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NZ738471B2 - New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them - Google Patents
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NZ738471B2 - New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them - Google Patents

New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them Download PDF

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NZ738471B2
NZ738471B2 NZ738471A NZ73847116A NZ738471B2 NZ 738471 B2 NZ738471 B2 NZ 738471B2 NZ 738471 A NZ738471 A NZ 738471A NZ 73847116 A NZ73847116 A NZ 73847116A NZ 738471 B2 NZ738471 B2 NZ 738471B2
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New Zealand
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group
branched
linear
alkyl
formula
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NZ738471A
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NZ738471A (en
Inventor
Balazs Balint
Maia Chanrion
I Jen Chen
Marton Csekei
James Edward Paul Davidson
Olivier Geneste
Andras Kotschy
James Brooke Murray
Levente Ondi
Agnes Proszenyak
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Les Laboratoires Servier
Vernalis (R&D) Limited
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Priority claimed from FR1555750A external-priority patent/FR3037959B1/en
Application filed by Les Laboratoires Servier, Vernalis (R&D) Limited filed Critical Les Laboratoires Servier
Publication of NZ738471A publication Critical patent/NZ738471A/en
Publication of NZ738471B2 publication Critical patent/NZ738471B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
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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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    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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    • C07D495/04—Ortho-condensed systems

Abstract

Compounds of formula (I); wherein R1, R2, R3, R4, R5, R6, R7, R8, R14, W, A and n are as defined in the description and their use as medicaments for the treatment of cancer and immune/auto-immune diseases.

Claims (49)

1. Compound of formula (I): wherein: ? A represents the group in which 1 is linked to the W group and 2 is linked to the phenyl ring, wherein: - E represents a furyl, thienyl or pyrrolyl ring, - X , X , X and X independently of one another represent a carbon atom or a 1 3 4 5 nitrogen atom, 10 - X represents a C-R group or a nitrogen atom, and - means that the ring is aromatic, ? R represents a halogen atom, a linear or branched (C -C )alkyl group, a linear or 1 1 6 branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear 2 6 2 6 or branched (C -C )polyhaloalkyl group, a hydroxy group, a hydroxy(C -C )alkyl 1 6 1 6 15 group, a linear or branched (C -C )alkoxy group, -S-(C -C )alkyl, a cyano group, a 1 6 1 6 nitro group, -alkyl(C -C )-NR R ’, -O-alkyl(C -C )-NR R ’, 0 6 11 11 1 6 11 11 -O-alkyl(C -C )-R , -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’, -NR -C(O)-R ’, 1 6 12 11 11 11 11 11 11 -NR -C(O)-OR ’, -alkyl(C -C )-NR -C(O)-R ’, -SO -NR R ’, 11 11 1 6 11 11 2 11 11 - 151- -SO -alkyl(C -C ), 2 1 6 ? R , R , R and R independently of one another represent a hydrogen atom, a 2 3 4 5 halogen atom, a linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear or 2 6 2 6 5 branched (C -C )polyhaloalkyl, a hydroxy group, a hydroxy(C -C )alkyl group, a 1 6 1 6 linear or branched (C -C )alkoxy group, a -S-(C -C )alkyl group, a cyano group, 1 6 1 6 a nitro group, -alkyl(C -C )-NR R ’, -O-alkyl(C -C )-NR R ’, 0 6 11 11 1 6 11 11 -O-alkyl(C -C )-R , -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’, -NR -C(O)-R ’, 1 6 12 11 11 11 11 11 11 -NR -C(O)-OR ’, -alkyl(C -C )-NR -C(O)-R ’, -SO -NR R ’, or 11 11 1 6 11 11 2 11 11 10 -SO -alkyl(C -C ), 2 1 6 or the substituents of the pair (R , R ) form together with the carbon atoms carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that resulting ring may be substituted by from 1 to 2 15 groups selected from halogen, linear or branched (C -C )alkyl, -alkyl(C -C )-NR R ’, -NR R ’, -alkyl(C -C )-Cy or oxo, 0 6 11 11 13 13 0 6 1 ? R and R independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl 1 6 2 6 group, a linear or branched (C -C )alkynyl group, a linear or branched 20 (C -C )polyhaloalkyl, a hydroxy group, a linear or branched (C -C )alkoxy group, 1 6 1 6 a -S-(C -C )alkyl group, a cyano group, a nitro group, -alkyl(C -C )-NR R ’, 1 6 0 6 11 11 -O-Cy , -alkyl(C -C )-Cy , -alkenyl(C -C )-Cy , -alkynyl(C -C )-Cy , 1 0 6 1 2 6 1 2 6 1 -O-alkyl(C -C )-R , -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’, -NR -C(O)-R ’, 1 6 12 11 11 11 11 11 11 -NR -C(O)-OR ’, -alkyl(C -C )-NR -C(O)-R ’, -SO -NR R ’, 11 11 1 6 11 11 2 11 11 25 -SO2-alkyl(C1-C6), or the substituents of the pair (R , R ), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or non- aromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that 30 resulting ring may be substituted by a group selected from a linear or branched (C -C )alkyl group, -NR R ’, -alkyl(C -C )-Cy or an oxo, 1 6 13 13 0 6 1 ? W represents a -CH - group, a -NH- group or an oxygen atom, - 152- ? R represents a hydrogen atom, a linear or branched (C -C )alkyl group, a -CHR R 8 1 8 a b group, an aryl group, a heteroaryl group, an arylalkyl(C -C ) group, or a heteroarylalkyl(C -C ) group, ? R represents a hydrogen atom, a linear or branched (C -C )alkyl group, a linear or 9 1 6 5 branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, -Cy , 2 6 2 6 2 -alkyl(C -C )-Cy , -alkenyl(C -C )-Cy , -alkynyl(C -C )-Cy , -Cy -Cy , 1 6 2 2 6 2 2 6 2 2 3 -alkynyl(C -C )-O-Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy , a halogen atom, a 2 6 2 2 0 6 0 6 3 cyano group, -C(O)-R , or -C(O)-NR R ’, 15 15 15 ? R represents a hydrogen atom, a linear or branched (C -C )alkyl group, a linear or 10 1 6 10 branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, an 2 6 2 6 arylalkyl(C -C ) group, a cycloalkylalkyl(C -C ) group, a linear or branched 1 6 1 6 (C -C )polyhaloalkyl, -alkyl(C -C )-O-Cy , 1 6 1 6 4 or the substituents of the pair (R , R ), when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them an aromatic or non- 15 aromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, ? R and R ’ independently of one another represent a hydrogen atom, a linear or 11 11 branched (C -C )alkyl group, or the substituents of the pair (R , R ’) form together with the nitrogen atom 11 11 20 carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, or a linear or branched (C -C )alkyl group, 25 ? R represents -Cy , -Cy -alkyl(C -C )-O-alkyl(C -C )-Cy , 12 5 5 0 6 0 6 6 -Cy -alkyl(C -C )-Cy , -Cy -alkyl(C -C )-NR -alkyl(C -C )-Cy , 5 0 6 6 5 0 6 11 0 6 6 -Cy -Cy -O-alkyl(C -C )-Cy , -C(O)-NR R ’, -NR R ’, -OR , 5 6 0 6 7 11 11 11 11 11 -NR -C(O)-R ’, -O-alkyl(C -C )-OR , -SO -R , -C(O)-OR , or 11 11 1 6 11 2 11 11 -NH-C(O)-NH-R , 30 ? R , R ’, R and R ’ independently of one another represent a hydrogen atom, or 13 13 15 15 a linear or branched (C -C )alkyl group, ? R represents a hydrogen atom, a hydroxy group, or a hydroxy(C -C )alkyl group, 14 1 6 - 153- ? R represents a hydrogen atom, a halogen atom, a linear or a branched (C -C )alkyl group, or a cyano group, ? R