Patent GB-1526978-A (GB)
Title: 3-thiosubstituted cephalosporin antibiotics
IPC: C07D501/16
Filed: 1975-12-09
Abstract: 1526978 3-Thio-substituted cephalosporins ELI LILLY & CO 9 Dec 1975 [13 Dec 1974] 50321/75 Heading C2C Novel 3-thio-substituted cephalosporins of the general Formula I wherein R is H or R<SP>1</SP>CO and R<SP>1</SP> is C 1 -C 6  alkyl, C 1 -C 3  haloalkyl, C 1 -C 3  cyanoalkyl, phenyl, methylphenyl, hydroxyphenyl, halophenyl, nitrophenyl, aminophenyl or methoxyphenyl; or R<SP>1</SP> is a group of the Formula III wherein a and a<SP>1</SP> independently are hydrogen, C 1 -C 4  lower alkyl, C 1 -C 4  lower alkoxy, halogen, hydroxy, nitro, amino, or carboxy; Z is 0 or S; and m is 0 or 1; or R<SP>1</SP> is a group of the formula P-CHQ-in which P is 2- or 3-thienyl or a group of the Formula IV wherein a and a<SP>1</SP> are as defined above, Q is hydroxyl, formyloxy, acetoxy, carboxy, sulfo, amino, or amino protected by t-butyloxy carbonyl, 2,2,2-trichloroethoxycarbonyl, or the group of the formula or R<SP>1</SP> is a group of the formula wherein R<SP>11</SP> is 2-thienyl, 3-thienyl, 2-furyl, 2- oxazolyl, 2-thiazolyl, or 1-tetrazolyl; R 1  is hydrogen, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethyl, 2,2,2-trichloroethyl, or t-butyl; R 2  is C 1 -C 4  alkyl, phenyl, or a substituted phenyl group of the Formula IV or R 2  is a heterocyclic group having one of the following formulae wherein R 3  is C 1-3  alkyl, and, when R 1  is H, pharmaceutically acceptable non-toxic salts thereof, when Q is amino, pharmaceutically acceptable acid addition salts thereof and, when R 1  is hydrogen and Q is amino, the zwitterionic form thereof, are prepared by reacting a halide or sulphonate of the general Formula II wherein R 1  is a carboxylic acid-protecting esterforming group and A is Cl, Br or -OSO 2 W in which W is C 1-3  alkyl, phenyl, halophenyl- C 1-3  alkyl-phenyl or nitrophenyl, with a mercaptan of the general formula R 2 SH and optionally removing the group R 1  to give the free acid (a resulting product may be de-N-protected or a resulting #<SP>2</SP>-cephem may be converted to the #<SP>3</SP>-cephem by oxidation and reduction of the resulting #<SP>3</SP>-sulphoxide). Halides and sulphonotes (II) are prepared from an appropriate 3-hydroxy derivative by halogenation or reaction with a sulphonyl halide, followed, if necessary, by N-acylation, de-N- protection, de-esterification and/or #<SP>2</SP>##<SP>3</SP> isomerization via the #<SP>3</SP>-sulphoxide. p - Nitrobenzyl 7 - [2 - (2 - thienyl)acetamido]- 3 - hydroxy - 3 - cephem - 4 - carboxylate is prepared by treating p-nitrobenzyl 7-phenoxyacetamido - 3 - methylenecepham - 4 - carboxylate with PCl 5 , treating the resulting 7-amino hydrochloride derivative with O 3  and then SO 2  and reacting the resulting 7-amino-3-hydroxy hydrochloride derivative with 2-thienylacetyl chloride. p - Nitrobenzyl 7 - (N - t - butoxycarbonyl - D- phenylgylcylamido) - 3 - hydroxy - 3 - cephem - 4- carboxylate is prepared by reacting the corresponding 7-amino hydrochloride derivative with N-(t-butoxycarbonyl)phenylglycine. Pharmaceutical compositions having antibacterial activity comprise, as active ingredient, a 3-thio-substituted cephalosporin (I) wherein R 1  is hydrogen or pharmaceutically acceptable non-toxic salt thereof, together with a pharmaceutically acceptable carrier.