Eli Lilly and Company

Allen S Katner

Jean C Miller

Gerald E Gutowski

Stephen J Bogard

Cephalosporin compounds substituted in the 7-position by a 2-(5- or 6-membered heterocyclic)-2-oximinoacetylamino group and in the 3-position with an imidazolo, oxazolo or thiazolopyridinium-methyl group are broad spectrum antibiotics highly effective in combating bacterial infections of gram-negative and gram-positive microorganisms. The cephalosporins are best prepared by reacting a silylated 7-[2-(heterocyclic)-2-oximinoacetylamino-3-iodomethyl-3-cephem-4-carboxyli c acid with an imidazolopyridine, an oxazolopyridine or a thiazolopyridine. Pharmaceutical formulations comprising a compound of the invention and a method for treating bacterial infections comprising their use are also provided.

3-bicyclicpyridinium-methyl cephalosporins

O-Substituted oximinocephalosporins represented by the formula ##STR1## wherein R is a 5-membered or 6-membered heterocycle, preferably amino-substituted, e.g., 2-aminothiazol-4-yl, R.sub.1 is an arylalkyl, aryloxyalkyl, or arylthioalkyl group, especially substituted benzyl; R.sub.2 is a 1,2,4-triazin-3-yl thio group; and M is a salt or a biologically labile ester group; are potent antibacterial agents. Also provided are antibiotic formulations of said compounds and a method for treating infectious diseases in man or animals comprising the administration of said compounds.

7[2-(2-aminothiazol-4-yl)-2-benzyloximino]acetamido-3[4-al

Cephalosporin compounds substituted in the 7-position by a 2-(5- or 6-membered heterocyclic)-2-oximinoacetylamino group and in the 3-position with an imidazolo, oxazolo or thiazolopyridinium-methyl group are broad spectrum antibiotics highly effective in combating bacterial infections of gram-negative and gram-positive microorganisms. The cephalosporins are best prepared by reacting a silylated 7-[2-(heterocyclic)-2-oximinoacetylamino]-3-iodomethyl-3-cephem-4-carboxyl ic acid with an imidazolopyridine, and oxazolopyridine or a thiazolopyridine. Pharmaceutical formulations comprising a compound of the invention and a method for treating bacterial infections comprising their use are also provided.

7.beta.-Acylamino-3-cephem-4-carboxylic acids substituted in the 3-position with a bis-tetrazolemethylthiomethyl group and the corresponding 7.alpha.-methoxy cephalosporins represented by the formula ##STR1## wherein R is an acyl group, R.sub.2 is H or OCH.sub.3 and R.sub.4 is H or C.sub.1 -C.sub.3 alkyl; are broad spectrum antibiotics useful in the treatment and control of microorganisms pathogenic to man and animals. 7.beta.-Amino nucleus compounds represented when R is hydrogen are intermediates useful in the preparation of the antibiotics where R is acyl.

Bis-tetrazoylmethyl substituted cephalosporin antibiotics

Tetrazole thiols represented by the formulae ##STR1## and the C.sub.1 -C.sub.3 alkyl derivatives thereof are provided. The tetrazole thiols are useful in the preparation of broad spectrum cephalosporin antibiotics.

1-and 2-(1-Alkyl-1H-tetrazol-5-yl-methyl)-1H-tetrazol-5-thiols and

Broad spectrum .beta.-lactam antibiotics represented by the formula ##STR1## wherein R is the residue of a carboxylic acid, R.sub.2 is H or OCH.sub.3, and R.sub.4 is hydrogen or C.sub.1 -C.sub.3 alkyl; are obtained by reacting a 7-acylamino-3-halomethyl-1-oxa-.beta.-lactam ester with the desired 1- or 2-tetrazolemethyl substituted 1H or 2H tetrazole-5-thiol. Alternatively, a 7-amino-3-halo-methyl-1-oxa-.beta.-lactam ester is first reacted with the bis-tetrazole thiol and then the product is N-acylated with the desired carboxylic acid.

Bis-tetrazolmethyl substituted .beta.-lactam antibiotics

Bicyclic 1-oxa-.beta.-lactam diacid antibiotics represented by the formula ##STR1## wherein R is phenyl, hydroxyphenyl, acetoxyphenyl, alkylphenyl, or halophenyl, thienyl or furyl; R.degree. is H or OCH.sub.3 ; and the pharmaceutically acceptable non-toxic salts thereof are broad spectrum antibiotics useful for controlling infections in man and animals. The compounds are prepared by reacting the corresponding 3-halomethyl diester with 1-cyanomethyl-1H-tetrazole -5-thiol followed by deesterification.

1-Oxa-.beta.-lactam antibiotics

Cephalosporin compounds of the formula ##STR1## wherein R and R.sub.2 are hydrogen or protecting groups, R.sub.1 is hydrogen or methoxy, R.sub.3 is hydrogen or C.sub.1 -C.sub.4 alkyl and R.sub.4 is C.sub.1 -C.sub.4 alkyl, are broad spectrum antibiotics or intermediates thereto.

7[2-(2-Aminothiazol-4-yl)-2-alkoxyimino]acetamido

Vincaleukoblastine (VLB, vinblastine) is reacted with thionyl chloride to form a bis-sulfite ester which is converted to various 5'-oxygenated derivatives.

5' Acetoxy vinblastine 4' bis-sulfite

Vincaleukoblastine (VLB, vinblastine) is converted to leurosidine, its 4' epimer, by reaction with thionyl chloride to form a bis-sulfite ester followed by treatment of the bis-sulfite ester with silver perchlorate. The bis-sulfite ester is covertible to novel 4' ethers by treatment with a lower alkanol or 4' esters of leurosidine perchlorate with acetic anhydride.

Preparation of leurosidine and novel leurosidine 4'-ethers and esters

Novel 1H-tetrazole-1-acetate esters and acids are prepared by reacting azidoacetate esters and acids with certain acyl cyanides or cyanoformates. The products of the process are useful as intermediates in the preparation of 1H-tetrazole-1-acetic acids which have utility in preparing certain cephalosporin and penicillin antibiotics.

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Indianapolis, IN, United States of America

Allen S Katner