy-7Q-(5-piperidinovateryLoxy)Labda-S,14-dien-11-one 1 M-p. 166 169 0

C.

21. 1c,9cx-Dihydroxy-8e13-epoxy-7B-(5-nmorphoLilnovateryLoxy)tabda-S,14-dien-11-one, mn.p. 168 169 0

C.

22. lte9xt-D $hydroxy-8,13-epoxy-7Q-(5..N-methytpiperazino* vaLeryLoxyP)tsbda-5,14-dien-.11one, 161 162 0

C.

23. lcz,9ci-bihydroxy-8, I 3 'epoxy-78-A2-piporidinopropionyi.

oxy)Labda-5014-dien-11-one, in.p. 159 203 0

C,

tXAMPLE 6 ihydroxy-8, l3-epoxy-B-( 2R03-0-sopropytidenegtyceroyLoxy)labda-.5,14-,dien-l1-one 8,13-Epoxy-1ca,70,9ct-trihydroxyLabda-,14.dien.1i-one go 2.86 mmot) in dr~y ethyL acetate (25 Wd, was -31 added to a cooled mixture of 4-N,N-dimethyLaminopyridine (0.7 g, 5.73 mmoL), dicy.LohexyLcarbodiimide (1.85 g, 8.97 mmol) and 2R,3-O'-isopropyLidenegLyceric acid (0.926 g, 6.34 mmoL) in dry ethyl acetate (50 ml). The reaction mixture was Left to stand at room temperature for 16 hours. Acetic acid (0.5 ml, 8.73 mntoL) was then added to the reaction mixture, which was stirred at room temperature for 15 min. The reaction mixture was diluted with further ethyL acetate, filtered, and the filtrate was washed with a cooled solution of aqueous sodium bicarbonate solution, followed by brine. The organic Layer was dried over anhydrous sodium sulfate and concentrated.

The residue was purified by flash column chromatography using ethyl acetate:diisopropyL ether:petroLeum ether (8:46:46) as eluent. Pure fractions were combined and evaporated, and the product was crystallized from n- 41 46 OvA pentane, yield 22.6%, melting point 151-1530C.

M 0 The compound 14L,9c.-Dihydroxy-8,13-epoxy-7S-(2.s f3-O-isopropylidino-propionyloxy-labd-5,14-dien-11-one was prepared *0;0 similarly using 2S,3-O-isopropylidinopropionic acid in place of 2R,3-0-isopropylidinopropionic acid.

EXAMPLE 7 #Xtlci,9ct-o hydroxy-.8, 13-epoxy-7B,-(2R,3-dihydroxypropionyL- 5 oxy)Labda-5,14-d len-1l-one p-ToLuenesuLfonic acid monohydrate (0.384 g, 2.02 mmoL) was added under an N 2 atmosphere to a stirred solution of 1ot9t-dihydroxy-8,13-poxy-76.-(2R,3-0-isoprop-yLidene- _OttU glyceroyLoxy)Labda-5,14-dlen-11-one (0.52 g, 1.09 mmoL) aftt in methanol (24 Wl. The reaction mixture was stirred at room temperature for 1.5 hours and concentrated in vacuo at a temperature 400%. The residue was extracted with ethyl acetate. The organic Layer was washed with 10% strength aqueous sodium bicarbonate solution foLLowed by water, dried over anhydrous sodium sutfate and concentrated. rhe residue was purified by flash column chromatography using ethyl acetate~diisopropyL ether (3:M as eLuent. Pure fractions were combined and concentrated, and the residue was crystallized from ithyL acetate/petoleum ether. Yield 79.8%p melting point 162-1840c, i iiiiii.i~r~_~ 32 The compound loc,9o-Dihydroxy-8,13-epoxy-7B-(2S,3-dihydroxypropionyloxy)-labd-5,14-dien-1-one quasihydrate, m.p. 2150C was prepared in a similar manner.

