Patent EA-004140-B1 (EA)
Title: beta-CARBOLINE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Inventor: GOLDSTEIN SOLO
IPC: A61P1/00
Filed: 2000-07-21
Abstract: 1. A compound selected from those of formula (I): wherein --- represents a single or double bond capable optionally of conferring aromatic character to the ring carrying them, R1 represents a group selected from: Hydrogen, linear or branched (C1-C6)alkyl, -R6-aryl, -R6 -cycloalkyl, -R6-imidazolyl, in which R6 represents linear or branched (C1-C6)alkylene, -CO2R7 wherein R7 represents linear or branched (C1-C6)alkyl, aryl, cycloalkyl, imidazolyl, -R6-aryl, -R6-cycloalkyl, or -R6-imidazolyl, wherein R6 is as defined hereinbefore, -COR8 wherein R8 represents hydrogen, linear or branched (C1-C6)alkyl, aryl, cycloalkyl, imidazolyl, -R6-aryl, -R6-cycloalkyl, or -R6-imidazolyl, wherein R6 is as defined hereinbefore, and -CONH-R8 wherein R8 is as defined hereinbefore, or R1 does not exist when the nitrogen atom carrying it is already carrying an intracyclic double bond, R2 represents a group selected from: cyano, -CO2R8 wherein R8 is as defined hereinbefore, -CONHR8 is as defined hereinbefore, mono(C1-C6)alkylamino(C1-C6)alkylaminocarbonyl, di(C1-C6)alkylamino-(C1-C6)-alkylaminocarbonyl, alkyl moieties of each of which groups are linear or branched, NH2; -NH-CO2R7 wherein R7 is as defined hereinbefore, and -COR8 wherein R8 is as defined hereinbefore, R3 and R4 together form (C4-C8)cycloalkyl, R5 represents hydrogen, linear or branched (C1-C6)alkyl, or aryl-(C1-C6)alkyl in which alkyl is linear or branched, Ra, Rb, Rc and Rd, which may be identical or different, each represents, independently of the others, a group selected from hydrogen, halogen, linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched trihalo-(C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl in which alkyl is linear or branched, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof, it being understood that: "cycloalkyl" is a mono- or bi-cyclic ring system that is saturated or optionally contains one or more unsaturations that do not confer aromatic character to the ring, contains4 to 8 carbon, and is 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; "aryl" is phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, indenyl or indanyl, each of those groups being optionally substituted by one or more, identical or different, groups selected from halogen, hydroxy, cyano, nitro, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, amino, linear or branched (C1-C6)alkylamino, di(C1-C6)alkylamino, in which each of the alkyl moieties is linear or branched, aryloxy, aryl-(C1-C6)alkoxy in which the alkoxy moiety is linear or branched, linear or branched trihalo(C1-C6)alkyl, linear or branched (C1-C6)acyl, linear or branched (C1-C6)alkoxycarbonyl, linear or branched (C1-C6)alkylaminocarbonyl, and oxo; "heterocyclyl" is to be understood as a saturated or unsaturated, mono- or bi-cyclic group of aromatic or non-aromatic character having from 5 to 12 ring members and containing one, two or three hetero atom, identical or different, hetero atoms selected from oxygen, nitrogen and sulphur, wherein more preferable, it being understood that the "heterocyclyl" comprises a group selected from pyridinyl, thienyl, furyl, imidazolyl, pyrazinyl, pyrimidinyl, isoxazolyl, tetrazolyl, pyrrolyl, piperidyl, piperazinyl, wherein the heterocyclic moiety may be optionally substituted by one or more identical or different groups selected from linear or branched (C1-C6)alkyl and oxo. 2. A compound of formula (I) according to claim 1, wherein R3 and R4 together form saturated monocyclic (C4-C8)cycloalkyl 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, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 3. A compound of formula (I) according to claim 1 or 2, wherein R3 and R4 together form unsubstituted saturated monocyclic (C4-C6)cycloalkyl, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 4. A compound of formula (I) according to any one of claims 1 to 3, wherein R3 and R4 together form cyclobutyl, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 5. A compound of formula (I) according to claim 1, wherein R1 represents hydrogen, or -COR8 wherein R8 is as defined for formula (I), its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 6. A compound of formula (I) according to claim 1 or 5, wherein R1 represents -COR8a wherein R8a represents aryl, or imidazolyl, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 7. A compound of formula (I) according to claim 1, wherein R2 represents -CO2R8 wherein R8 is as defined for formula (I), its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 