Patent EA-005160-B1 (EA)
Title: OCTAHYDRO-2H-PYRIDO [1,2-alpha]PYRAZIN COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Inventor: GOLDSTEIN SOLO
IPC: A61K31/5025
Filed: 2002-07-11
Abstract: 1. A compound of formula (I): wherein: Ra represents linear or branched (C1-C6)alkylene, X represents a group selected from W1, -C(W1)-W2-, -W2-C(W1)-, -W2-C(W1)W2-, -W2-Ra- wherein Ra is as defined hereinbefore, and -CH(OR1)- wherein: W1 represents oxygen, sulphur, or a group of formula -NR2 wherein R2 represents hydrogen, linear or branched (C1-C6)-alkyl, aryl, aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched, and linear or branched (C1-C6)acyl, W2- represents a group as defined for W1, R1 hydrogen and linear or branched (C1-C6)alkyl, when Y represents aryl or heteroaryl, or X represents a group selected from single bond, -C(W1)-, -W2-C(W1)-, -W2-Ra- and -CH(OR1)- wherein W1, W2, Ra and R<1> are as defined hereinbefore, when Y represents fused bicyclic group, of formula: wherein A represents nitrogen-containing heterocycle containing from 4 to 7 ring members that is unsaturated or partially saturated and optionally contains a second hetero atom selected from oxygen, nitrogen and sulphur, and is optionally substituted by one or more oxo and linear or branched (C1-C6)alkyl, B represents phenyl ring optionally substituted by one or more halogen, nitro, cyano, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)alkyl, linear or branched trihalo-(C1-C6)-alkyl, linear or branched (C1-C6)acyl, linear or branched (C1-C6)acyloxy, carboxy, linear or branched (C1-C6)alkoxy-carbonyl, sulphanyl, linear or branched (C1-C6)-alkylsulphanyl, and amino optionally substituted by one or two identical or different linear or branched (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base, with the proviso that the compounds: 2-octahydro-2H-pyrido[1,2-a]pyrazin-2-yl-1-phenylethanol, 3-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylpropyl-3,4,5-trimethoxybenzoate, and 2-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylethyl-3,4,5-trimethoxybenzoate, are not included in the compounds of the invention, and it also being understood that: "aryl group" is understood to mean a monocyclic or bicyclic aromatic system, containing from 5 to 10 carbon atoms, optionally substituted by one or more identical or different groups each independently of the others selected from halogen, nitro, cyano, hydroxy, linear or branched (C1-C6)alkoxy, aryloxy, aryl-(C1-C6)-alkoxy in which the alkoxy moiety is linear or branched, linear or branched (C1-C6)alkyl, linear or branched (C2-C6)alkenyl, linear or branched (C2-C6)alkynyl, linear or branched trihalo-(C1-C6)alkyl, carboxy, linear or branched (C1-C6)alkoxy-carbonyl, linear or branched (C1-C6)acyl, linear or branched (C1-C6)acyloxy, sulphanyl, linear or branched (C1-C6)alkylsulphanyl, methylenedioxy, ethylenedioxy, amide-oxime and amino optionally substituted by one or two identical or different groups each independently of the other selected from linear or branched (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched, and linear or branched (C1-C6)acyl, "heteroaryl group" is understood to mean monocyclic or bicyclic aromatic system, containing from 5 to 12 ring members, and containing within the same ring system from 1 to 3 identical or different hetero atoms each independently of the others selected from oxygen, nitrogen and sulphur, each of the said systems being optionally substituted by one or more identical or different groups each independently of the others selected from the list of substituents described above in the case of aryl, and "isomer" is understood to include the optical isomers, enantiomers and diastereoisomers. 2. A compound of claim 1, wherein Ra represents linear (C2-C5)alkylene, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 3. A compound of claim 1, wherein R2 represents hydrogen, linear or branched (C1-C6)alkyl, or linear or branched (C1-C6)-acyl, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. A compound of claim 1, wherein it represent a compound of formula (IA): wherein: Ra represents linear or branched (C1-C6)alkylene, X represents a group selected from W1, -C(W1)-W2-, -W2-C(W1)-, -W2-C(W1)W2-, -W2-Ra- wherein Ra is as defined hereinbefore, and -CH(OR1)- wherein: W1 represents oxygen, sulphur, or a group of formula -NR2 wherein R2 represents hydrogen, linear or branched (C1-C6)-alkyl, aryl, aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched, and linear or branched (C1-C6)acyl, W2- represents a group as defined for W1, R1 hydrogen and linear or branched (C1-C6)alkyl, Y1 represents aryl or heteroaryl, its enantiomers, diastereoisomeres, and addition salts thereof with a pharmaceutically acceptable acid or base. 5. A compound of claim 4, wherein X represents oxygen, and groups -C(W1)-W2-, -W2-C(W1)- and -N(R2)- wherein W1 represents oxygen, W2 represents