EXAMPLE 8 76-Acetoxy-l1-t-butyLdimethysiLyLoxy-8,13-epoxy-9chydroxyLabda-5,14-dien-11-one Thiony chloride (0.73 mL, 10 mmot) was added to an izecooled, stirred mixture of 7$-acetoxy-1a-t-butydimethylsilytoxy-6B,9a-dihydroxy-8,13-epoxyLabd-14-ef-11-one g, 6.68 mmol) in methylene chloride (200 mL) and pyridine (1.61 mL, 19.9 mmol). The reaction mixture was stirred at 28 0 C overnight and was washed with ,1 strength aqueous HCI followed by saturated sodium bii carbonate solution and water. The organic layer was dried over anhydrous sodium sulfate and concentrated.

The product was obtained as an oil in 96% yield.

EXAMPLE 9 lc-t-utytdmethylsiLyloxy-778,9Q-dihydroxy-8,13-epoxy- Labda-.S,14-dien-l 1-one sodium hydroxide (0.54 g, 13.5 mimot) in water (30 ml) was added to a stirred soLution of 78-acetoxy-t -t-butyLidimethytsilyloxy-8, 13-epoxy-9c"hydroxyLabda-5,14-din-11one (3.4 g, 6.71 mmol) in methanol (90 ni). The reaction mixture wits stirred at 28 0 C for 45 min, and was concentrated in vacuo to one quarter of its volume in order to remove methanol. The residue was extracted with ethyl acetate. The organic Layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography using ethyl acetatetpetroLeum ether (218) as etuent, meLting point 104 0 -105 0

C.

cIm I -33- EXAMPLE ityLoxy-8, 13-epoxy-9a-hydroxy-7B 14-dienl 1-one 1,1e-CarbonyLdiimidazoLe (0.419 g, 2.58 mmoL) was added under an N2 atmosphere to a stirred solution of lot-tbutyLdimethyLsiLy~oxy78,9dihydroxyBl3-epoxyLabda- 5,14-dien-il-one (1.0 g, 2.16 mmol) in dry ethyl acetate Wl. The reaction mixture was stirred at room ternperature overnight and then a second aliquot of 1,1'carbonytdiimidazoLe (0.419 9, 2.58 mmoL) was added to the reaction mixture, which was stirred for a further 12 hours. Plperidine (1 Wl was added to this reaction mix- I tit ture, and stirring was continued at room temperature for one hour. It was diluted with further ethyl acetate and washed with water,, dried over anhydrous sodium sulfate and concentrated.

11 t EXAMPLE 11 lcio9c-ihydroxy-8, l3-epoxy-78-piperidinocarbonyLoxytabdo- 5,04-diene-1 1-one TetrabutyLarnmonlum fluoride trihydrate (0.484 g, 1.53 mmol) was added at 0 0 c to a stirred solution of 1Ct-t-butyLdino thyIs iLyLoxy-8, 13-OPox y-9cz-hyd roxy-78-p iper id inoca rbonytoxyLabda-5e14-dien-11-one (0.4 ge 0.73 mmot) in dry tetrahydrofuran (10 Wl. Stirring was continued for one hour, The reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate, and the organic layer was washed with water, dried over anhydrous sodium SULfate and concentrated. The residue was Purified by flash column chrom3tography using ethyl acetbte:petroLeum ether, as eLuentp and the product was crystallized from ethyl acetate/petroLeum ether.

Yield 84.3%e melting Point 199-200 0

C.

The Compounds in Table 11 were Prepared by the methods described in Example 10 and txample# 11.

34 EXAMPLE 12 78-AcryLoyLoxy-cz,9-dihydroxy-8,13-epoxy.abda-5,14.dien 11-on e Using acrylic acid in place of 2R,3-O-isopropyLidenegLyceric acid in the process described in Example 6 the compound 75-acryLoyLoxy-lz,9cz-dihydroxy-8, 13-epoxylabda- 5,14-dien-il-one was prepared, melting point 142-143 0

C

Similarly following compounds were prepared starting from 1cc,94.- Dihydroxy-8,l 3-epoxy-7B-(hydroxy) acetoxy-labd-5,114-dien-1 1-one and lo-t-Butyldimethylsilyloxy-8 ,13-epoxy-7B- (hydroxy) acetoxy- 9 -hydroxy-labd-5 1 4-dien-1 1-one respectively.

7B- (Acryloyloxy) acetoxy-1 9& -dihydroxy-8 ,113-epoxy-tabd-5, 14dien-1 1-one.

