Abstract:
3-Heterothio(carbamoylthioacetyl)cephalosporin derivatives of the general formula ##EQU1## wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, tri(lower alkyl)silyl, a salt forming ion or the group ##EQU2## R 1  is hydrogen, lower alkyl, phenyl, thienyl, or pyridyl; R 2  is lower alkyl or phenyl-lower alkyl; R 3  is a five or six membered nitrogen, sulfur and/or oxygen containing ring system; and R 4  is lower alkyl, phenyl or phenyl-lower alkyl; are useful as antibacterial agents.

Description:
SUMMARY OF THE INVENTION 
     This invention relates to new 3-heterothio(carbamoylthioacetyl)cephalosporin derivatives of the formula ##EQU3## R represents hydrogen, lower alkyl, phenyl-lower alkyl, tri(lower alkyl)silyl, a salt forming ion or the group ##EQU4## R 1  represents hydrogen, lower alkyl, phenyl, thienyl, or pyridyl; R 2  represents lower alkyl or phenyl-lower alkyl; R 3  represents a five or six-membered heterocycle including thiadiazole, oxadiazole, isoxazole, isothiazole, tetrazole, pyridine-N-oxide and their lower alkyl substituted analogs; R 4  represents lower alkyl, phenyl or phenyl-lower alkyl. 
     The preferred members within each group as as follows: R is hydrogen, alkali metal, trimethylsilyl, diphenylmethyl or ##EQU5## especially hydrogen, pivaloyloxymethyl, sodium or potassium; R 1  is hydrogen, phenyl or thienyl, especially hydrogen or phenyl; R 2  is lower alkyl, especially methyl or ethyl; R 3  is preferably (lower alkyl)-tetrazole or (lower alkyl)thiadiazole, especially wherein the lower alkyl group is methyl; R 4  is methyl or t-butyl. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification. 
     The lower alkyl groups are the straight and branched chain hydrocarbon groups in the series from methyl to heptyl, the C 1  to C 4  members and especially methyl and ethyl being preferred. 
     The phenyl-lower alkyl radicals include a phenyl ring attached to a lower alkyl group of the kind described above as well as those containing two phenyl groups such as diphenylmethyl. 
     The salt forming ions represented by R are metal ions, e.g., alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, e.g., a (lower alkyl)amine like methylamine or triethylamine or a cycloalkylamine, like dicyclohexylamine, etc. 
     R 3  is thiadiazole, oxadiazole, isoxazole, isothiazole, tetrazole, pyridine-N-oxide and their lower alkyl substituted analogs, especially 1,3,4-thiadiazole, 1,2,4-thiadiazole, tetrazole, 5-methyl-1,3,4-thiadiazol-2-yl, 3-methyl-1,2,4-thiadiazol-5-yl, tetrazole and 1-methyltetrazol-5-yl. 
     The new cephalosporin derivatives of this invention are produced by several methods. According to one method, a 7-aminocephalosporanic acid (7-ACA) derivative of the formula ##EQU6## is reacted with a carbamoylacetic acid of the formula ##EQU7## or an activated derivative of the former (II). 
     The activated derivatives referred to include, for example, the reaction product with an anhydride forming reagent such as ethylchloroformate, benzoyl chloride, pivaloyl chloride, etc., an acid chloride or an activated ester like the benzhydryl ester, t-butyl ester, trimethylsilyl ester or trimethylstannyl ester or triethylamine salt. Dicyclohexylcarbodiimide can also be used to effect the reaction. 
     One preferred synthesis comprises reacting the acid of formula III with the diphenylmethyl ester of the 7-ACA derivative of formula II and then hydrolyzing the ester with trifluoroacetic acid and anisole to obtain the free carboxyl group in the 4-position. 
     The reaction between the 7-aminocephalosporanic acid compound and the carbamoylacetic acid can be carried out, for example, by dissolving or suspending the acid in an inert organic solvent such as chloroform, tetrahydrofuran, methylene chloride, dioxane, benzene or the like, and adding, at a reduced temperature of about 0°-5°C, about an equimolar amount of the 7-ACA compound in the presence of an activating compound such as dicyclohexylcarbodiimide. The product of the reaction is then isolated by conventional procedures, e.g., by concentration or evaporation of the solvent. If a derivative of the 7-aminocephalosporanic acid compound, such as the diphenylmethyl ester is used, the free acid is obtained by hydrolysis, e.g., with trifluoroacetic acid or the like. Salts can then be derived from the free acid. 
