Patent EA-002979-B1 (EA)
Title: Spiro imidazoline compounds, a process for their preparation and pharmaceutical composition containing them
Inventor: CIRDI ALEX
IPC: C07D235/02
Filed: 1999-12-17
Abstract: 1. Compounds of formula (I):   wherein: A represents a benzene ring unsubstituted or substituted by from 1 to 4 identical or different groups selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy, polyhalo-(C1-C6)alkyl in which the alkyl moiety is linear or branched, and halogen, B represents an imidazoline ring as represented in formulae (Ia) and (Ib):   wherein R represents a hydrogen atom, their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 2. Compounds of formula (I) according to claim 1 wherein R represents a hydrogen atom, their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 3. Compounds of formula (I) according to claim 1 wherein the ring A is unsubstituted, their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to claim 1 wherein the ring A is substituted by from 1 to 4 identical or different substituents selected from linear or branched (C1-C6-alkyl, hydroxy, linear or branched (C1-C6)alkoxy, polyhalo-(C1-C6)alkyl in which the alkyl moiety is linear or branched, and halogen atoms, their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1 having a trans ring junction, their tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 6. Compound of formula (I) according to claim 1 which is spiro[(1,3-diazacyclopent-1-ene)-5:2'-(trans-1',2',3',4',4'a,9',9'a,10'-octahydroanthracene)], its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 7. Compound of formula (I) according to claim 1 composed of the mixture of spiro-[(1,3-diazacyclopent-1-ene)-5:2'(S)-(trans-1',2',3',4',4'a(9) 9',9'a (S),10'-octahydroanthracene)] and spiro[( 1,3-diazacyclopent-1-ene)-5 2'(R)-(trans-1',2',3',4',4'a(S), 9',9'a(R),10'-octahydroanthracene)], its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 8. Compound of formula (I) according to claim 1 composed of the mixture of spiro-[(1,3-diazacyclopent-1-ene)-5:2'(S)-(trans-1',2',4',4'a(S),9',9'a(R), 10'-octahydro-anthracene)] and spiro[(1,3-diazacyclopent-1-ene)-5 :2'(R)-(trans-1',2',3',4',4'a(R),9',9'a(S),10'-octahydroanthracene)], its tautomers, enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base. 9. 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 A is as defined hereinbefore, which is condensed with 1,4-cyclohexanedione mono-ethylene acetal enolate in order to obtain a compound of formula (III):   wherein A is as defined hereinbefore, which is subjected to the action of methyl(triphenyl)phosphonium iodide to yield a compound of formula (IV):   wherein A is as defined hereinbefore, which is cyclised in the presence of tributyltin hydride and AIBN to yield a compound of formula (V):   wherein A is as defined hereinbefore, which is subjected, in succession, to the action of an acidic medium followed by a Strecker reaction to obtain a compound of formula (VI):   wherein A is as defined hereinbefore, which is subjected to the action of a reducing agent, such as LiAlH4 for example, to yield a compound of formula (VII):   wherein A is as defined hereinbefore, which is reacted with formamidine acetate to obtain a compound of formula (I/a), a particular case of the compounds of formula (I):   wherein A is as defined hereinbefore, which is subjected, in succession, to the action of an acidic medium followed by a Strecker reaction to obtain a compound of formula (VI):   wherein A is as defined hereinbefore, which is subjected to the action of a reducing agent, such as LiAlRi for example, to yield a compound of formula (VII):   wherein A is as defined hereinbefore, which is reacted with formamidine acetate to obtain a compound of formula (I/a), a particular case of the compounds of formula (I):   wherein A is as defined hereinbefore and B' represents an unsubstituted imidazoline ring as represented in the formulae (Ia/a) and (Ib/a):                                       and may be purified according to a conventional separation technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and are separated, where appropriate, into their isomers according to a conventional separation technique. 10. A pharmaceutical composition comprising as active ingredient at least one of the compounds of formula (I) according to any one of claims 1 to 9 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients. 11. A pharmaceutical composition according to claim 9 for use in the production of a medicament for the treatment of depression, obesity, panic attacks, anxiety, obsessive-compulsive disorders, cognitive disorders, phobias, impulsive disorders associated with the abuse of drugs and withdrawal therefrom, sexual dysfunctions and Parkinson's disease.