represents a hydrogen atom or a linear or branched (C -C )alkyl group, a 1 6 ? R represents a -O-C(O)-O-R group, a -O-C(O)-NR R ’ group, or a -O-P(O)(OR ) b c c c c 2 5 group, ? R and R ’ independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl group, a cycloalkyl group, a (C -C )alkoxy(C -C )alkyl 1 8 1 6 1 6 group, a (C -C )alkoxycarbonyl(C -C )alkyl group, 1 6 1 6 or the substituents of the pair (R , R ’) form together with the nitrogen atom 10 carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched (C -C )alkyl group, ? Cy1, Cy2, Cy3, Cy4, Cy5, Cy6 and Cy7 independently of one another, represent a 15 cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group, ? n is an integer equal to 0 or 1, it being understood that: - “aryl” means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, - “heteroaryl” means any mono- or bi-cyclic group composed of from 5 to 10 ring 20 members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, - “cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, - “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group 25 containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may be substituted by from 1 to 30 4 groups selected from linear or branched (C -C )alkyl which may be substituted by a - 154- group representing hydroxy or (C -C )alkoxy which may be substituted by hydroxy; linear or branched (C -C )alkenyl; linear or branched (C -C )alkynyl; linear or 2 6 2 6 branched (C -C )alkoxy which may be substituted by a group representing halogen or -NR’R’’; (C -C )alkyl-S-; hydroxy; oxo (or N-oxide where appropriate); nitro; cyano; 5 -C(O)-OR’; -O-C(O)-R’; -C(O)-NR’R’’; -O-C(O)-NR’R’’; -NR’R’’; -(C=NR’)-OR’’; -O-P(O)(OR’) ; -O-P(O)(O M ) ; linear or branched (C -C )polyhaloalkyl; trifluoromethoxy; halogen; or an aldohexose of formula: in which each R’ is independent; 10 it being understood that R’ and R’’ independently of one another represent a hydrogen atom or a linear or branched (C -C )alkyl group, and M represents a pharmaceutically acceptable monovalent cation, with the proviso that E cannot represent , their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a 15 pharmaceutically acceptable acid or base.
2. Compound of formula (I) according to claim 1, wherein: ? R and R independently of one another represent a halogen atom, a linear or branched (C -C )alkyl group, a hydroxy group, a linear or branched (C -C )alkoxy 1 6 1 6 group, 20 or the substituents of the pair (R , R ) form together with the carbon atoms carrying them an aromatic ring composed of from 5 to 7 ring members, which may contain - 155- from 1 to 3 nitrogen atoms, ? R represents a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl 3 1 6 group, a hydroxy group, a linear or branched (C -C )alkoxy group, or -O-alkyl(C -C )-NR R ’, 1 6 11 11 5 ? R and R independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl group, a hydroxy group, a linear or branched (C -C )alkoxy group, ? R and R independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl group, a linear or branched 10 (C -C )polyhaloalkyl group, a hydroxy group, a linear or branched (C -C )alkoxy 1 6 1 6 group, a cyano group, a nitro group, -alkyl(C -C )-NR R ’, -alkyl(C -C )-Cy , 0 6 11 11 0 6 1 -O-alkyl(C -C )-R , or -C(O)-NR R ’, 1 6 12 11 11 ? R represents a hydrogen atom, a linear or branched (C -C )alkyl group, or a 8 1 8 -CHR R group, 15 ? R represents a hydrogen atom, a linear or branched (C -C )alkyl group, a linear or 9 1 6 branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, -Cy , or 2 6 2 6 2 a halogen atom, ? R represents a hydrogen atom, a linear or branched (C -C )alkyl