     According to another preferred embodiment an acid of formula III is reacted with a compound of the formula ##EQU8## preferably wherein R is diphenylmethyl. When R is the preferred diphenylmethyl group, it is converted to the free acid with trifluoroacetic acid and anisole. The product of the formula ##EQU9## is then reacted with a thiol of the formula 
     
         (VI) R.sub.3 --SH 
    
     in basic solution, e.g., at a pH of about 7.8, to obtain the product of formula I. 
     Additional details of the procedure for producing compounds of formula III and V are found in our copending application Ser. No. 471,080, filed May 17, 1974. 
     When R is the acyloxymethyl group ##EQU10## this group can be introduced into the 7-aminocephalosporanic acid moiety prior to the reaction with the carbamoylthioacetic acid or the activated derivative by treatment with one to two moles of a halomethyl ester of the formula 
     
         (VII) hal--CH.sub.2 OCOR.sub.4 
    
     wherein hal is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like, at about ambient temperature or below. 
     The carbamoylacetic acid of formula III is produced by reacting a mercaptoacetic acid of the formula ##EQU11## with a base, e.g., an alkylamine like triethylamine, and with an isocyanate R 2  N=C=O, in an inert solvent like tetrahydrofuran, then acidifying, e.g., with hydrochloric acid or the like. 
     Alternatively the acid of formula V is converted to an ester like the diphenylmethyl or t-butyl ester by reaction with a diphenyldiazomethane or isobutylene, followed by reaction with the isocyanate and treatment with trifluoroacetic acid/anisole. 
     Further process details are also provided in the illustrative examples. 
     Certain of the compounds of this invention may exist in different optically active forms. The various stereoisomeric forms as well as the racemic mixtures are within the scope of the invention. 
     The compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coli and Streptococcus pyogenes. They are useful as antibacterial agents, e.g., to combat infections due to organisms such as those named above, and in general they can be utilized in a manner similar to cephradine and other cephalosporins. For example, a compound of formula I or a physiologically acceptable salt thereof can be used in various animal species affected by infections of such bacterial origin in an amount of about 1 to 75 mg/kg daily, orally or parenterally, in single or two to four divided doses. 
     Up to about 500 mg. of a compound of formula I or a physiologically acceptable salt thereof is administered by incorporating in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice. 
     The following examples are illustrative of the invention. All temperatures are in degrees celsius. Additional variations are produced in the same manner by appropriate substitution in the starting material. 
     EXAMPLE 1 
     DL-[[(Methylamino)carbonyl]thio]phenylacetic acid 
     10.08 g. (60 mM) of α-mercaptophenylacetic acid and 6.6 g. (60 mM) of triethylamine are dissolved in 50 ml. of tetrahydrofuran and 3.42 g. (60 mM) of methylisocyanate dissolved in 20 ml. of tetrahydrofuran are added dropwise with stirring. After stirring for 2 hours, the solvent is drawn off in a vacuum and the oily residue is dissolved in water. The mixture is then acidified with 2N hydrochloric acid and extracted three times each with 20 ml. of ether. After drying off the ether, 10.5 g. of white crystalline DL-[[(methylamino)carbonyl]thio]phenylacetic acid are obtained, which is recrystallized from ether/petroleum ether, m.p. 128°-129°. 
     EXAMPLE 2 
     DL-[[(Ethylamino)carbonyl]thio]phenylacetic acid 
     By substituting ethylisocyanate for the methylisocyanate in the procedure of Example 1, white crystalline DL-[[(ethylamino)carbonyl]thio]phenylacetic acid is obtained and recrystallized from cyclohexane, m.p. 115°-117° (dec.). 
