Patent EA-005004-B1 (EA)
Title: Amino acid derivatives and use thereof as nep, ace and ece inhibitors
Inventor: ROQUES BERNARD P
IPC: A61P9/08
Filed: 2001-02-16
Abstract: 1. A compound selected from those of formula (I): wherein: n represents an integer wherein 0 <= n <= 3, m represents an integer wherein 0 <= M <= 6, R<3> and R<4> together form, with the two carbon atoms carrying them, phenyl which may be unsubstituted or substituted by 1 to 3 identical or different groups selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, nitro, amino, alkylamino, dialkylamino, polyhaloalkyl, azido, carboxy, alkoxycarbonyl, amido, carbamoyl, formyl, acyl, aryl, heteroaryl, and halogen, B represents heteroaryl, R<2> represents hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, acyl, aryl, arylalkyl, or aroyl, R<1> represents hydrogen, acyl, aroyl, cycloalkylcarbonyl, or a group of formula (II): wherein m, n, R<2>, R<3>, R<4> and B are as defined hereinbefore, it being understood that: "alkyl" is a linear or branched, 1 to 6 carbon alkyl group, "alkenyl" is a 2 to 6 carbon alkyl group with one or more double bonds, "alkynyl" is a 2 to 6 carbon alkynyl group with one or more triple bonds, "cycloalkyl" is a 3 to 8 carbon cyclic alkyl group, "acyl" is a group RCO wherein R represents alkyl as defined hereinbefore, it being possible for the groups "alkyl", "alkenyl" and "alkynyl" to be substituted by one or more identical or different groups selected from hydroxy, alkoxy, polyhaloalkyl, amino, and halogen, and it being possible for the groups "cycloalkyl" and "cycloalkylalkyl" to be substituted on the cyclic moiety by one or more identical or different groups selected from hydroxy, alkoxy, polyhaloalkyl, amino, and halogen, "aryl" may be phenyl or naphthyl, unsubstituted or substituted by one or more identical or different groups selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, nitro, amino, alkylamino, dialkylamino, polyhaloalkyl, azido, carboxy, alkoxycarbonyl, amido, carbamoyl, formyl, acyl, and halogen, "heteroaryl" may be any mono- or poly-cyclic aromatic group containing 1 to 3 hetero atoms selected from oxygen, sulphur and nitrogen, the aromatic groups being unsubstituted or substituted by one or more identical or different groups selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, nitro, amino, alkylamino, dialkylamino, polyhaloalkyl, azido, carboxy, alkoxycarbonyl, amido, carbamoyl, formyl, acyl, and halogen, it being possible for the polycyclic groups also to be partially or completely hydrogenated on one of the rings, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 2. A compound of claim 1 wherein R<1> represents hydrogen, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 3. A compound of claim 1 wherein R<1> represents acyl, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 4. A compound of claim 1 wherein R<2> represents hydrogen, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 5. A compound of claim 1 wherein R<2> represents alkyl, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 6. A compound of claim 1 wherein R<3> and R<4> together form a substituted phenyl, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 7. A compound of claim 1 wherein R<3> and R<4> together form phenyl substituted by halogen or by methoxy, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 8. A compound of claim 1 wherein n is 1, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 9. A compound of claim 1 wherein m is 1, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 10. A compound of claim 1 wherein B represents heteroaryl containing NH, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 11. A compound of claim 1 wherein B represents indolyl, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 12. A compound of claim 1 wherein B represents pyrrolo-pyridinyl, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 13. A compound of claim 1 wherein B represents pyrrolo-quinolinyl, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 14. A compound of claim 1 of configuration 2S-3R, its diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 15. A compound of claim 1 of configuration 2S-3R-4S, and addition salts thereof with a pharmaceutically-acceptable acid or base. 16. A compound of claim 1 which is selected from N[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan, its enantiomers, diastereo-isomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 17. A compound of claim 1 which is selected from N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan (2S-3R-4S) and its addition salts thereof with a pharmaceutically-acceptable acid or base. 18. A compound of claim 1 which is selected from N-[2-(5-methylthio-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 19. A compound of claim 1 which is selected from N-[2-(5-methoxy-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]tryptophan, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 20. A compound of claim 1 which is selected from N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)alanine, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically-acceptable acid or base. 21. A compound of claim 1 which is selected from N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)alanine (2S-3R-4S) and its addition salts thereof with a pharmaceutically-acceptable acid or base. 22. A compound of claim 1 which is selected from N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-5-methoxytryptophan (2S-3R-4S) and its addition salts thereof with a pharmaceutically-acceptable acid or base. 23. A compound of claim 1 which is selected from N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-5-fluorotryptophan (2S-3R-4S) and its addition salts thereof with a pharmaceutically-acceptable acid or base. 24. A compound of claim 1 which is selected from N-[2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-mercaptopropanoyl]-3-(1H-pyrrolo[3,2-h]quinolin-3-yl)alanine (2S-3R-4S) and its addition salts thereof with a pharmaceutically-acceptable acid or base. 25. A method for preparing a compound of formula (I) according to claim 1, characterized in that a compound of formula (III) is used as an initial product: in which R<3>, R<4> and n are as defined for formula (I) which reacts with a reducing agent such as NaBH4, for example, to yield a compound of formula (IV): in which R<3>, R<4> and n are as defined above, which is transformed using halogenation agent such as Me3SiBr, for example, into a corresponding halogen compound of formula (V): in which R<3>, R<4> and n are as defined above, which is condensed, in the basic medium, with 2-(diethoxyphosphoryl) acetate ethyl to yield a compound of formula (VI): in which R<3>, R<4> and n are as defined above, which reacts with formaldehyde, in the basic medium, to yield a compound of formula (VII): in which R<3>, R<4> and n are as defined above, which is hydrolyzed in the presence of sodium hydroxide to yield a compound of formula (VIII): in which R<3>, R<4> and n are as defined above, which is condensed with a compound of formula (IX): in which R'<1> is alkyl, aryl or cycloalkyl group to yield a compound of formula (X): in which R<3>, R<4> and n are as defined above, which is condensed in the presence of a binding agent, such as 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide, for example, with a compound of formula (XI): in which B and m are as defined for formula (I) and R'<2> is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, acyl, arylakyl or aroyl group, to yield a compound of formula (I/a), a particular case of a compound of formula (I): in which R'<1>, R<3>, R<4>, m, n and B are as defined above, which may be partially or totally hydrolyzed, to yield a compound of formula (I/b), a particular case of a compound of formula (I): in which R<3>, R<4>, m, n and B are as defined above, R"<1> is a R'<1> group or a hydrogen atom, and R"<2> is R'<2> or a hydrogen atom, provided that at least one of R"<1> and R"<2> groups is a hydrogen atom, this compound of formula (I/b), if R"<1> is a hydrogen atom, may be placed in an oxidant medium to yield a compound of formula (I/c), a particular case of a compound of formula (I): in which R<2>, R<3>, R<4>, m, n and B are as defined above, and R"<1> is a group of formula (II), the compounds of formulae (I/a) to (I/c) form a totality of compounds and may be, if necessary, purified using traditional methods of separation, if necessary, they are transformed into its addition salts thereof with a pharmaceutically-acceptable acid or base and they are optionally separated to their stereoisomers using traditional methods of separation. 26. A method of claim 25 for preparing a compound of formula (I) according to claim 1, characterized in that a compound of formula (X) is used as an initial product as defined above, diastereoisomers of which are separated using chromatography to yield compounds of formulae (Xa) and (Xb): in which R'<1>, R<3>, R<4>