'Vq1 7B-(Acryloyloxy) acetoxy-1&Ct-butyldimethylsilyloxy-8, 13-epoxy- 9&(hydroxy-labd-5,14-dien-11-one, I EXAMPLE 13

F

"It9Q-Dihydroxy-8, l 3 -epoxy-7B-(3-piperidinopropionyLoxy)- .0 o Labda-5,14-dien-11-one A mixture of piperidine (5 Wl and 76-acryLoyoxy-la,9adiyrx-,3ooyabo51-in1-n (0.12 go 0.3 mmol) was heated at 70 0 C for 45 minutes. The react on mixture was concentrated in vacuo. The residue was extracted with ethyl acetate, and the organic loyer was washed with brine, dried over anhydrous sodium sutfate and concentrated. The residue was crystaltized from chloroform:petroLeum ether. Yield 91%. Melting point 169-170 0

C.

The following compounds were prepared in a similar manner.

1. lii9ci-D ihydroxy-78..(B-dlmethylamlnopropionyLoxy).8, j3.

epoxyLabda-5,14-dion-11-.one, meLting point 113-164 0

C,,

using dimethytamine in toLuene in place of piperidine (pure).

2. 7B-(3'O iethyLAminoproplonyoxy)1c1,9a-dihydroxy-8, 13epoxytabda-S,.14'.dien-11-one, meLting point 1$53.j40C.

3. 1ca,9-Dihydoxy-8,13-epoxy-70-(3-morphoLinopropionyLoxy)Labda-'5,14-dien-11-one, melting point 168-169 0

C.

4. Ia,9ca-Dihydroxy-8, 13-epoxy-70-(3-N-methyLpiperazino- 5propionyLoxy)Labda-5,14-dien-11-one, melting point 154-155 0

C.

la,9a-Dihydroxy-8,13-epoxy-70-E3-(4-(4-hydroxyphenyL)piper idin o rop iony'lox>')Lab d a-5,14 -die n-Il-one, melting point 187-188 0

C.

6, 1* 9d.DVJ.ydroxy-73- (3-N ,N-d~LnOthyla*ninop1ropionyloxy) acetoxy." 8, 13-epoxy-labdl-5, 14-dicon-1 1-one, 15 7. l0,ct9&Dihydroxy-8, 13-opoxy-78-(3-inorpholiflopropionyloxy) acetoxy-labd-5,1 4-dien-1 1-one.

8. 1x,9o.-Dihycroxy-8, 13-epoxy-70- (3-N-mothylpiporazino-propionyl- 14-dion-1 1-ono.

EXAMPLE 14 lc-t-Butytdimethylsi LyoxX-Oj 3-eooxy-9cz-hydroxy-7S- 14-dien-11V-one 4 25 EBroroacetyt bromide Wl was added to lot-t-butytdimethyLsiLtyLoxy-7$,9cx-dihydroxy-8, 13-epoxytabda-5, 14dien-il-one (11.0 g) by the process described in Example 3. The residue from the working up of the reaction was I dissolved in hoxamethytphosphoramide (40 mt) and treated at room temperature with sodium lormat,- (1.8 The reaction mixturt was stirred for 6 hours and Left to stand at room temperature for 48 hours. the reaction mixture was then diluted with chloroform,* and tho Mhoroform solution was passed through a column of neutral alumina (1250 extracting with chloroform (2 Liters) followed by chloroformimethaftot (911, 4 liters). The fractions containing the compound wore combined and concontrated* The resulting oil which remained was further purified by flash chromatography using ethyl acetate, petroleum ether (28) as eLuent (Yield 10.0 o, 4M~.

36 The foltowing compounds were prepared in a similar manner.

The compound 1c,9-dihydroxy-8,13-epoxy-70-hydroxyactoxyLabda-5,.14-dien-11-one, melting point 156 0 C, was obtained from 8, 13-epoxy-1cet,,9c-trlhydroxyLabda-5, 14dien-1 I-one.

in a similar manner, the compound 1ci.9c-dihydroxy-8,i13- 14-dien-11-one was obtained from 8,13-epoxy-1Q,7B,9o-trihydroxyLabd8-5,14dien-1 1-one.