     EXAMPLE 3 
     DL-3-[(Acetyloxy)methyl]-7β-[[[[(methylamino)carbonyl]thio]-phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenylmethyl ester 
     1 g. (5 mM) of dicyclohexylcarbodiimide is added to 1.1 g. (5 mM) of DL-[[(methylamino)carbonyl]thio]phenyl acetic acid in 50 ml. of tetrahydrofuran and stirred for 1 hour at -5°. 2.1 g. (5 mM) of 7-aminocephalosporanic acid, benzhydryl ester in 15 ml. of tetrahydrofuran are then added and the mixture is stirred for 5 hours at 0° and for 1 hour at room temperature. The precipitate of dicyclohexylurea is filtered off and the filtrate is evaporated. The oily residue is dissolved in 20 ml. of methylene chloride. Filtration over charcoal and precipitation with petroleum ether produces 1.3 g. of white DL-3-[(acetyloxy)methyl-7β-[[[[(methylamino)carbonyl]thio]phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenylmethyl ester which is reprecipitated from methylene chloride/carbon tetrachloride, m.p. 73° (dec.). 
     EXAMPLE 4 
     DL-3-[(Acetyloxy)methyl]-7β-[[[[(methylamino)carbonyl]thio]-phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     3 g. of the product of Example 3 are dissolved at 0° in 25 ml. of trifluoroacetic acid/anisole and stirred for 15 minutes. After drawing off the trifluoroacetic acid in vacuum, an oily residue remains which is washed repeatedly with absolute ether until it becomes quite firm. The residue is dissolved in sodium bicarbonate solution, filtered and acidified with hydrochloric acid, with cooling, to a pH of 2.5. The solution is extracted three times each with 20 ml. of ethyl acetate. The organic phase is dried and evaporated. 0.9 g. of DL-3-[(acetyloxy)methyl]-7β-[[[[(methylamino)carbonyl]thio]phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained as a light yellow powder m.p. 121° (dec.) after reprecipitation from methylene chloride/petroleum ether. 
     EXAMPLE 5 
     Alternate method for producing the product of Example 4 
     4.5 g. (20 mM) of DL-[[(methylamino)carbonyl]thio]-phenylacetic acid are dissolved in 50 ml. of tetrahydrofuran. 2 g. (20 mM) of triethylamine are added and while stirring at a temperature of 0° 2.5 g. (20 mM) of ethyl chloroformate are added dropwise. After 1 hour, a solution of 5.4 g. (20 mM) of 7-aminocephalosporanic acid, triethylamine salt in 200 ml. of methylene chloride are added and the whole mixture is stirred for 14 hours at 5°. After filtering and drawing off the solvent, the oily residue is treated with water. The aqueous solution is extracted with ethyl acetate, filtered and acidified to pH 2.5.  Repeated extraction with ethyl acetate and evaporation of the ethyl acetate solution in vacuum yields after recrystallization from methylene chloride/petroleum ether, DL-3-[(acetoxy)-methyl]-7β-[[[[(methylamino)carbonyl]thio]phenyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-carboxylic acid as a light yellow powder, 2.5 g., m.p. 61°. The product produced by this method is only 67% pure. 
     EXAMPLE 6 
     DL-3-[(Acetyloxy)methyl]-7β-[[[[(ethylamino)carbonyl]thio]-phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 
     4.8 g. (20 mM) of DL-[[(ethylamino)carbonyl]thio]-phenylacetic acid are dissolved in 150 ml. of tetrahydrofuran and stirred with 8.4 g. (20 mM) of 7-ACA benzhydryl ester and 4.05 g. (20 mM) of dicyclohexylcarbodiimide for 8 hours at 20°. By evaporating the filtered solution, 9 g. of DL-3-[(acetyloxy)methyl]-7β-[[[[(ethylamino)carbonyl]thio]-phenylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester are obtained as a yellow powder, m.p. 75° (dec.). 
     EXAMPLE 7 
     3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     A mixture of 13.6 g. (0.5 M) of 7-aminocephalosporanic acid (7-ACA) in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring. 9.8 g. (0.57 M) of 2-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80° for 4 hours. After cooling to 5°, this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes. The precipitated solid is filtered under suction and washed with acetone. This 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206°. 
     EXAMPLE 8 
     3-[[(3-Methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     By substituting 3-methyl-1,2,4-thiadiazole-5-thiol for the 2-methyl-1,3,4-thiadiazole-5-thiol in the procedure of Example 7, 11.6 g. of 3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oxo-2-ene-2-carboxylic acid, m.p. 186° (dec.) are obtained. 
