US 3,992,377 AGranted

3-Thio-substituted cephalosporin antibiotics

AssigneeEli Lilly and Company

InventorsRobert R. Chauvette, Gary A. Koppel

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Abstract

7-Acylamido-3-cephem-4-carboxylic acid antibiotics directly substituted in the 3-position of the cephem ring system with a sulfur atom bonded to a 5- or 6-membered heterocyclic ring, a lower alkyl group, or a phenyl or substituted phenyl group are prepared with the corresponding 3-halo-3-cephem esters. For example, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate reacts with 1-methyl-1H-tetrazol-5-ylthiol to provide p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thio]-3-cephem-4- carboxylate. The p-nitrobenzyl ester group is removed by catalytic hydrogenolysis to provide the antibiotic carboxylic acid compound. Alternatively, the antibiotics are prepared by reacting a 3-alkylsulfonyloxy, or 3-arylsulfonyloxy-3-cephem, for example, 3-methanesulfonyloxy-3-cephem, or a 3-p-toluenesulfonyloxy-3-cephem with the heterocyclic thiol, the phenyl or substituted phenylthiol, or with the lower alkylthiol.

Claims13

Dependent claims

A cephalosporin compound of the formula ##SPC23##

wherein R is hydrogen or an acyl group derived from a carboxylic acid and represented by the formula ##EQU1## wherein R' is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.3 haloalkyl, C.sub.1 -C.sub.3 cyanoalkyl, phenyl, mono- or di-methylphenyl, mono- or di-hydroxyphenyl, mono- or di-halophenyl, mono- or di-nitrophenyl, mono- or di-aminophenyl, and mono- or di-methoxyphenyl;
or R' is a group of the formula ##SPC24##
wherein a and a' independently are hydrogen, C.sub.1 -C.sub.4 lower alkyl, C.sub.1 -C.sub.4 lower alkoxy, halogen, hydroxy, nitro, amino, or carboxy;
Z is 0 or S;
and
m is 0 or 1;
or R' is a group of the formula ##EQU2## wherein P is 2-thienyl, 3-thienyl, phenyl or a substituted phenyl group of the formula ##SPC25##
wherein a and a' are as defined above, Q is hydroxyl, formyloxy, acetoxy, carboxy, sulfo, amino, or amino protected by t-butyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, or the group of the formula ##EQU3## or R' is a group of the formula
R"--CH.sub.2 --
wherein R" is 2-thienyl, 3-thienyl, 2-furyl, [2-oxazyl, 2-thiazyl, or 1 tetrazyl] 2-oxazolyl, 2-thiazolyl, or 1-tetrazolyl;
R.sub.1 is hydrogen, benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethyl, 2,2,2-trichloroethyl, or t-butyl;
R.sub.2 is a heterocyclic ring selected from the group consisting of ##SPC26##
wherein R.sub.3 is C.sub.1 -C.sub.3 lower alkyl;
and where R.sub.1 is hydrogen, the pharmaceutically acceptable non-toxic salts thereof.

11 more elements

Dependencies are inferred from the claim text.