Patent Document

SUMMARY OF THE INVENTION 
     This invention is concerned with compounds of the formula: ##STR3## wherein R 1  is hydrogen, alkyl(C 1  -C 3 ), vinyl, acetyloxy or ##STR4## where R 3  is hydrogen or alkyl(C 1  -C 6 ); R 2  is hydrogen or diphenylmethyl and A is R 4  --C, where R 4  is acetyl or benzoyl. 
     This invention is further concerned with processes for the production of these compounds as well as their use as intermediates in the preparation of biologically active cephalosporin derivatives. 
     DESCRIPTION OF THE INVENTION 
     The compounds of this invention may be prepared according to the following reacting scheme: ##STR5## According to the above reaction scheme a 3-substituted-7-[(amionthioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 1, where R 1  is as described above, is reacted with N,N-dimethylformamide diethylacetal in dichloromethane, giving the 3-substituted-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 2, which is reacted with a 2-bromo-substituted ethanone of the formula R 4  COCH 2  Br, where R 4  is as described above, and potassium carbonate in acetonitrile, giving the product 3. 
     The diphenylmethyl ester 3 may be converted to the free carboxylic acid where R 2  is hydrogen, by treatment with anisole and trifluoroacetic acid in dichloromethane. 
     The compounds of this invention where R 2  is hydrogen are biologically active and possess antibacterial activity when tested by the Mueller-Hinton agar dilution method against a variety of organisms. The results of this test with representative compounds of this invention appear in Table I. 
     
                       TABLE I______________________________________In vitro Antibacterial Activity              Minimal Inhibitory              Concentration              (mcg/ml)              Compound of              Example No.Organism             5         6______________________________________Escherichia coli CMC 84-11                &gt;128      &gt;128Escherichia coli 311 &gt;128      &gt;128Escherichia coli ATCC 25922                &gt;128      &gt;128Klebsiella pneumoniae CMC 84-5                128       &gt;128Klebsiella pneumoniae AD                32        128Klebsiella oxytoca IO 83-1                &gt;128      &gt;128Enterobacter cloacae CMC 84-4                &gt;128      &gt;128Enterobacter aeruginosa IO 83-44                &gt;128      &gt;128Serratia marcescens CMC 83-27                &gt;128      &gt;128Serratia marcescens F-35                &gt;128      &gt;128Proteus rettgherii IO 83-21                &gt;128      &gt;128Morganella morganii IO 83-18                &gt;128      &gt;128Providencia stuartii CMC 83-82                &gt;128      &gt;128Citrobacter diversis K 82-24                128       &gt;128Citrobacter freundii IO 83-13                &gt;128      &gt;128Acinetobacter CMC 83-89                &gt;128      &gt;128Acinetobacter IO 83-49                &gt;128      &gt;128Pseudomonas aeruginsa CMC 83-19                &gt;128      &gt;128Pseudomonas aeruginsa  12-4-4                &gt;128      &gt;128Pseudomonas aeruginosa ATCC 27853                &gt;128      &gt;128Staphylococcus aureus SSC 82-31                1         0.12Staphylococcus aureus ATCC 25923                1         0.12Staphylococcus aureus SSC 82-20                4         1Staphylococcus aureus SSC 82-26                2         1Staphylococcus aureus SSC 82-24                128       64Staphylococcus aureus SSC 82-57                128       128Staphylococcus epidermidis CMC 83-133                1         0.12Staphylococcus epidermidis ATCC 12228                2         1Enterococcus CMC 83-53                128       32Streptococcus faecalis ATCC 29212                64        16Micrococcus lutea PCI 1001                2         1Bacillus subtilis ATCC 6633                0.25      0.5______________________________________ 
    
    
    
     EXAMPLE 1 
     (6R-trans)-3-[(Acetyloxy)methyl]-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 
     A 650 mg portion of N,N-dimethylformamide diethylacetal in 10 ml of dichloromethane was added dropwise to a solution of 2 g of (6R-trans)-3-[(acetyloxy)methyl-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester in 35 ml of dichloromethane. The mixture was stirred for 20 minutes, then filtered, evaporated and the residue purified by flash chromatography using the system ethyl acetate:petroleum ether (1:1) and giving 1.08 g of the desired product. 
     EXAMPLE 2 
     [2R-(2α,6α,7β)]-3-[(Acetyloxy)methyl]-7-[(5-benzolyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylic acid, diphenylmethyl ester 
     A mixture of 940 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 380 mg of 2-bromo-1-phenylethanone, 235 mg of potassium carbonate and 30 ml of acetonitrile was reacted as described in Example 1, giving 900 mg of the desired compound. 
     EXAMPLE 3 
     (6R-trans)-3-[(Acetyloxy)methyl]-7-[(5-benzoyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 
     A mixture of 720 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 260 mg of 2-bromo-1-phenylethanone and 90 mg of potassium carbonate in 15 ml of dry acetonitrile was stirred for about 1 hour, then filtered and the filtrate evaporated, giving 526 mg of the desired product. 
     EXAMPLE 4 
     (6-R-trans)-3-[(Acetyloxy)methyl]-7-[(5-acetyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 
     A mixture of 585 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 127 mg of propionyl chloride, 188 mg of sodium iodide and 15 ml of acetontrile was stirred for 90 minutes, then 99 mg of pyridine was added. This mixture was stirred for 90 minutes, then dichloromethane was added and the mixture was refluxed for 20 minutes. The solution was washed with 10% hydrochloric acid, brine and aqueous sodium bicarbonate, dried and evaporated, giving 418 mg of the desired product. 
     EXAMPLE 5 
     (6R-trans)-3-[(Acetyloxy)methyl]-7-[(5-acetyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     A mixture of 255 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(5-acetyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester was reacted with anisole and trifluoroacetic acid in dichloromethane with stirring at 0° C. for 30 minutes, then at room temperature for 30 minutes. The addition of ether and petroleum ether gave a precipitate which was washed with ether, giving 135 mg of the desired product as a pale yellow powder. 
     EXAMPLE 6 
     (6R-trans)-3-[(Acetyloxy)methyl]-7-[(5-benzoyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     A 235 mg portion of (6R-trans)-3-[(Acetyloxy)methyl]7-[(5-benzoyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester was reacted with anisole and trifluoroacetic acid in dichloromethane as described in Example 5, giving 143 mg of the desired product as a pale yellow powder. 
     EXAMPLE 7 
     (6R-trans)-3-[(Acetyloxy)methyl]-8-oxo-7-(1,2,4-thiadiazol-5-ylamino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 
     A mixture of 60 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[[[[(dimethylamino)methylene]amino]thioxomethyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 14 mg of hydroxylamine-O-sulfonic acid and 17.14 mg of pyridine in a mixture of 3 ml of ethanol and 1 ml of methanol was stirred at room temperature. A 0.5 ml portion dioxane was added to enhance solubility. After 1 hour the mixture was concentrated, dichloromethane added to the residue, the solution washed with 10% hydrochloric acid and brine, then decolorized, filtered and evaporated, giving the desired product.

Technology Category: 8