EXAMPLE lc-t-But IdimethyLsiL yLox y-7B-chLoroaceoxvacotox y-8,13- *15 epoxy-9ca-hydroxyLabdo5,14-din-ii-on 2 The compound lo-t-buty~dimethyLsiLyloxy-?Q-chLoroacetoxyacetoxy-8,13-opoxy-9ct-ydroxytabda-5,14-dion11i-ono was 4120 obtained in 5 'X yield,, motting point 143-i4SQCt by the process described in Example 6t using loi-t-lbutdimethytsiLyLoxy-8,i3-Ooxoy-?B-hydroxyacoeoxy-9 (x-hydtoxyLahda- 5,14-dien-11-one and chtoroscoti4 acd, The following compounds wore preparod in a similar mfannert ?Q-Acryloyloxy-1co-t-butytdirmothyLs iLyLoxyw8,1'*epoxy-9czhydroxytabdo-S..14-.dion-il-one was Prepared from Itutt *14'butyLdimethylsLYtoxy.B,13-poxy-?O9t-diliydroxy~bda.

5,14-dien-11ono and atrytic acid, ?B-AcryLoytxyaoxyct-tbutycimthy.s tytoxy-8,1j3oox-t-yr-yad-.1-inl-n Vol proparoed ftrom -t-butyLdimethyts Ilytoy8opo~Ixy7hydroxyaetoxy* 9~ci-hydroxy abdaw5..14-tdinuk11-one and acryLic acid, -36a EXAMPLE 16 I9C-Dihdroxy-8,13-epoxy-7B-piperidinoacetoxyacetoxy- 14-dien-1 1-one Piperidine (0.5 Wl was reacted for 1.5 hours with 1ca-tbutyLdimethylsiLyLoxy-70-chltoroacetoxyacetoxy-8,13-epoxy- 9a-hydroxylabda-S,14-dien-11-one (0.5 Jissolved in dichLoromethane (20 Wl. The residue from the working up of the reaction was treated as described in Example 11 with tetrabutyLammonium fluoride (0.85 ml, IM solution) in tetrahydrofuran. The reaction was complete after minutes. The resutting product was purified by flash chromatography us ing acotoni triLo:chLoroform~di isopropyL cther:triethyLamine (2:50:47:1) as eLuent. Yield 0.240 g, 11*16 54%, meLting point 108-110 0

C.

The compound l1u,9adihydroy-813-poxy-7-morphoino.

14-dien-1 1-one, melt ing point 145- 146 0 C, was prepared in a similar manner by use of morpholine in place of piperidine.

Similarly, following compounds were prepared using appropriate aminazi 14. 9o&-Dihydroxy-70- (N #N-dizehylaminoacetoxy) acotoxy-8 13opoxy-labd-5,114-dian-1 1-ona.

epoxy-labd-5,1I4-diot-1 1-ona.

1#4l,9t-'Dihydroxy-O II13 aoox-7t- (mrrolir=-cotoxy) acotolaIbd- 5#14-dion-11-ono, m.p* 145-1460C.

14, 9o-Dihydroxy-7 0- -dimothylmorpholinoacotoxy) acotoxy- 8,13-opoxy-labd-5,14-dion-11-ona, 14(t 94-Dihydroxy-O, 13- o~W7-4he*--hnypprdn-ctx) acatoxy-labd-50,I4-didn-1 1-one, TPrA (0.34 ml, 4,4 mmol) Was added, to a stirred mixture of potassium eyahatt (0.34 qf 4*2 inmol) and. lol-t-butyldimathylsilyloxy-7f,9c(dihydroxy-a, 13-epoxy-5, 14-dien-1 1-one (1.3 j# 36b 2.69 mmol) in dry toluene (25 ml) Stirring was continued for 12 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate and The residuo was purified by flash chromatography using ethyl acetate:pot. ether as cluant gave 7B-Aininocarbonyloxy-lo.-t-butyldimethylsilyloxy-8, 13-epoxy-9ce-hydroxylabd-5,14-dion-11-one (0,26 g) and 73-Aminocarbonyloxy-1cl9ocdihydroxy-8,13-epoxy-5, 14-dien-1 1-one (0.023 The formrno compound was deprotected using the procedure reportedin Example It. Yield 0.182 g, m.p. 233-234*0 EXAMPLE 18 1.9, 9'-Dihydroxy-8rl13-epoxy-7B-mori~holinoacetoxy-labd-$, 14- Etheral, 101 was added to an ice cooled solution of ila,9a- DIhY,;droxy-8, 13-epoxy-7B-morpholinoaoetoxy-labd-5, 14-dien-1 1-otic (0.3 q) in methanol (t0 ml) till it reached to pH 2. A precipitate separates otit which wan fltered and washed with dry, ether. The residue wan recrystallized with methanlodiethy. ether. Yield 50 t Mi-P. 192-194*0 (decomposod).