8. A compound of formula (I) according to claim 1 or 7, wherein R2 represents -CO2R8b wherein R8b represents linear or branched (C1-C6)alkyl, or cycloalkyl, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 9. A compound of formula (I) according to claim 1 or 8, wherein R2 represents -CO2R8b wherein R8b represents ethyl, or cyclopentyl, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 10. A compound of formula (I) according to claim 1, wherein R5 represents hydrogen, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 11. A compound of formula (I) according to claim 1, having formula (I'): wherein R1, R2, R3, R4, R5, Ra, Rb, Rc and Rd are as defined for formula (I), its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 12. A compound of formula (I) according to claim 1 which is cyclopentyl 1-(6-chloro-2,3,4,9-tetrahydro-1H-beta-carbonlin-1-yl)cyclobutanecarboxylate, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 13. A compound of formula (I) according to claim 1 which is ethyl 1-(6-bromo-2,3,4,9-tetrahydro-1H-beta-carbonlin-1-yl)cyclobutanecarboxylate, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 14. A compound of formula (I) according to claim 1 which is ethyl 1-[6-chloro-2-(1H-imidazol-5-ylcarbonyl)-2,3,4,9-tetrahydro-1H-beta-carbonlin-1-yl]cyclobutanecarboxylate, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 15. A compound of formula (I) according to claim 1 which is ethyl 1-(6-methyl-2,3,4,9-tetrahydro-1H-beta-carbonlin-1-yl)cyclobutanecarboxylate, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 16. A compound of formula (I) according to claim 1 which is ethyl 1-(5,6-dichloro-2,3,4,9-tetrahydro-1H-beta-carbonlin-1-yl)cyclobutanecarboxylate, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 17. A compound of formula (I) according to claim 1 which is ethyl 1-(6-chloro-2,3,4,9-tetrahydro-1H-beta-carbonlin-1-yl)cyclobutanecarboxylate, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 18. A compound of formula (I) according to claim 1claim 1 which is ethyl 1-(6,7-dichloro-2,3,4,9-tetrahydro-1H-beta-carbonlin-1-yl)cyclobutanecarboxylate, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 19. A compound of formula (I) according to claim 1 which is ethyl 1-(6-methoxy-2,3,4,9-tetrahydro-1H-beta-carbonlin-1-yl)cyclobutanecarboxylate, its isomers, and pharmaceutically-acceptable acid or base addition salt thereof. 20. Process for the preparation of the compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): wherein Ra, Rb, Rc, Rd and R5 are as defined for formula (I), which compound of formula (II) is reacted, in accordance with synthesis conditions of the type used for peptide coupling, with a compound of formula (III): wherein R3 and R4 are as defined for formula (I), to yield a compound of formula (IV): wherein Ra, Rb, Rc, Rd, R3, R4 and R5 are as defined hereinbefore, which compounds of formula (IV) are treated in the presence of phosphorus oxychloride in a solvent, such as toluene or benzene, to yield the compounds of formula (I/a), a particular case of the compounds of formula (I): wherein Ra, Rb, Re, Rd, R3, R4 and R5 are as defined hereinbefore, which compounds of formula (I/a) are: ( either reduced according to the conditions conventional in organic synthesis to yield the compounds of formula (I/b), a particular case of the compounds of formula (I): wherein Ra, Rb, Rc, Rd, R3, R4 and R5 are as defined hereinbefore, which compounds of formula (I/b) are treated under basic conditions in the presence of a compound of formula (V) R1-X (V) wherein R1 is as defined for formula (I) and X represents a leaving group customarily used in organic synthesis, to yield the compounds of formula (I/c), a particular case of the compounds of formula (I): ( or subjected to the action of oxidising agents customarily used in organic synthesis to yield the compounds of formula (I/d), a particular case of the compounds of formula (I): wherein Ra, Rb, Rc, Rd, R3, R4 and R5 are as defined hereinbefore, the totality of the compounds of formula (I/a), (I/b), (I/c) and (I/d) constituting the compounds of formula (I/e), a particular case of the compounds of formula (I): wherein Ra, Rb, Rc, Rd, R1, R3, R4 and R5 are as defined for formula (I), which compound of formula (I/e), ( is subjected to the conditions of trans-esterification in the presence of a Lewis acid and of a compound of formula (VI): R7-OH (VI) wherein R7 is as defined for formula (I), to yield the compounds of formula (I/f), a particular case of the compounds of formula (I): wherein Ra, Rb, Rc, Rd, R1, R3, R4, R5 and R7 are as defined hereinbefore, ( or is hydrolysed under basic conditions to