Patent EA-005165-B1 (EA)
Title: N-benzylpiperazine compounds, a process for their preparation and pharmaceutical composition containing them
Inventor: LABIDALLE SERGE
IPC: A61P41/00
Filed: 2002-07-15
Abstract: 1. A compound selected from those of formula (I): wherein R1 represents linear or branched (C1-C6)alkyl, R2 represents hydroxy, linear or branched (C1-C6)alkoxy, or amino, optionally substituted by one or two linear or branched (C1-C6)alkyl groups, n represents an integer from 1 to 12 inclusive, R3 represents hydrogen, linear or branched (C1-C6)alkyl optionally substituted by phenyl, (which may also be optionally substituted by one or more identical or different substituents selected from halogen and linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy and trihalomethyl), (C3-C7)cycloalkyl, pyrimidine optionally substituted by one or two pyrrolidinyl groups, or phenyl optionally substituted by one or more identical or different substituents selected from halogen and linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, hydroxy and trihalomethyl, its optical isomers, or an addition salt thereof with a pharmaceutically acceptable acid or base. 2. A compound of claim 1 wherein R1 represents methyl. 3. A compound of claim 1 wherein R3 is alkyl substituted by phenyl, optionally benzyl, pyrimidinyl, phenyl optionally substituted by methoxy or hydrogen. 4. A compound of claim 1 wherein n is an integer from 1 to 7. 5. A compound of claim 4 wherein n is 6. 6. A compound of claim 1 wherein R2 represents hydroxy. 7. A compound of claim 1 which is 7-{6-[(4-benzyl-1-piperazinyl)methyl]-2,3-dimethoxyphenoxy}heptanoic acid, or an addition salt thereof. 8. A compound of claim 1 selected from 7-{6-{[4-(pyrimidin-2-yl)-1-piperaziny])methyl}-2,3-dimethoxyphenoxy}heptanoic acid, 4-{6-[(piperazin-1-yl)methyl]-2,3-dimethoxy-phenoxy}butyric acid, 7-{6-[(4-(2-methoxyphenyl)-1-piperazinyl)methyl]-2,3-amethoxy}heptanoic acid, 4-{6-[(4-(2-methoxyphenyly)-1-Piperazinyl)methyl]-2,3-dimethoxyphenoxy}butyric acid, or an addition salt thereof. 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 R1 is as defined for formula (I), which is reacted, in the presence of formaldehyde, with a substituted piperazine of formula (III): wherein R'3 is as defined for R3 with the exception of an alkyl group substituted by a carboxy group, to yield a compound of formula (IV): wherein R1 and R'3 are as defined hereinbefore, which is reacted with a compound of formula (V): X-(CH2)n-COR'2   (V) wherein X represents a halogen atom and R'2 represents a linear or branched (C1-C6)alkoxy group, to yield a compound of formula (I/a), a particular case of the compounds of formula (I): wherein R1, R'2, R'3 and n are as defined hereinbefore, which compound of formula (I/a) is converted, if desired, - to the corresponding mono- or di-acid of formula (I/b), a particular case of the compounds of formula (I): - or to the corresponding amide of formula (I/c): wherein R1, R3 and n are as defined for formula (I) and R"2 represents an amino group optionally substituted by one or two linear or branched (C1-C6)alkyl groups, which compounds of formulae (I/a), (I/b) and (I/c) are purified, if necessary, in accordance with a conventional purification technique, are separated, where appropriate, into their isomers, and are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base. 10. Pharmaceutical compositions comprising as active principle an effective amount of a compound of any one of claims 1-8 together with one or more inert, non-toxic pharmaceutically acceptable excipients or vehicles. 11. Pharmaceutical compositions of claim 10 comprising as active principle an effective amount of a compound of any one of claims 1-8 for use in prophylaxis or treating acute and chronic cell ischaemia, acute or chronic cerebral, cardiac or peripheral ischaemic accidents, whether followed by reperfusion or not, the ischemia incident to any surgical intervention requiring a temporary interruption of blood circulation, the ischemia associated with or resulting in chronic neurodegenerative diseases, the ischemia incident to the storage of organs intended for transplantation, or the ischemia incident to the resumption of functioning of transplant organs after reperfusion.