group, a linear or 10 1 6 branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, an 2 6 2 6 20 arylalkyl(C -C ) group, a cycloalkylalkyl(C -C ) group, a linear or branched 1 6 1 6 (C -C )polyhaloalkyl, or -alkyl(C -C )-O-Cy , 1 6 1 6 4 or the substituents of the pair (R , R ) when grafted onto two adjacent carbon atoms, form together with the carbon atoms carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 3 heteroatoms 25 selected from oxygen, sulphur and nitrogen, ? R and R ’ independently of one another represent a hydrogen atom, a linear or 11 11 branched (C -C )alkyl group, or the substituents of the pair (R , R ’) form together with the nitrogen atom 11 11 carrying them a non-aromatic ring composed of from 5 to 7 ring members, which 30 may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched (C -C )alkyl group, - 156- ? R represents -Cy or -Cy -alkyl(C -C )-Cy , 12 5 5 0 6 6 ? W represents a -NH- group or an oxygen atom, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may be substituted by from 1 to 5 4 groups selected from linear or branched (C -C )alkyl which may be substituted by a group representing hydroxy or a linear or branched (C -C )alkoxy which may be substituted by hydroxy; linear or branched (C -C )alkoxy which may be substituted by a group representing halogen or -NR’R’’; hydroxy; oxo (or N-oxide where appropriate); -C(O)-OR’; -C(O)-NR’R’’; -O-C(O)-NR’R’’; -NR’R’’; -O-P(O)(OR’) ; 10 -O-P(O)(O M ) ; linear or branched (C -C )polyhaloalkyl; halogen; or an aldohexose 2 1 6 of formula: in which each R’ is independent; it being understood that R’ and R’’ independently of one another represent a hydrogen 15 atom or a linear or branched (C -C )alkyl group and M represents a pharmaceutically acceptable monovalent cation.
3. Compound of formula (I) according to claim 1, wherein n is an integer equal to 1.
4. Compound of formula (I) according to claim 1, which is compound of formula (I-a): - 157- (I-a) wherein R , R , R , R , R , R , R , R , R , R , X , X , X and W are as defined in 1 2 3 4 5 6 7 8 9 14 1 2 3 claim 1.
5. Compound of formula (I) according to claim 1, which is compound of formula (I-b): (I-b) wherein R , R , R , R , R , R , R , R , R , R , X , X , X and W are as defined in 1 2 3 4 5 6 7 8 9 14 1 2 3 claim 1.
6. Compound of formula (I) according to claim 1, which is compound of formula (I-c): - 158- (I-c) wherein R , R , R , R , R , R , R , R , R , R , R , X , X , X and W are as defined in 1 2 3 4 5 6 7 8 9 10 14 1 2 3 claim 1.
7. Compound according to claim 6, wherein R represents hydrogen; methyl; isopropyl; 5 2,2,2-trifluoroethyl; benzyl; 4-methoxybenzyl; phenethyl; 3-phenyl-propyl; cyclopropylmethyl; cyclopentylethyl; naphthalenylmethyl; 2-(naphthalen yloxy)ethyl; butynyl; propen-1yl; or butenyl.
8. Compound of formula (I) according to claim 1, which is compound of formula (I-d): (I-d) 10 wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R14, X1, X2, X3 and W are as defined in - 159- claim 1.
9. Compound according to claim 8, wherein R represents a hydrogen atom or a halogen atom.
10. Compound of formula (I) according to claim 1, which is compound of formula (I-e): (I-e) wherein R , R , R , R , R , R , R , R , R , R , X , X , X and W are as defined in 1 2 3 4 5 6 7 8 9 14 1 2 3 claim 1.
11. Compound according to claim 1, wherein at least one of the groups selected from R ,
12.R , R and R does not represent a hydrogen atom. 3 4 5 10 12. Compound according to claim 1, wherein R represents a hydrogen atom.
13. Compound according to claim 1, wherein R represents a hydrogen atom, a fluorine atom, a methyl group or a cyano group.
