Patent EA-004147-B1 (EA)
Title: Benzothiophene, indole derivatives, a process for their preparation and pharmaceutical compositions containing them
Inventor: DE NANTEUTL GUILLAUME
IPC: A61P7/04
Filed: 2000-10-13
Abstract: 1. Benzothiophene and indole derivatives of formula (I): wherein X represents a nitrogen atom or a NH group; Y represents an oxygen atom, a nitrogen atom or a Nh group; T represents a nitrogen atom, when the bond that links it to the adjacent carbon is single (-), or a carbon atom or a CH group depending on whether the bond that links it to the adjacent carbon is single (-) or double ((); A represents a single bond or a group selected from (C1-C6)alkylene (optionally substituted by one or more linear or branched (C1-C6)alkyl groups, aryl groups, aryl-(C1-C6)alkyl groups, in which the alkyl moiety is linear or branched, cycloalkyl groups, heterocycloalkyl groups or heteroaryl groups), arylene and a -SO2-R4-(SO2 moiety being linked to T) in which R4 represents arylene; W represents a group selected from hydroxy, linear or branched (C1-C6)alkoxy; U1 represents an oxygen atom, a sulphur atom or a linear or branched (C1-C6)alkylene chain wherein one or more of the carbon atoms may optionally be replaced by one or more hetero atoms selected from oxygen, nitrogen and sulphur, the said alkylene chain being optionally substituted by one or more identical or different groups selected from halogen, hydroxy, linear or branched (C1-C6)alkyl and linear or branched (C1-C6)alkoxy; V1 represents an arylene group; U2 represents a single bond, an oxygen, nitrogen or sulphur atom or a linear or branched (C1-C6)alkylene chain wherein one or more carbon atoms may optionally be replaced by one or more identical or different groups selected from oxygen, sulphur and nitrogen atoms (a nitrogen atom being substituted by a group selected from hydrogen and linear or branched (C1-C6)alkyl) and an SO2 group; V2 represents an aryl or pyridyl; Ra, Rb and Re, which may be identical or different, each independently of the others represents a group selected from: - hydrogen; - linear or branched (C1-C6)alkyl; - phenoxyphenoxy, pyridylmethylphenoxy, benzylbenzyloxy, phenoxybenzyloxy, phenylthiobenzyloxy, phenylsulfonylbenzyloxy, phenoxyphenylsulfonylbenzyloxy, and - aryl (C1-C6) alkoxy, in which the alkoxy moiety is linear or branched; R1 represents phenyl, pyridyl, quinolyl, pyridyloxyphenyl, imadazolylphenyl, optionally substituted by one to five identical or different substituents, each of them is independently selected from halogen, hydroxy, cyano, nitro, carboxy, linear or branched (C1-C6) alkoxy; R2 represents a group selected from a hydrogen atom, aryl or pyridyl group; wherein it is understood that: - an aryl group represents a phenyl, biphenyl, naphthyl, tetrahydronaphthyl or dihydronaphthyl group, each of them is optionally substituted by one or a plurality of identical or different groups selected from halogen, hydroxy, cyano, nitro, linear or branched (C1-C6) alkyl (optionally substituted by one or a plurality of groups selected from hydroxy, amino and mono- or di- (C1-C6) alkylamino, in which each of the alkyl moiety is linear or branched), linear or branched (C1-C6) trihalogenalkyl, linear or branched (C1-C6) alkoxy, aryloxy, linear or branched (C1-C6) acyl, carboxy, linear or branched (C1-C6) alkoxycarbonyl and amino (optionally substituted by one or two linear or branched (C1-C6)alkyl groups), their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 2. Compounds of formula (I) according to claim 1, characterised in that Y represents an oxygen atom, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1, characterised in that R1 represents a group selected from phenyl optionally substituted by a group as defined for formula (I), optionally substituted quinolyl and optionally substituted pyridyl, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1, characterised in that R2 represents a group selected from aryl and pyridyl, each of those groups being optionally substituted, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to either claim 1 or claim 4, characterised in that R2 represents a pyridyl group, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1, characterised in that U1 represents a linear (C1-C4)alkylene chain wherein one of the carbon atoms is replaced by an oxygen atom, V1 represents an arylene group, U2 represents a single bond and V2 represents an aryl group optionally substituted by one of the groups as defined for formula (I), their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to either claim 1 or claim 6, characterised in that -U1-V1-U2-V2 represents