     EXAMPLE 9 
     3-[[(1-Methyl-1H-tetrazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     By substituting 0.57 M of 1-methyl-1H-tetrazole-5-thiol for the 2-methyl-1,3,4-thiadiazole-5-thiol in the procedure of Example 7, 3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is obtained. 
     EXAMPLE 10 
     7-Amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 
     18 g. of 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are suspended in 350 ml. of tetrahydrofuran. 4.1 ml. of 70% perchloric acid are added dropwise. After 30 minutes, a slightly turbid solution forms. This solution is filtered and to the filtrate is added dropwise with stirring 12 g. of diphenyldiazomethane and 20 ml. of tetrahydrofuran. After 3 hours, the reaction mixture is poured into 2 liters of absolute ether. The solid, light brown precipitate, which is the perchloric acid salt of the desired product, is dried over Kieselgel in a desiccator. To obtain the base, the perchloric acid salt is dissolved in water and treated with the calculated equivalent of potassium bicarbonate. The aqueous solution obtained is extracted with chloroform. The chloroform phase is treated with activated carbon and sodium sulfate to obtain the 10 g. of the product, 7-amino-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, as a light brown powder, m.p. 157°-159°. The product is recrystallized from tetrahydrofuran/petroleum ether. 
     EXAMPLE 11 
     7-Amino-3 -[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenylmethyl ester 
     The product, 7-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, diphenylmethyl ester, m.p. 168°-169° (dec.), is obtained by the procedure of Example 10 utilizing as starting material 7-amino-3[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. 
     EXAMPLE 12 
     7β-[[[[(Methylamino)carbonyl]thio]phenylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 
     1.15 g. of DL-[[(methylamino)carbonyl]thio]phenylacetic acid and 1 g. (5 mol.) of dicyclohexylcarbodiimide are stirred in 50 ml. of tetrahydrofuran at a temperature of 0°-5°. After 10 minutes a solution of 2.5 g. (5 mol.) of 3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester is added dropwise. The whole is stirred for 12 hours, filtered from the dicyclohexylurea formed and after drawing off the solvent, 2.8 g. of the product, 7β-[[[[(methylamino)carbonyl]thio]phenylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic aicd, diphenylmethyl ester are obtained. Recrystallization from chloroform/carbon tetrachloride yields a beige powder, m.p. 122°-124° (dec.). 
     EXAMPLE 13 
     7β-[[[[(Methylamino)carbonyl]thio]phenylacetyl]amino]-3-[[ (1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     2 g. of the product of Example 1 are stirred for 10 minutes at 5° in a mixture of 20 ml. of trifluoroacetic acid and 5 ml. of anisole. After drawing off the trifluoroacetic acid, the mixture is washed with ether/petroleum ether (1:1) and the brown powder obtained is added to a solution of sodium bicarbonate. The whole is filtered, treated with charcoal, cooled at 5° and acidified with 2N hydrochloric acid at pH 2.5. After extraction with ethyl acetate and drawing off of the solvent, the free acid, 7β-[[[[(methylamino)carbonyl]thio]phenylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, in the form of a beige powder, is obtained from the organic phase, m.p. 139° (dec.). The product is recrystallized from tetrahydrofuran/petroleum ether. 
     EXAMPLE 14 
     7β-[[[[(Methylamino)carbonyl]thio]phenylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, potassium salt 
     The potassium salt is obtained by freeze drying a molecularly equivalent aqueous solution of the acid obtained in Example 2 and potassium bicarbonate as a light colored powder, m.p. 164° (dec.). 
     EXAMPLES 15 - 49 
     The products below are obtained by the procedure of Example 12 by reacting the acid ##EQU12## with the diphenylmethyl ester of one of the following (prepared as in Example 10) and then proceeding according to Example 13 (also Example 14 to obtain a salt): 
     3-[[(5-methyl-1,3,4-thiadiazolyl-2-yl)thio]-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid. 