Similarly the following compounds were prepared.

1. Ica,9a-Dihydroxy-70-dimothylaminoaootoxy-8p 13-opoxy-labd- 5,14-dion-Il-one hydroohlorido, w.p. 243*0.

2. 70-Diothylaminonatoxy-ia,9a-dihyd roxy-8, 13-.poxy.'Thbd- 5,14-dien-Ib..one hydrochloride, 21-211P0- 3* is, 9saihydroxyMB, i3-epoxy-.7--pyrrolidinoaetoxy-I1td.

I04-dien.'il-ono hydrochloride) m.p. 220-22i*C.

4. 1s,9aw4Dihydroxy-8, I3-epoxy"70pperidinoaetoxI-labd.

5j14-dien-ilI-one hydrochloride, ii.~p* 227-22810.

tat,9-Dihydroxy-Bf i-oxy7-hoopiprdtocetoxy-l.1bd- 5)14-~dieft-lt-olie hydroahloridt, mn*P. 2t5u216*0.

36c 6. la,9c-Dihydroxy-8, I5-epo xy-7P -N-m ethyl pipe ra zincacetoxy-labd-5t1i4-diern-11-onie dihydrochioride hydrate, rn-p. 220-223C0.

7. 1a,9a-Dihydroxy-8, 15-epoxy-7p-thiomorpholinoaoetoxylabd-5,14-dien-11-one hydrochltoride; m.p. 203-2Q4C0.

S. 1a,9ca-ihydroxy-8, 13-epoxy-70- (4 1-nethylpiper Idrino- 14-dien-11-one hy~drochloride, rn-pi 228-23O0bCl 9. 1cac-1ihyd roxy-S, I -px-k 31-ehlierdnaeoy 14-dien-Il-one hydrochloride hemihydrate, m~p.

219-220*0.

1C 4a~ -Dihydroxy-Sj I 3-epoxy-7 (4-hydroxy-4-pheny.l4-die.-11l-ono hydrochloride hydrate, 194-195C0.

11. ha,9 Dihydroxy-8, 13-opoxy-1.(2-iperidino-propionyltoxy)-lahd-5#14-dien-11-ono hydrochlioride, m.p, 225-226' 0.

12. 1%,9.-Dihydroxy-S* I 3-epxy-7- (pipe rid inoaoet oxy) ~~xlbd5,4~din~11onohydroohl.oride, m.p.

13I, iu9-ihydroxy-8, 3-opoxy-7p-(morphoIlitnaetoxy)- 4-dien-i i-one hydrochl.oride, m.p.

~192-194'0 (decompos-Ition).

14. Icz ,9a-Uhyd roxy-'7B-(t ,N-dimethylhininoaatoxy) aetoxy-' 8, 3-opoxy- hbd-,14-di-ib-one hydrochloride, map.

209*C.

i4-dien- Ii -one hyaroclorida hydrate, nmp.

130- i3.0 0 7 36Gd 16. la~g9a-Dihydroxy-7p-(26-dimethylmorphoinoacetoxy)-.

aoetoxy-Sp I 3-epoxy-labRX-5, tI4-dien- I I-one hydrochloride hydrate, zn.p. 18-4.t 17. lcz,9-Dihydroxy-8, 13-epoxy-70-(4-hydroxy-4-phenylpiperidinioacetoxy) acetoxy-labd-5, 14-dien-1ii-one hydrochloride hernihydrate, m.p. 157-160C.

18. la, 9-Dihydroxy-S, I 3-epoxy-7P- (N-methylpiperazAno ocetoxy)acetoxy-labd-5,14-dien-11-one dihydrochioridedehydrate, m.p. 177-18Q'C.

