Patent EA-003146-B1 (EA)
Title: New cyano-indole serotonin-reuptake inhibitor compounds, a process for their preparation and pharmaceutical compositions containing them
Inventor: LAVIELLE GILBERT
IPC: C07D209/08
Filed: 2000-01-25
Abstract: 1. Compounds of formula (I): wherein: x R1 and R2 each independently of the other represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, x A represents a linear or branched (C1-C6)alkylene group, a linear or branched (C2-C6)-alkenylene group or a linear or branched (C2-C6)alkynylene group, x G1 represents a grouping , wherein R3 and R4 each independently of the other represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, a (C3-C8)cycloalkyl group, a (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an optionally substituted aryl group, an optionally substituted aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl-(C1-C6)-alkyl group in which the alkyl moiety is linear or branched, or G1 represents a heterocycloalkyl group, bonded to A by any one of the ring junctions and optionally substituted at any one of the ring positions by a linear or branched (C1-C6)alkyl group, a (C3-C8)cycloalkyl group, a (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a nitrile group, a carboxy group, a linear or branched (C1-C6)alkoxy-carbonyl group, a carbamoyl group (optionally substituted by one or two substituents: linear or branched (C1-C6)alkyl, (C3-C8)cycloalkyl, optionally substituted phenyl and/or optionally substituted benzyl), an optionally substituted aryl group, an optionally substituted aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an optionally substituted heteroaryl group, or an optionally substituted heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, their enantiomers, diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 2. Compounds of formula (I) according to Claim 1 wherein the cyano group is attached in the 6-position of the indole group, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to Claim 1 wherein the cyano group is attached in the 5-position of the indole group, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to Claim 1 wherein A represents a linear or branched (C1-C6)alkylene group, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to Claim 1 wherein G1 represents a grouping , their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to Claim 1 wherein G1 represents an optionally substituted heterocycloalkyl group, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to Claim 1 wherein the cyano group is attached in the 5- or 6-position of the indole group, R1 and R2 each represents a hydrogen atom, A represents a linear or branched (C1-C6)alkylene group, and G1 represents a grouping wherein R3 and R4 are each independently of the other selected from a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group and an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, or G1 represents an optionally substituted heterocycloalkyl group selected from piperazine, pyrrolidine, piperidine and 1,4-diazepan, their enantiomers, diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compound of formula (I) according to Claim 1 which is 1-{3-[4-(5-methoxy-4-pyrimidinyl)-1-piperazinyl]propyl}-1H-indole-6-carbonitrile dihydrochloride, and its addition salts with a pharmaceutically acceptable acid. 9. Compound of formula (I) according to Claim 1 which is 1-[3-(dimethylamino)-propyl]-1H-indole-6-carbonitrile hydrochloride, and its addition salts with a pharmaceutically acceptable acid. 10. Compound of formula (I) according to Claim 1 which is 1-{[1-(2-chlorophenethyl)-3-pyrrolidinyl]methyl}-1H-indole-6-carbonitrile, and its addition salts with a pharmaceutically acceptable acid. 11. Process for the preparation of compounds of formula (I) according to Claim 1, characterised in that there is used as starting material a compound of formula (II): wherein R1 and R2 are as defined for formula (I), which, after treatment in a basic medium, may be subjected to : the action of a compound of formula (III): P-A-G1 (III) wherein A and G1 are as defined for formula (I), and P represents a leaving group, to yield a compound of formula (I), or the action of a compound of formula (IV): Hal-A-OH (IV) wherein A is as defined for formula (I), and Hal represents a halogen atom, to yield a compound of formula (V) : wherein R1, R2 and A are as defined hereinbefore, which, after bromination of the hydroxyl function, or conversion of the latter to a leaving group, is subjected, in a basic medium, to the action of a compound of formula (VI) : G1-H (VI) wherein G1 is as defined for formula (I), to yield a compound of formula (I), it being understood that the grouping G1, when it represents an amino group or an unsubstituted heterocycloalkyl group, may be substituted in a final step, in order to introduce substituents as defined for formula (I), using conventional reactions of organic chemistry, which compound of formula (I): - may be purified, if necessary, according to a conventional purification technique, - is separated, where appropriate, into its isomers according to a conventional separation technique, - is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base. 12. Pharmaceutical compositions comprising as active ingredient at least one compound according to any one of Claims 1 to 10, on its own or in combination with one or more inert, non-toxic pharmaceutically acceptable excipients or carriers. 13. The use of at least one of compositions according to any one of Claims 1-10 as an active ingredient of pharmaceutical composition inhibiting serotonin-reuptake in the treatment of depression, obsessive-compulsive disorders, phobias, impulsive disorders associated with drug abuse, bulimia nervosa and anxiety.