oxygen or a group -NR2 and R2 represents hydrogen, linear or branched (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched, and linear or branched (C1-C6)acyl, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 6. A compound of claim 4, wherein Y, represents phenyl optionally substituted by from 1 to 3 halogen, cyano, hydroxy, linear or branched (C1-C6)alkoxy, aryloxy, aryl-(C1-C6)alkoxy in which the alkoxy moiety is linear or branched, linear or branched (C1-C6)alkyl, linear or branched trihalo-(C1-C6)-alkyl, methylenedioxy and ethylenedioxy, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 7. A compound of claim 1, wherein it represent a compound of formula (IB): wherein: Ra represents linear or branched (C1-C6)alkylene, X represents a group selected from single bond, -C(W1)-, -W2-C(W1)-, -W2-Ra- and -CH(OR1)- wherein W1, W2, Ra and R<1> are as defined hereinbefore, Y2 represents a group of formula: wherein A and B are as defined for formula (I), its enantiomers, diastereisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. A compound of claim 7, wherein Y2 represents a group of formula: wherein Rb represents a saturated or unsaturated linear chain, containing 2 or 3 carbon, nitrogen and oxygen, and/or optionally containing carbonyl, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 9. A compound of claim 7, wherein Y2 represents a group selected from 2,3-dihydro-1H-indol-1-yl, 1H-indol-1-yl, 1H-indazol-1-yl, 1H-benzimidazol-1-yl, 3,4-dihydro-2H-quinol-1-yl, 2,3-dihydro-1H-4-quinolon-1-yl, 3,4-dihydro-2H-quinoxalin-1-yl and 2,3-dihydro-4H-1,4-benzoxazin-4-yl, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 10. A compound of claim 7, wherein X represents single bond, its isomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 11. A compound of claim 1 which is: 2-[4-(2,3-dihydro-1H-indol-1-yl)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, 2-[4-(3,4,5-trimethoxyphenoxy)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, 2-[4-(3,4,5-trimethoxyphenoxy)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, enantiomer alpha, 2-[4-(3,4,5-trimethoxyphenoxy)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, enantiomer beta, N-(4-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylbutyl)-N-(3,4,5-trimethoxyphenyl)amine, N-(4-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylbutyl)-N-(3,4,5-trimethoxyphenyl)-amine, enantiomer alpha, N-(4-octahydro-2H-pyrido[1,2-a]pyrazin-2-ylbutyl)-N-(3,4,5-trimethoxyphenyl)-amine, enantiomer beta, N-(4-trifluorophenyl)-N-(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutyl)amine trihydrochloride, N-(3,4-dichloro-phenyl)-N-(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutyl)amine, N-(3,5-dichloro-phenyl)-N-(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutyl)amine, N-(2-chlorophenyl)-N-(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutyl)amine, 2-[4-(3,4-dihydro-1(2H)-quinolyl)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, 2-[4-(1H-benzimidazol-1-yl)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, 2-[4-(1H-indol-1-yl)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, 2-[4-(1H-indazol-1-yl)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, 2-[4-(2,3-dihydro-1H-indol-1-yl)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, enantiomer alpha, 2-[4-(2,3-dihydro-1H-indol-1-yl)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, enantiomer beta, 3-(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutoxy)benzonitrile, 3-methoxy-4-(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutoxy)benzonitrile, 2-[4-(2,3,4-trimethoxyphenoxy)butyl]octahydro-2H-pyrido[1,2-alpha]pyrazine, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 12. A compound of claim 1 which is: 4-[(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutyl)amino]benzonitrile, 4-[(3-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylpropoxy)benzonitrile, 4-[(3-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylpropoxy)benzonitrile, enantiomer alpha, 4-[(3-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylpropoxy)benzonitrile, enantiomer beta, 4-(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutoxy)benzonitrile, 4-(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutoxy)benzonitrile, enantiomer alpha, 4-(4-octahydro-2H-pyrido[1,2-alpha]pyrazin-2-ylbutoxy)benzonitrile, enantiomer beta, 4-(2-octahydro-2H-pyrido [1,2-alpha]pyrazin-2-ylethoxy)benzonitrile, its enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 13. A pharmaceutical composition comprising at least one compound as claimed in any one of claims 1-12 as an active principle, alone or in a combination with one or more inert, non-toxic pharmaceutically acceptable excipients or vehicles. 14. A pharmaceutical composition as claimed in claim 13 comprising at least one compound as claimed in any one of claims 1-12 as an active principle for use as antagonists of type H3 central