Patent EA-003300-B1 (EA)
Title: New substituted dimeric compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: LESIEUR DANIEL
IPC: A61K31/33
Filed: 2000-03-24
Abstract: 1. Compounds of formula (I): A-G1-Cy-G2-Cy-G3-B  (I) wherein A represents a grouping of formula: wherein Q represents a sulphur or oxygen atom, - R<1> represents linear or branched (C1-C6)alkyl group an unsubstituted or substituted by a halogen atom, linear or branched (C2-C6)alkenyl group, (C3-C8)cycloalkyl group, aryl or heteroaryl group, - R2 represents linear or branched (C1-C6)alkyl group, - B represents a grouping of formula: -NHC(Q)R<1>, -NHC(Q)NHR<2>, -NHC(Q)OR<2>, -C(Q)OR<3> or -NHR<3>, wherein R<1> and R<2> are as defined hereinbefore and R<3> represents a hydrogen atom, linear or branched (C1-C6)alkyl group, - G1 and G3, which may be identical represent a linear or branched alkylene chain having from 1 to 4 carbon atoms, - Cy represents - a ring structure of formula (II): wherein - X and Y, which may be identical or different, represent a sulphur, oxygen or carbon atom, or a CH or CH2 group, - R<4> represents a hydrogen or halogen atom, or a CF3, hydroxy, carboxy, formyl, amino, NHRa, NRaRa<1>, NHCORa, CONHRa, Ra, ORa, CORa or COORa group (wherein Ra is as defined hereinbefore and Ra<1> can have any of the meanings of Ra), - the symbol - - - means that the bonds are single or double, with the proviso that the valency of the atoms is respected, wherein G2 substitutes the benzene ring, and G1 (and G3 respectively) substitutes the ring containing X and Y, - or a ring structure of formula (III): wherein: - Z represents a sulphur or oxygen atom, or a NH, NSO2Ph or NRa group (wherein Ra is as defined hereinbefore), - D represents a benzene or pyridine ring, it being understood that when D is a pyridine ring, then Z represents the NH, NSO2Ph or NRa group, - R<4> is as defined hereinbefore, wherein G2 substitutes the D ring, and G1 (and G3 respectively) substitutes the ring containing Z, - the symbol - - - means that the bond is single or double, with the proviso that the valency of the atoms is respected, it being understood that the two rings (Cy) of the compounds of formula (I) represent the same basic ring structure (indole/indole, naphthalene/naphthalene, benzofuran/ benzofuran, etc.), but the substituent R<4> may be different, - G2 represents a chain of formula (IV): wherein: - W1 and W3, which may be identical or different, represent a bond, an oxygen or sulphur atom, or a NH group, W2 represents a bond or an oxygen atom, - n represents an integer wherein 0 <= n <= 6, - m represents an integer wherein 0 <= m <= 6, with the proviso that it is not possible to have two consecutive hetero atoms and that the chain of formula (IV) so defined may have one or more unsaturated bonds, wherein: - the compound of formula (I) cannot represent diethyl 2-(acetylamino)-2-{[5-({3-(2-(acetylamino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxopropyl]-1H-indol-5-yl} methyl)-1H-indol-3-yl]methyl} malonate, or N-{2-[5-({3-[2-(acetylamino)ethyl]-1H-indol-5-yl}methyl)-1H-indol-3-yl]-ethyl}acetamide, - "aryl" is understood to mean the groups naphthyl, phenyl and biphenyl, - "heteroaryl" is understood to mean any saturated or unsaturated mono- or bi-cyclic group containing from 5 to 10 atoms and containing from 1 to 3 hetero atoms selected from nitrogen, sulphur and oxygen, it being possible for the "aryl" and "heteroaryl" groups to be substituted by one or more identical or different radicals selected from hydroxy, carboxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, polyhalo-(C1-C6)-alkyl in which the alkyl moiety is linear or branched, formyl, cyano, nitro, amino, linear or branched (C1-C6)alkylamino, di-(C1-C6)alkylamino in which each alkyl moiety is linear or branched, and halogen atoms, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 2. Compounds of formula (I) according to claim 1 wherein Cy represents a ring structure of formula (II), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1 wherein Cy represents a naphthalene, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1 wherein Cy represents a ring structure of formula (III), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1 wherein Cy represents a benzothiophene or a benzofuran, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1 wherein Cy represents an indole, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to claim 1 wherein Cy represents an azaindole, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compounds of formula (I) according to claim 