14. Compound according to claim 1, wherein R represents a linear or branched (C -C )alkyl group or a halogen atom.
15.15. Compound according to claim 1, wherein R represents a linear or branched (C -C )alkoxy group, a hydroxy group or a halogen atom. - 160-
16. Compound according to claim 1, wherein R represents a hydrogen atom, a hydroxy group, a linear or branched (C -C )alkoxy group or -O-alkyl(C -C )-NR R ’. 1 6 1 6 11 11
17. Compound according to claim 1, wherein R and R represent a hydrogen atom.
18. Compound according to claim 1, wherein represents , wherein R and R ’ are as defined in claim 1. 11 11
19. Compound according to claim 1, wherein the substituents of the pair (R , R ) are identical and the substituents of the pair (R2, R4) are identical.
20. Compound according to claim 1, wherein R represents a hydrogen atom, a linear or 10 branched (C -C )alkoxy group or a -O-alkyl(C -C )-R group. 1 6 1 6 12
21. Compound according to claim 1, wherein R represents a hydrogen atom.
22. Compound according to claim 1, wherein represents , wherein R is as defined in claim 1. - 161-
23. Compound according to claim 1, which is compound of formula (I-g):
24.(I-g) wherein R1, R6, R7, R8, R9, R10, R11, R11’, R14, X1, X2, X3, X4, X5, W and E are as defined in claim 1. 5 24. Compound according to claim 1, wherein R represents a hydrogen atom, a -CHR R 8 a b group, a linear or branched (C -C )alkyl group, or a heteroarylalkyl(C -C ) group. 1 8 1 6
25. Compound according to claim 1, wherein R represents a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl 1 6 2 6 group, a linear or branched (C -C )alkynyl group, an aryl group or a heteroaryl group. 10 26. Compound according to claim 1, wherein R11 and R11’ independently of one another represent a linear or branched (C -C )alkyl group, or the substituents of the pair
26.(R , R ’) form together with the nitrogen atom carrying them a non-aromatic ring 11 11 composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being 15 understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (C -C )alkyl group.
27. Compound according to claim 1, wherein R represents -Cy or - 162- -Cy -alkyl(C -C )-Cy . 5 0 6 6
28. Compound according to claim 27, wherein Cy represents a heteroaryl group.
29. Compound according to claim 27, wherein Cy represents a phenyl group.
30. Compounds according to claim 27 wherein R represents , in which p is an integer equal to 0 or 1 and R represents a hydrogen atom, a hydroxy group, a linear or branched (C -C )alkyl group which may be substituted by a group representing hydroxy or a linear or branched (C -C )alkoxy which may be substituted by hydroxy; a linear or branched (C -C )alkoxy group; a -O-(CHR -CHR -O) -R’ 1 6 17 18 q 10 group; a -O-P(O)(OR’) group; a -O-P(O)(O M ) group; a -O-C(O)-NR R group; a 2 2 19 20 di(C -C )alkylamino(C -C )alkoxy group; a halogen atom; or an aldohexose of 1 6 1 6 formula: in which each R’ is independent; 15 it being understood that: ? R’ represents a hydrogen atom or a linear or branched (C -C )alkyl group, ? R represents a hydrogen atom or a (C -C )alkoxy(C -C )alkyl group, 17 1 6 1 6 ? R represents a hydrogen atom or a hydroxy(C -C )alkyl group, 18 1 6 - 163- ? R represents a hydrogen atom or a (C -C )alkoxy(C -C )alkyl group, 19 1 6 1 6 ? R represents a (C -C )alkoxy(C -C )alkyl group, a -(CH ) -NR R ’ group or 20 1 6 1 6 2 r 11 11 a -(CH ) -O-(CHR -CHR -O) -R’ group, 2 r 17 18 q ? q is an integer equal to 1, 2 or 3 and r is an integer equal to 0 or 1, 5 ? M represents a pharmaceutically acceptable monovalent cation.
