GB1459392A - Heterocyclic compounds - Google Patents

Abstract

1459392 1,2,4-Oxadiazolyl acetic acid derivatives GIST-BROCADES NV 21 Dec 1973 [22 Dec 1972] 59524/72 Heading C2C The invention comprises compounds of Formulµ I, II and III wherein R 1 represents a C 1-6 alkyl group optionally carrying on the carbon atom attached to the oxadiazolyl ring, or the next carbon atom of the alkyl group, a fluorine or chlorine atom, a hydroxy group, a C 1-6 alkoxy group, or a C 5-8 cycloalkyl group optionally substituted with one or more C 1-6 alkyl groups, hydroxy groups or C 1-6 alkoxy groups, or wherein R 1 represents an adamantyl group or a phenyl group optionally substituted with at most three substituents selected from fluorine and chlorine atoms, a hydroxy group and C 1-6 alkyl and C 1-6 alkoxy groups, or wherein R 1 represents a mononuclear heterocyclic five membered group optionally carrying as substituent one or more C 1-6 alkyl groups, or wherein R 1 represents an aralkyl group optionally substituted in the phenyl nucleus as mentioned hereinbefore; Z 1 represents a hydrogen atom or a C 1-6 alkyl, aralkyl, C 5-8 cycloalkyl or phenyl group, the cycloalkyl or phenyl group optionally carrying substituents as mentioned hereinbefore, or Z 1 represents a C 1-6 alkyl group substituted with a mononuclear five membered heterocyclic group as mentioned hereinbefore, with the proviso that when Z 1 represents a hydrogen atom or a C 1-6 alkyl group, R 1 is other than a phenyl group, a phenyl group substituted by one or two F or Cl atoms or a phenyl group substituted by one C 1-6 alkyl group; Z 2 represents a hydrogen atom, a C 1-6 alkyl, phenyl, C 5-8 cycloalkyl or aryl-C 1-6 alkyl group, a carboxy group esterified with a C 1-6 alkyl, phenyl, C 5-8 cycloalkyl or aralkyl radical or N-disubstituted-carbamoyl or N-mono substituted-carbamoyl group; Z 3 represents a hydrogen atom or a phenyl group optionally substituted with at most three of the substituents as mentioned hereinbefore, or a N- disubstituted-carbamoyl group or a carboxy group esterified with a C 1-6 alkyl, phenyl, C 5-8 cycloalkyl or aralkyl radical; R 2 represents the group -(CH 2 ) n -CHR 3 R 4 in which n is 0, 1, 2 or 3 and R 3 is a hydrogen atom or a C 1-6 alkyl group, and R 4 represents a hydrogen atom, a C 1-6 alkyl, C 5-8 cycloalkyl, phenyl or aralkyl group, or R 4 -when n is 1, 2 or 3-represents a -COOE group, wherein E represents a C 1-6 alkyl, benzyl or phenyl group, or R 4 represents a carbamoyl group optionally N-substituted with one or two C 1-6 alkyl or alkenyl groups, one phenyl group, one C 5-8 cycloalkyl group, one or two aryl-C 1-6 alkyl or C 5-8 cycloalkyl-C 1-6 alkyl groups, the phenyl and cycloalkyl groups optionally being substituted with at most one of the substituents as hereinbefore mentioned, or wherein R 3 and R 4 , together with the carbon atom to which they are attached, represent a C 5-8 cycloalkyl group, and Z 4 represents a hydrogen atom, or an optionally substituted aryl group, and salts and esters thereof. Compounds I are prepared by metallation of the methylene group of compounds VI followed by replacement of the metal atom or component by a COOH group, e.g. by action of CO 2 (carbonation). Compounds II are prepared by double metallation and subsequent double carbonation of Compounds IX: Compounds III are prepared by double metallation of compounds X followed by double carbonation and monodecarboxylation of the substituent on the 5- position of the oxadiazole nucleus. The esters, amides and salts are obtained from the acids by methods known per se. The amides may also be obtained by reaction of appropriate α-metallated-1,2,4-oxadiazoles with isocyanates. Particularly preferred amides are those derived from penicillanic acid and cephalosporanic acid. Pharmaceutical compositions having antibacterial, antiphlogistic, antifungal and central depressive activity, comprise certain of the above novel compounds together with pharmaceutically acceptable carriers.