FORFARANDE FOR FRAMSTELLNING AV IMIDAZOLFORENINGAR, SOM OKAR DET CEREBRALA BLODFLODET

摘要

1423465 1 - Phenyl - 2 - aminoalkylimidazole derivatives YOSHITOMI PHARMACEUTICAL INDUSTRIES Ltd 8 Jan 1974 [24 Jan 1973 16 March 1973 20 March 1973 14 May 1973 16 June 1973 7 July 1973] 00885/74 Heading C2C Novel compounds of the Formula I wherein X is hydrogen, nitro, halogen, or C 1 -C 4 alkylsulphonyl; Ar is phenyl optionally substituted by one or two halogen atoms or pyridyl; each of R1 and R2 is hydrogen, C 1 -C 4 alkyl, cycloalkyl, or optionally substituted aryl or aralkyl including pyridyalkyl, but both of R1 and R2 are not hydrogen, or R1 and R2 together with the adjacent N atom form an optionally substitued 5- or 6-membered heterocyclic ring; each of R3 and R4 is hydrogen or C 1 -C 4 alkyl; and Alk is a C 1 -C 4 alkylene group and acid addition salts thereof may be prepared by (i) reacting a compound of the Formula II wherein Y is halogen with the proviso that Y is fluorine or chlorine when X is hydrogen or halogen, with a compound of the Formula III (ii) reacting a compound of the Formula IV of a salt thereof wherein Z is a reactive atom or group with a compound R 1 R 2 NH or a salt thereof or (iii) converting an amino group in a compound of the Formula VI wherein X1 is hydrogen or halogen, into a hydrogen or halogen atom. Intermediate benzophenones of the Formula II in which Y is chlorine are prepared by converting a corresponding amino compound to the 2-chlorobenzophenone. Intermediates of the Formula III are prepared by reacting 1-benzyl-2-hydroxymethyl imidazole with thionyl chloride followed by an amine R 1 R 2 NH to yield a 1-benzyl-2-substituted aminoimidazole followed by debenzylation to the intermediate III. Intermediates of the Formula IV wherein Z is chlorine or p-toluene sulphonyloxy- and Alk is methylene are prepared by reacting the corresponding 2-hydroxyimidazole with thionyl chloride or p-toluene sulphonyl chloride. 1 - (2 - Benzoyl 4 - nitrophenyl) - 2 - (hydroxymethyl)-imidazole is prepared by reacting 1- benzyl - 2 - (hydroxymethyl)imidazole with 3,4-dihydro-2-pyran to yield 1-benzyl-2-(2-tetrahydropyrauyloxymethyl)imidazole followed by debenzylation to yield 2-(2-tetrahydropyranyloxymethyl)imidazole followed by reaction with 2-fluoro-5-nitrobenzophenone in the presence of sodium hydride to yield the required compound. Pharmaceutical compositions of the compounds I or acid addition salts thereof show protective activity on cerebral hypoxic or anoxic conditions and cerebral blood flow increasing activity when administered orally or parenterally with the usual excipients.