19. la9a-Dihydroxy-70-(3-NN-dimethylaminopropionyloxy)acetoxy-S, 13-epoxy-labd-5, 14-dion-1 1-one hydrochloride hernihydrate, m.p. 178*C.

lcz,9a-Dihydroxy-6, 13-opoxy-70-(-piperidinopropionyloxy)- 14-dien-1 i-one hydrochloride hydrate, w.p. 171*0.

21. 1l,9a-Dihydroxy-, 15-opoxy-70-(3-mornholinopropionyloxy)- 14-dien-l i-one hydrochloride, m.p.

189-1 90 Cf.

22. iat,9a-Dihydroxy-8, 13-epoxy-.7-(3-N-mothylpiperazino- 14-die'n-i I-one iiihydrochloride hydraite) mnp. 230*0.

Claims

1.A compound of the formula I In which Rj denotes OH, or a group of the formula 1I A 11 1 5 R1 tR2 11 1 1 11 0- (O)r-(CH 2 (C)n (CH~ (C)n'Jp -11 23 I I 1 1 In which A and A' represent oxygen or sulfur, B represents -OH 2 oxygen, sulfur or 1

16-132 represent hydrogen, alkyl, aryl, araikyl, hydroxyl, acyl as horoinbofore defined, aikoxy, mercapto, halogen or a group of the formula NR 2 4R 28 6, In which R 2 4 and R26 denote, It they a~re Identical, hydrogen, alkyli substituted alkyl as hereinboforo defined, aryl as horeilnbeforo defined or araikyl as herolnboforo defined, or, If F324 represents hydroiun, R26 denotes alkyl, substituted alkyl as horeinbeforo defined, cycioalkyl, gralkyl as haoinboforo deined, aryl as herolnbefore defined, a heterocycic radicat, amino, dtikylamino, alkytamino, arylamino, aralkytamino, hydroxyl, morcapto, acyloxy, acyl as hereinbeforo deflned, carbamoyl, carboxyalkyl, carbalkoxy. alkyl or dialkylaminoalkyl, or, If 1324 represents alkyl, Rg$ denotes substituted alkyl as hereinbolore deined, cycloalkyl, aryl as horelnbofero defined, aralkyl as herein before defined or dialkylamlnoolkyl, or F124 and P26 represent, togother with the nitrogen atom to which they are bonded, a heterocyclic radical which can hove one or more hetoro atom$ and be optionally substituted once or several times by alkyl, aryl, hydroxynikyl, halogen, hydroxyO alkoxy or other heterocyclic groups, with the proviso that the radical of the formula It contains at least three of the substituonts F11 at least one of the throo, substituents having a hotero atom of the group consisting of N, 0 or Ai IL i i_ I i i 38 S, and L, m, n, ml', n' and p each denote 0 or an integer from 1 to 10, or R 1 represents a radical of the formulae x A 0 0 C R23 Ai16 18 A 0--3 or A in which A, R 16 -R 1 8 and R23 have the same meaning as indicated above, R 7 denotes -h a radical of the formula II RIB R 1 7 A 19 21 I I I I oa-c(C)(CH)m-(C)n- BC- )n 1pR23 R16 Ri8 R20 R22 or of the formulae X RO 00 -o-ci-64hl Fisj R ie p or 0-8 4 I II 4 4* Ii lit 4 i in which A, L, m, n, p and R 1 5 R 23 have the same meaning as indicated above, R 1 4 denotes vinyl, ethyl, cyclopropyl, CHOHCH 2 QF, or the radical -CiCH 2 in which Z represents chtorine, bromine or fluorine, X represents pharmacologically utilizable salts thereof, and the dotted lines denote that a double bond can be present in either the 5,6- or the 6,7-position. 2. A compound as claimed in claim 1, in 'hichs RI denotes OH, k f 7 denotes a radical of the formula it' -e Pr 39 r0 R 1 5 0 Rig -00 (C)l [B -C (Cp.n 2 3 tile 20 In which B, Rls, Rio, Rios R 2 01 AM~ I, I' and p have the abovemontioned meanings, but at least one of the s'jbstituents contains an atom from the group consisting of N, 0 or S, or a radical of tho formula 0 Rio Rio 00-0-0- R 2 3 00 In which R 1 0, Rig and R 23 represent hydrogen, and a doublo bond Is present In the 506- position, 3. A compound as claimed In claim 1, In vhIch: RI and R 7 each donote a radical of the formula IV' A His In which A, Ali;, RIG, R3 2 3 and I have the said meanings, and at loast ono of the substituonts Rt 1 5, Rio and R 2 3 containing an atom from the group consisting N, 0 or S, and a double bond is present in thle 5,6.positionk 4C A medicament which contains a compound as claimed In claim 1 in adjunct with ~~':pharmaceutically acceptable carriers or oxcipionts. S. A method of preparation of a modicamont having a positive Inotropic effect or ain effect lowering the blood pressure or reducing the intraocular pressuro comprising admixing In a pharmacologically offactive ratio, an effective amount of a compound of the formula 1, as claimed In claim 1 with pharmaceutically acceptable carriers Ahd exciplents. 