3-HETEROCYCLYLTHIOMETHYL CEPHALOSPORINS

摘要

1328340 3 - Heterocyclic - thiomethyl cephalosporins SMITH KLINE & FRENCH LABORATORIES 16 Dec 1971 [17 Dec 1970 18 Feb 1971 (2) 17 March 1971] 58386/71 Headings C2A and C2C The invention comprises novel cephalosporins having the Formula (I) wherein A is in which X and X1 are each hydrogen, hydroxy, amino, halo, nitro, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; M is hydrogen or alkali metal; Y is -NHR or -OR in which R is hydrogen, aminoalkanoyl having up to 6 carbons and in which the alkanoyl group may be straight or branched and may be substituted by hydroxy, mercapto, methylthio, carboxy, amino or phenyl; or R is alkanoyl having up to 8 carbons which may be substituted by C 1 -C 4 alkoxy, carbalkoxy in which the alkoxy group is C 1 -C 4 , hydroxy, allyloxy, C 1 -C 4 alkylthio, azido, halo, azido, cyano, carboxy or phenoxy; or R is carbocyclic acyl optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 8 dialkylamino, halo, nitro, trifluoromethyl, hydroxy, amino or cyano; or R is heterocyclic acyl optionally substituted by methyl; and R1 is a 5- or 6-membered heterocycle containing one or more atoms of N, O and/or S and optionally substituted by one or two of alkyl or alkenyl having up to 4 carbons, cycloalkyl, phenyl, benzyl, alkoxy or alkoxy-alkyl of 1-4 carbons, CF 3 , -SCH 3 , amino, halogen or -NHR3 or NR3 2 in which R3 is C 1 -C 4 alkyl; wtih the proviso that when R1 is thiadiazolyl or tetrazolyl or their alkyl substituted derivatives, A is not unsubstituted or mono-substituted phenyl and that when R1 is methyloxazolyl or methyloxadiazolyl and Y is NH 2 , A is not unsubstituted phenyl. The compounds (I) are prepared by (a) N- acylating an appropriate 7-amino-3-heterocyclic thiomethyl cephalosporanic acid with a carboxyl-activated glycine or glycolic acid; (b) subjecting an appropriate 7-acylamino-3-acetoxymethyl cephalosporanic acid to nucleophilic displacement of the acetoxy group with a mercaptoheterocycle; or (c) subjecting 7- aminocephalosporanic acid to both of reactions (a) and (b). Subsequent treatment to convert compounds wherein Y is NH 2 or OH to compounds wherein Y is NHR or OR and R is other than hydrogen is carried out if necessary, using conventional O- and N-acylation procedures. Labile groups (e.g. NH 2 and OH) in the starting materials are conventionally protected before carrying out procedures (a), (b) or (c) above, the protecting groups being subsequently removed if necessary. Succinimide ester of O-tetrahydropyranylmandelic acid is prepared by reacting the said acid with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide. 2 - Amino - 5 - trifluoromethyl - 1,3,4 - thiadiazole is diazotized and then treated with HBr to give 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole, which is reacted with thiourea with subsequent hydrolysis to give 2-mercapto-5-trifluoromethyl-1,3,4-thiadiazole. Pharmaceutical compositions having antibiotic activity comprise a compound of Formula (I) defined hereinbefore together with a pharmaceutically acceptable non-toxic diluent or carrier.