     3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-7-ACA 
     3-[[(3-isothiazolyl)thio]methyl]-7-ACA 
     3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA 
     3-[[(5-ethyl-1,3,4-oxadiazol-2-yl)thio]methyl]-7-ACA 
     3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-7-ACA 
     3-[[(1-ethyl-1H-tetrazol-5-yl)thio]methyl]-7-ACA 
     3-[[(3-methyl-5-isothiazolyl)thio]methyl]-7-ACA 
     3-[[(3-isothiazolyl)thio]methyl]-7-ACA 
     3-[[(3-isoxazolyl)thio]methyl]-7-ACA 
     3-[[(5-methyl-3-isoxazolyl)thio]methyl]-7-ACA 
     3-[[(1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA 
     3-[[(5-butyl-1,2,4-thiadiazol-3-yl)thio]methyl]-7-ACA 
     3-[[(5-ethyl-3-isoxazolyl)thio]methyl]-7-ACA 
     3-[[(3-methyl-4-isoxazolyl)thio]methyl]-7-ACA 
     3-[[(3-methyl-1,2,4-oxadiazol-5-yl)thio]methyl]-7-ACA 
     3-[[(5-ethyl-3-isothiazolyl)thio]methyl]-7-ACA 
     3-[[(2-methyl-1,3,4-thiadiazol-5-yl)thio]methyl]-7-ACA 
     3-[[(1,2,4-thiadiazol-5-yl)thio]methyl]-7-ACA 
     3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-ACA 
     3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-ACA 
     3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-7-ACA 
     3-[[(1-oxo-2-pyridyl)thio]methyl]-7-ACA 
     
         Example15     7β-[[[2-(methylamino)carbonyl]thio]-2-(2-pyridyl)acetyl]amino]  -3-[[(1,3,4-thiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2  .0]oct-2-ene-2-carboxylic acid16     7β-[[[2-(n-butylamino)carbonyl]thio]-2-phenylacetyl]amino]-3-[  [(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0  ]oct-2-ene-2-carboxylic acid17     7β-[[[2-(ethylamino)carbonyl]thio]-2-propionyl]amino]-3-[[(5-e  thyl-1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.  2.0]oct-2-ene-2-carboxylic acid18     7β-[[[2-(benzylamino)carbonyl]thio]acetyl]amino-3-[[(3-methyl-  5-isothiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-e  ne-2-carboxylic acid19     7β-[[[(2-phenethyl)amino]carbonyl]thio]-2-(2-thienyl)acetyl]am  ino]-3-[[(3-isothiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2  .0]oct-2-ene-2-carboxylic acid20     7β-[[[[2-(methylamino)carbonyl]thio]-2-phenylacetyl]amino]-3-[  [(3-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-e  ne-2-carboxylic acid21     7β-[[[2-(methylamino)carbonyl]thio]-2-phenylacetyl]amino]-3-[[  (5-methyl-3-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0  ]oct-2-ene-2-carboxylic acid22     7β-[[[2-(propylamino)carbonyl]thio]-2-phenylacetyl]amino]-3-[[  (1,2,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0  ]oct-2-ene-2-carboxylic acid23     7β-[[[2-(methylamino)carbonyl]thio]acetyl]amino]-3-[[(1,2,4-th  iadiazol-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en  e-2-carboxylic acid24     7β-[[[2-(ethylamino)carbonyl]thio]-2-phenylacetyl]amino]-3-[[(  5-butyl-1,2,4-thiadiazol-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicycl  o[4.2.0]oct-2-ene-2-carboxylic acid25     7β-[[2-(methylamino)carbonyl]  thio]butyramido]-3-[[(1,2,3,4-t  etrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene  -2-carboxylic acid26     7β-[[(2-methylamino)carbonyl]thio]propionamido]-3-[[(5-methyl-  3-isothiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-e  ne-2-carboxylic acid27     7β-[[[2-(methylamino)carbonyl]thio]-2-phenylacetyl]amino]-3-[[  (3-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.3.0]oct-2-en  e-2-carboxylic acid28     7β-[[[2-(butylamino)carbonyl]thio]acetyl]amino-3-[[(3-methyl-4  -isoxazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-  2-carboyxlic acid29     7β-[[[2-(methylamino)carbonyl]thio]-2-phenylacetyl]amino]-3-[[  (3-methyl-1,2,4-oxadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyc  lo[4.2.0]oct-2-ene-2-carboxylic acid30     7β-[[[2-(methylamino)carbonyl]thio]acetyl]amino]-3-[[(1-ethyl-  1H-tetrazol-5-yl)thio]methyl]-1-azabicyclo[4.2.0]oct-2-ene-2-carbox  ylic acid31     7β-[[[2-(methoxy)carbonyl]thio]-2-(2-pyridyl)acetyl]amino]-3-[  [(1-ethyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4  .2.0]oct-2-ene-2-carboxylic acid32     7β-[[[2-(ethylamino)carbonyl]thio]-2-(2-pyridyl)acetyl]amino]-  3-[[3-thiazolyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-  ene-2-carboxylic acid33     7β-[[[2-(benzylamino)carbonyl]thio]-2-(2-furyl)acetyl]amino]-3  -[[2-(2-methyl-1,3,4-thiadiazol-5-yl]thio]methyl]-8-oxo-5-thia-1-az  abicyclo[4.2.0]oct-2-ene-2-carboxylic acid34     7β-[[[2-(ethylamino)carbonyl]thio]-2-(2-furyl)acetyl]amino]-3-  [[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabi  cyclo[4.2.0]oct-2-ene-2-carboxylic acid and potassium salt35     7β-[[[2-(propylamino)carbonyl]thio]-2-(2-thienyl)acetyl]amino]  -3-[[(1,3,4-oxadiazol-2-yl)thio]  methyl]-8-oxo-5-thia-1-azabicyclo  [4.2.0]oct-2-ene-2-carboxylic acid and sodium salt36     7β-[[[(2-phenylethyl)carbonyl]thio]acetyl]amino]-3-[[(5-ethyl-  1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]o  ct-2-ene-2-carboxylic acid37     7β-[[[2-(n-butylamino)carbonyl]thio]-2-(2-pyridyl)acetyl]amino  -3-[[(1,2,3,4-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[  4.2.0]oct-2-ene-2-carboxylic acid38     7β-[[[2-(methylamino)carbonyl]thio]-2-(3-thienyl)acetyl]amino]  -3-[[(2-methylthiazol-5-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.  2.0]oct-2-ene-2-carboxylic acid triethylamine salt39     7β-[[[[2-(ethylamino)carbonyl]thio]-2-(3-furyl)acetyl]amino]-3  -[[(1,2,4-thiadiazol-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.  2.0]oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester40     7β-[[[[2-(methylamino)carbonyl]thio]-2-(3-pyridyl]acetyl]amino  ]-3-[[(3-isoxazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oc  t-2-ene-2-carboxylic acid trimethylsilyl ester41     7β-[[[[2-(methylamino)carbonyl]thio]-2-(2-thienyl)acetyl]amino  ]-3-[[(1,3,4-oxadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[  4.2.0]oct-2-ene-2-carboxylic acid42     7β-[[[2-(ethylamino)carbonyl]thio]-2-(2-pyridyl)acetyl]amino]-  3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-aza  bicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester43     7β-[[[2-(benzylamino)carbonyl]thio]-2-(2-thienyl)acetyl]amino]  -3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-az  abicyclo[4.2.0]oct-2-ene-2-carboxylic acid44     7β-[[[2-(ethylamino)carbonyl]thio]-2-phenylacetyl]amino]-3-[[(  1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.  2.0]oct-2-ene-2-carboxylic acid45     7β-[[[2-(benzylamino)carbonyl]  thio]-2-(2-thienyl)acetyl]amin  o]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabi  cyclo[4.2.0]oct-2-ene-2-carboxylic acid46     7β-[[[2-(methylamino)carbonyl]]thio]-2-(2-pyridyl)acetyl]amino  ]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabic  yclo[4.2.0]oct-2-ene-2-carboxylic acid47     7β-[[[2-(benzylamino)carbonyl]thio]-2-(2-furyl)acetyl]amino]-3  -[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicycl  o[4.2.0]oct-2-ene-2-carboxylic acid48     7β-[[[2-(methylamino)carbonyl]thio]phenylacetyl]amino]-3-[[(1-  oxo-2-pyridyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en  e-2-carboxylic acid49     7β-[[[[(methylamino)carbonyl]thio]phenylacetyl]amino]-3-[[(5-m  ethyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[  4.2.0]oct-2-ene-2-carboxylic acid and potassium salt