1 wherein G2 represents a single bond, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 9. Compounds of formula (I) according to claim 1 wherein G2 represents a grouping -W4-(CH2)p-W'4- wherein W4 and W'4, which may be identical or different, represent an oxygen or sulphur atom or an NH group, and p represents an integer wherein 1 <= p <= 12, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 10. Compounds of formula (I) according to claim 1 wherein G2. represents a grouping -O-(CH2)p-O- wherein p represents an integer wherein 1 <= p <= 12, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 11. Compounds of formula (I) according to claim 1 wherein G2 represents a grouping W4-(CH2)p-W'4-(CH2)p-W"4- wherein W4, W'4 and W"4, which may be identical or different, represent an oxygen or sulphur atom or an NH group, and p' and p" are integers wherein 2 <= p' + p" <= 12, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 12. Compounds of formula (I) according to claim 1 wherein G2 represents a grouping -O-(CH2)p-O-(CH2)p"-O- (wherein p' and p" are as defined hereinbefore), their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 13. Compounds of formula (I) according to claim 1 wherein A and B, which may be identical or different, represent a grouping NR<1>COR<2> or CONR<2>R<3>, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 14. Compounds of formula (I) according to claim 1 which are N-(2-{7-[2-({8-[2-(acetyl-amino)ethyl]-2-naphthyl}oxy)ethoxy]-1-naphthyl}ethyl)acetamide, N-(2-{7-[3-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)propoxy]-1-naphthyl} ethyl)acetamide, N-(2-{7-[4-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)butoxy]-1-naphthyl} ethyl)acetamide, N-[2-(7-{[6-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)hexyl]oxy}-1-naphthyl)ethyl]acetamide, N-[2-(7-{[5-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)pentyl]oxy}-1-naphthyl)ethyl]-acetamide, N-[2-(7-{[8-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)octyl]oxy}-1-naphthyl)ethyl]acetamide, N-[2-(7-{[10-({8-[2-(acetylamino)ethyl]-2-naphthyl} oxy)-decyl]oxy}-1-naphthyl)ethyl]acetamide and N-(2-{7-[4-({8-[2-(acetylamino)ethyl]-7-methoxy-2-naphthyl} oxy)butoxy]-2-methoxy-1-naphthyl}ethyl)acetamide, and addition salts thereof with a pharmaceutically acceptable acid or base. 15. Compound of formula (I) according to claim 1 which is N-[2-(7-{2-[2-({8-[2-(acetylamino)ethyl]-2-naphthyl}oxy)ethoxy]ethoxy}-1-naphthyl)ethyl] acetamide and its addition salts with a pharmaceutically acceptable acid or base. 16. Compounds of formula (I) according to claim 1 which are N-(2-{7-[4-({8-[2-(2-ruroylamino)ethyl]-2-naphthyl} oxy)butoxy]-1-naphthyl} ethyl)-2-furamide, 2-bromo-N-[2-(7-{4-[(8-{2-[(bromoacetyl)amino]ethyl}-2-naphthyl)oxy]butoxy}-1-naphthyl)ethyl]-acetamide, N-[2-(7-{4-[(8-{2-[(cyclopropylcarbonyl)amino]ethyl}-2-naphthyl)oxy]butoxy}-1-naphthyl)ethyl] cyclopropanecarboxamide and N-(2-{7-[4-({8-[2-(3-butenoylamino)ethyl]-2-naphthyl}oxy)butoxy]-1-naphthyl}ethyl)-3-butenamide, and addition salts thereof with a pharmaceutically acceptable acid or base. 17. Compound of formula (I) according to claim 1 which is N-(2-{7-[4-({8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthalenyl}oxy)butoxy]-1,2,3,4-tetrahydro-1-naphthalenyl}ethyl)acetamide, its enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 18. Compounds of formula (I) according to claim 1 which are N-{2-[5-(4-{[3-[2-(acetylamino)ethyl]-1-(phenylsulphonyl)-1H-indol-5-yl]oxy}butoxy)-1-(phenyl-sulphonyl)-1H-indol-3-yl]ethyl}acetamide and N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1H-indol-5-yl}oxy)butoxy]-1H-indol-3-yl}ethyl)acetamide, and addition salts thereof with a pharmaceutically acceptable acid or base. 19. Compounds of formula (I) according to claim 1 which are N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl} oxy)butoxy]-1-benzofuran-3-yl}ethyl)acetamide and N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-benzothien-5-yl}oxy)butoxy]-1-benzothien-3-yl}ethyl)acetamide, and addition salts thereof with a pharmaceutically acceptable acid or base. 20. Compounds of formula (I) according to claim 1 which are N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl}oxy)butoxy]-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}ethyl)acetamide and N-(2-{5-[4-({3-[2-(acetylamino)ethyl]-1-methyl-1H-pyrrolo[[3,2-b]pyridin-5-yl} oxy)propoxy]-1 -methyl-1H-pyrrolo[3,2-b]pyridin-3-yl}ethyl)acetamide, and addition salts thereof with a pharmaceutically acceptable acid or base. 21. Compound of formula (I) according to claim 1 wh