a [1,1'-biphenyl]-4-ylmethoxy grouping, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compounds of formula (I) according to claim 1, characterised in that at least one of the groups Ra, Rb or Rc represents a grouping of formula -U1-V1-U2-V2 as defined for formula (I), their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 9. Compounds of formula (I) according to either claim 1 or claim 2, characterised in that X represents a sulphur atom and Y represents an oxygen atom, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 10. Compounds of formula (I) according to claim 1, characterised in that X represents a sulphur atom, Y represents an oxygen atom, R1 represents an optionally substituted phenyl group or an optionally substituted pyridyl group, and A represents a single bond when T represents a carbon atom or a CH group, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 11. Compounds of formula (I) according to claim 1, characterised in that X represents a sulphur atom, Y represents an oxygen atom, R1 represents a phenyl group optionally substituted by a group as defined for formula (I), and A represents an alkylene group (optionally substituted by a linear or branched (C1-C6)alkyl group, an aryl group or by an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched) or an arylene group when T represents a nitrogen atom, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 12. Compounds of formula (I) according to claim 1, characterised in that they represent compounds of formula (I bis): wherein: X represents a sulphur atom, Y represents an oxygen atom, R1 represents an optionally substituted phenyl group or a heteroaryl group selected from an optionally substituted pyridyl, and optionally substituted quinolyl, A represents a single bond, T represents a carbon atom, Ra and Rc each represents a hydrogen atom, U1 represents a linear (C1-C4)alkylenoxy chain, V1 represents an arylene group, U2 represents a single bond, V2 represents an aryl group, Rb represents a U1-V1-U2-V2 grouping as defined hereinbefore, R2 represents a heteroaryl group, W represents a group as defined for formula (I), their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 13. Compounds of formula (I) according to claim 12, characterised in that they represent compounds of formula (I bis) wherein Rb and -U1-V1-U2-V2 each represents a [1,1'-biphenyl]-4-ylmethoxy grouping, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 14. Compounds of formula (I) according to claim 12, characterised in that they represent compounds of formula (I bis) wherein R2 represents a pyridyl group, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 15. Compounds of formula (I) according to claim 12, characterised in that they represent compounds of formula (I bis) wherein R1 represents: - a phenyl group optionally substituted by from one to three groups selected from halogen atoms, linear or branched (C1-C6)alkyl, heteroaryl, heteroaryl-(C1-C6)alkoxy in which the alkoxy moiety is linear or branched, linear or branched -(C1-C6) alkoxy, amino and linear or branched amino-(C1-C6) alkoxy, it being possible for the amino moiety to be substituted by one or two identical or different linear or branched -(C1-C6)alkyl groups, - or a heteroaryl group selected from pyridyl and quinolyl optionally substituted by a halogen atom or a linear or branched -(C1-C6)alkyl group, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 16. Compounds of formula (I) according to claim 1 which is (E)-3-[5,6-bis([1,1'-biphenyl]-4-ylmethoxy)-3-(4-chlorophenoxy)benzo[6]thiophen-2-yl]-2-(4-pyridyl)-2-propenoic acid, its isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 17. Compounds of formula (I) according to claim 1 which are: -ethyl (E)-3-[5,6-bis-([1,1'-biphenyl]-4-ylmethoxy)-3-(4-chlorophenoxy)-benzo[b]thiophen-2-yl]-2-(4-pyridyl)-2-propenoate, -(E)-3-[5,6-bis-([1,1'-biphenyl]-4-ylmethoxy)-3-(3-pyridyloxy)-benzo[b]thiophen-2-yl]-2-(4-pyridyl)-2-propenoic acid, -3-(E)-{5,6-bis-([1,1'-biphenyl]-4-ylmethoxy)-3-[6-(methyl)pyridyl-3-oxy]-benzo[b]-thiophen-2-yl}-2-(4-pyridyl)-2-propenoic acid, -3-(E)-[5,6-bis-([1,1'-biphenyl]-4-ylmethoxy)-3-(6-quinolyloxy)-benzo[b]thiophen-2-yl]-2-(4-pyridyl)-2-propenoic acid, -(E)-3-[5,6-bis-([1,1'-biphenyl]-2-ylmethoxy)-3-(4-chlorophenoxy)-benzo[b]thiophen-2-yl]-2-(4-pyridyl)-2-propenoic acid, their isomers and addition salts thereof with a pharmaceutically acceptable acid or base. 18. Pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) according to any one of claims 1 to 17, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers. 19. Pharmaceutical compositions according to claim 18 for use as a