31. Compounds according to claim 30, wherein the aldohexose is D-mannose.
32. Compounds according to claim 1, which are: - (2R){[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4- fluorophenyl)furo[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl) 10 pyrimidinyl]methoxy}phenyl)propanoic acid; - (2R){[5-{3-chloroethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4- fluorophenyl)furo[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl) pyrimidinyl]methoxy}phenyl)propanoic acid; - N-[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4- 15 fluorophenyl)furo[2,3-d]pyrimidinyl]{[2-(2-methoxyphenyl)pyrimidinyl] methoxy}-D-phenylalanine; - (2R){[(3S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 2-(4-fluorophenyl)benzothiophenyl]oxy}(2-{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid; 20 - (2R){[(3S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 2-(4-fluorophenyl)benzofuranyl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidin- 4-yl]methoxy}phenyl)propanoic acid; - (2R){[(3S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-fluoro(4-fluorophenyl)benzofuranyl]oxy}(2-{[2-(2-methoxyphenyl) 25 pyrimidinyl]methoxy}phenyl)propanoic acid; - (2R){[3-{(3S )chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 2-(4-fluorophenyl)methyl-1H-indolyl]oxy}(2-{[2-(2-methoxyphenyl) pyrimidinyl]methoxy}phenyl)propanoic acid; - 164- - (2R){[(3S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 2-(4-fluorophenyl)thieno[2,3-b]pyridinyl]oxy}(2-{[2-(2-methoxyphenyl) pyrimidinyl]methoxy}phenyl)propanoic acid; - (2R)[5-[3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl](4- 5 fluorophenyl)methyl-pyrrolo[2,3-d]pyrimidinyl]oxy[2-[[2-(2-methoxy phenyl)pyrimidinyl]methoxy]phenyl]propanoic acid; - 1-[(dimethylcarbamoyl)oxy]ethyl (2R){[(3S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-b]pyridin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; 10 - 1-[(ethoxycarbonyl)oxy]ethyl (2R){[(3S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-b]pyridin yl]oxy}(2-{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}phenyl)propanoate; - N-[3-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4- fluorophenyl)thieno[2,3-b]pyridinyl]{[2-(2-methoxyphenyl)pyrimidinyl] 15 methoxy}-D-phenylalanine; - N-[3-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4- fluorophenyl)thieno[3,2-c]pyridinyl]{[2-(2-methoxyphenyl)pyrimidinyl] methoxy}phenylalanine; - 2-{[(3R ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4- 20 fluorophenyl)imidazo[1,2-c]pyrimidinyl]oxy}(2-{[2-(2-methoxyphenyl) pyrimidinyl]methoxy}phenyl)propanoic acid.
33. Process for the preparation of a compound of formula (I) according to claim 1, wherein the starting material used is the compound of formula (II-a): (II-a) 25 wherein Z represents bromine or iodine, Z represents chlorine, bromine or hydroxy, and A is as defined for formula (I) in which 1 is linked to the Z group and 2 is linked to the Z group, which compound of formula (II-a) is subjected to coupling with a compound of formula (III): - 165- (III) wherein R , R , R , W and n are as defined for formula (I), and Alk represents a linear 6 7 14 or branched (C -C )alkyl group, to yield the compound of formula (IV): wherein R , R , R , A, W and n are as defined for formula (I), and Z and Alk are as 6 7 14 1 defined before, compound of formula (IV) which is further subjected to coupling with compound of formula (V): wherein R , R , R , R and R are as defined for formula (I), and R and R represent 1 2 3 4 5 B1 B2 a hydrogen atom, a linear or branched (C -C ) alkyl group, or R and R form with 1 6 B1 B2 the oxygen carrying them an optionally methylated ring, - 166- to yield the compound of formula (VI): wherein R , R , R R , R , R , R , R , A, W and n are as defined for formula (I) and 1 2 3 4 5 6 7 14 Alk is as defined before, 5 the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolyzed to yield the carboxylic acid, which may optionally be reacted with an alcohol of formula R ’-OH or a chlorinated compound of formula R ’-Cl wherein R ’ represents a linear 8 8 8 or branched (C -C )alkyl group, a -CHR R group, an aryl group, a heteroaryl group, 1 8 a b an arylalkyl(C -C ) group, or a heteroarylalkyl(C -C ) group, R and R are as defined 1 6 1 6 a b 10 for formula (I), to yield the compound of formula (I), which may be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional separation technique, 15 it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino…) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.