8*A process for the preparation of a compound of the formula- I -U, 6, A process for the preparation of a compound of the formula I 0 6H In which R 1 denotes OH, or a group of the formula 11 A Rt A1 2 0 -0C- (C)(CH 2 )m -G 0 (C) 1 (CH 2 (O)n'1 R 2 3 I I II Rio min 120"2 In which A and A' reprosent oxygen or sulfur, B represents -01- 2 oxygen, sulfur or Fh -R2 represent hydrogen, alkyl, aryl, aralkyl, hydroxyl, acyl as horeinbeforo defined, alkoxy, mercapto, halogen or a group of the formula. NR 24 RI26, In which R24 and R125 denote, If they are Identical, hydrogen, alkyl, substituted alkyl as hereinbeforo defined, aryl as herolnbefo-re detined or aralkyl as horelnbeforo defined, or, It R24 represents hydrogen, R 2 6 denotes alkyl, substituted alkyl as hereinbeforo defined, #*Vt cycloalkyl, aralkyl as horoinbeforo defined, aryl as horeinbefore defined, a heterocyclic radical, amino, dialkylamino, alkyinmino, arylamino, aralkylamino, hydroxyl, mercapto, acyloxy, acyl as hereinbefore defined, carbamoyl, carboxyalkyl, carbakoxy- alkyt or dialkylaminoalkyt, or, If Ra4 represents alkyl, R126 denotes substituted alkyl as A t heroinbefore defined, cycloalkyl, aryl as horeinboforo definod, aralkyl as heroin before 4 41 definod or dinlkylaminoalkyl, or Rl 24 and 1126 reprocont, together with the nitrogen atom 44 to which they are bonded, a heterocyclic radical which can have one or more hetero at1oms and be optionally substituted once or several times by alkyl, aryl, hydroxyalkyl, halogen, hydroxy, aikoxy or other hotorocycie groups, with the proviso that the radical of the formula It Contains at least three of the substituents r_ i 41 R 15 -R 23 at Least one of the three. substituents having a hetero atom of the group aempr&4~ei 0 or S, and m, n, in', n' and p each denote 0 or an integer from 1 to 10, or R1 represents a radical of the for- muIae X, C-C-C-R23 R16 18 O-G4 o r in which A, R 16 -RIB and R 2 3 have as indicated above, the same meaning R7 denotes H A a radical of the formula 11 A I517 At' fig R21 O-C (C) 3 w(CH2)m(C)n([B-c (C)1 p-R23 R16 RIB R20 R22 or of the lormuLae A WO-86-9-23 islB A I or in which A, A, it mp have the some meaning R1 4 denotes vinyl, ethyl, n, L' ml', p and RIS R 23 as indicated above, cycloproPyL, CHOHCH 2 OH, CH2OH 2 or the radical -i'Ci1 2 in which I represents chLorine, bromine or fLuorine, X reprsents pharmcologiCaLLy utiLilabLe salts thereof, and the dotted Lines denote that a double bond can be present in either the 506- or the 647-positon, 1 ~1 i- i I~-lr 42 which comprises reaction of a compound of the formula I' ,OR 14 1, .HI' C7 in which R 1 represents H and R7 represents OH=v the group o1C-CH 2 f, or R'l represents a protective group for a hydroxyL group and R 7 represents '044-4 the group *1 0 0-C-CH 2 OH, 11 a) with a compound of the formula III i A RIS R A ]R R 21 HO-C- (C)I-(CH26-(C) 11 CH2)ml(C)n I p'R23 111 R16 R18 R 20 R 22 in which R 15 R 22 At B, 1, m, n, n' and p have the abovementioned meanings, and R23 reprezents a halogen atom, or the grouo OW, W representing aryl-Cj- C6-aLkyl or ary, to give k compound of the formula I in which Rl and/or R7 denotes a radical of the formula II AR1 19 R 21 (CH2)- (C)ntBI C% (CH26 I I )nflp-R23 IX R16 koAp20 R 22 in which R15- R22# A# 01 L, m ne I' n) and p have the said meanings, and RZ3 represents a halogen atom or an O-aryl-Cl-t6-Atkyt or aryt radial, and eaiiination by customary nethods of A 1 if it represents a protective