34. Process for the preparation of a compound of formula (I) according to claim 1, 20 wherein the starting material used is the compound of formula (II-b): (II-b) - 167- wherein Z represents iodine, Z represents chlorine, hydroxy, and A is as defined for formula (I) in which 1 is linked to the Z group and 2 is linked to the Z group, which compound of formula (II-b) is subjected to coupling with a compound of formula (V): wherein R , R , R , R and R are as defined for formula (I), and R and R represent 1 2 3 4 5 B1 B2 a hydrogen atom, a linear or branched (C -C ) alkyl group, or R and R form with 1 6 B1 B2 the oxygen carrying them an optionally methylated ring, to yield the compound of formula (VII): (VII) wherein R , R , R R , R and A are as defined for formula (I), and Z is as defined 1 2 3 4 5 4 before, compound of formula (VII) which is further subjected to coupling with compound of formula (III): - 168- (III) wherein R , R , R , W and n are as defined for formula (I), and Alk represents a linear 6 7 14 or branched (C -C )alkyl group, to yield the compound of formula (VI): wherein R , R , R R , R , R , R , R , A, W and n are as defined for formula (I) and 1 2 3 4 5 6 7 14 Alk is as defined before, the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolyzed to yield the carboxylic acid, which may optionally be reacted with an alcohol of formula 10 R ’-OH or a chlorinated compound of formula R ’-Cl wherein R ’ represents a linear 8 8 8 or branched (C -C )alkyl group, a -CHR R group, an aryl group, a heteroaryl group, 1 8 a b an arylalkyl(C -C ) group, or a heteroarylalkyl(C -C ) group, R and R are as defined 1 6 1 6 a b for formula (I), to yield the compound of formula (I), which may be purified according to a 15 conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional separation technique, - 169- it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino…) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis. 5
35. Pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 32 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.
36. Pharmaceutical composition according to claim 35 for use as pro-apoptotic agents.
37. Pharmaceutical composition according to claim 36 for use in the treatment of cancers 10 and of auto-immune and immune system diseases.
38. Pharmaceutical composition according to claim 37 for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non- 15 small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
39. Use of a compound of formula (I) according to any one of claims 1 to 32 or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament useful as a pro-apoptotic agent.
40. Use of a compound of formula (I) according to any one of claims 1 to 32 or an 20 addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament for the treatment of cancers and of auto-immune and immune system diseases.
41. Compound of formula (I) according to any one of claims 1 to 32, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of 25 cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer - 170- of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer. 5
42. Use of a compound of formula (I) according to any one of claims 1 to 32, or an addition salt thereof with a pharmaceutically acceptable acid or base, in the manufacture of medicaments for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, 10 malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
43. Combination of a compound of formula (I) according to any one of claims 1 to 32 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies. 15
44. Pharmaceutical composition comprising a combination according to claim 43 in combination with one or more pharmaceutically acceptable excipients.
45. Combination according to claim 43 for use in the treatment of cancers.
46. Use of a combination according to claim 43 in the manufacture of a medicament for the treatment of cancers.
47. Compound of formula (I) according to any one of claims 1 to 32 for use in the treatment of cancers requiring radiotherapy.
48. Use of a compound of formula (I) according to any one of claims 1 to 32 or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament for the treatment of cancers requiring radiotherapy.
49. Compound according to any one of claims 1 to 32, claim 41, or claim 47; process - 171- according to claim 33 or claim 34; pharmaceutical composition according to any one of claims 35 to 38, or claim 44; use according to any one of claims 39, 40, 42, 46, or 48; or combination according to claim 43 or claim 45 substantially as herein described with reference to any example thereof.
NZ738471A 2016-06-22 New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them NZ738471B2 (en)

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PCT/EP2016/064418 WO2016207217A1 (en) 2015-06-23 2016-06-22 New bicyclic derivatives, a process for their preparation and pharmaceutical compositions containing them

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