43- group, or b) with a compound of the formuLa HOC CH CH2 11 1 1 0 0 0 to give a compound of the formula I in which one of the two substituents Rl and R7 represents the rlodicot 0C CH QH 2 x where appropriote cl treatment of a compound of the formuLa I 1 91 I I If 4 *1 ~1~ II I I' I in which the slbstituont Rj tan~A=q.- repi-osonts the OH group, and -O*t4-.rrpresents 6 radicaL of the lormut a 00-CH -CH 2 x with an organic acid, resulting In a compound of the formula I In which R 7 represents the radical CH.CH-COH andR, represents the OH group, or 1i 1 O OH d) reaction of a compound of the formula I In which the Su~tituent R7 represents the radical -OCCH 2 11 23 R 2 3 denoting halogeno and R 1 ropresents the OH group, with 11 0 sodium formato to give a compound of the formula I In which the substituont R 7 represents tho radical -CC~Oc4 o) where appropriate reaction~ of the compound In stop c) with aluminum oxide to give a compound of (he formula I In which tho substituent R7 represents the radicai 1) whore appropriate Initial acylation, by customary methods, of the compound of the formula I obtained In stop d)o and subsequent reaction of the rosulting compound with an amine of the formula HNR1 2 4R 2 6, In which R24t and 11 2 6 have the abovomontionod meanings, to give a compound of the formula Ia 0 to it 1# out* flO In wich doolo thoOH goupandR ooo aia f h oml ii 0 In which ml has the bvmnindmu~g n g3rpoot h ru 1419 111 and ARs having P: the abovementioned meanings, g) where appropriate, initial reaction of a compound of the formula in which R 1 ld enhtes a protective group for a hydroxyt group, and R 7 donites Ofl, with a compou;nd of the formula IV I V in which I denotes oxygen or sulfur, subsequent addition of on amine of the formula HNR2 4 R25 to the reaction mixture, or by treatment of a compound of the formul.a with potassium cyanate and trifluoroactic acid and finally elimination of the protective group in the I-position in a known manner, resulting in a com- pound of the formula I in which RI denotes 011, and R7 denotes a radical of the formula -OCONR2gRaS, in which RZ4 and R25 have the abovemontloned meanings, h) wherv appropriate acylation of a compound of the formula I in which R'denotes a protective group for a hydroxyt group, and R 7 denotes OlH, with a compound of the formulae Hal (cl H al HOOC V C o C Ale in which Hat denotes a halogen atom, and R1t R17 and Rig each represent hydrogen, optionaly substituted CI-C 6 alkyl, aryl Or Aryt-Cl-64-tkytp reaction of the resulting reaction product with an amine of the tormul HNft4R2 in, n which R24 and R25 have the abovementoned meanings# and finally elimination of the pr'otective group in the Iwoosition,. rttutlino In a conpound of the tormuLa I in which RI repreSents the Oil group# and R? ripreCnts a radical of the formula -46 O RI5 II I -OC-C~l- N'R 24 R 2 R 1 6 in which RI~o R 1 6t R 24 R 25 and L. havo tho abovemontioned moanings. DATED) TIS 290 (lay of November, 1988 1I0E.C11ST AI(TI ENGESELL$C1AFT 1'AITNT ATTORNE~YS 50Q1UP'It -STRIRT m~miLol1RNEICii' 3000.