Patent Publication Number: US-4927922-A

Title: 7β-(substituted)amino-3-substituted cephalosporanic acids and esters

Description:
This application is a continuation-in-part of Ser. No. 882,996, filed July 8, 1986, now abandoned. 
    
    
     SUMMARY OF THE INVENTION 
     This invention is concerned with compounds of the formula: ##STR1## wherein R 1  is selected from the group consisting of hydrogen, alkyl(C 1  -C 6 ), polyfluorinated alkyl(C 1  -C 6 ), phenyl, multisubstituted phenyl wherein the substituents are selected from alkyl(C 1  -C 6 ), alkoxy(C 1  -C 3 ), chloro, fluoro and trifluoromethyl, naphthyl, thienyl, phenylthio, tetrahydropyranyl, benzyl, and --COOC 2  H 5  ; R 2  is selected from the group consisting of hydrogen, diphenylmethyl, α-acyloxyalkyl, t-butyl, benzyl, 4-nitrobenzyl and 4-methoxybenzyl and pharmaceutically acceptable salts (sodium and potassium); and R 3  is selected from the group consisting of hydrogen, ##STR2## where R 5  is selected from the group consisting of phenyl, substituted phenyl, 2-thienyl, 2-furyl, trifluoromethylthiomethyl, 4-(2-aminothiazoyl), 5-(2-aminothiazoyl) and cyanomethylthiomethyl, and R 6  is selected from the group consisting of hydrogen, 4-alkyl(or aryl)-2,3-dioxopiperazine-1-carbonyl, ureido and carboxyamido, phenylacetyl, heterocyclic acetyl, ##STR3## where X is selected from the group consisting of OH, SO 3  H, COOH and tetrazolyl; and R 4  is selected from the group consisting of hydrogen, --O--alkyl, --S--alkyl and formamido. 
     DESCRIPTION OF THE INVENTION 
     The compounds of the present invention may be prepared according to the following reaction schemes. ##STR4## 
     According to Scheme A, a cephalosporin 1, where R 3  is hydrogen, is reacted with a 1,2,3-thiadiazol-4-thiolate 2, where R 1  is as described above, with the proviso that R 1  cannot be hydrogen, methyl, propyl, isopropyl or n-butyl, and M is sodium or potassium in a solvent such as water at 50°-70° C. for 2-12 hours with pH adjustment to 6.0-7.0, giving the products 3. ##STR5## 
     According to Scheme B, diphenylmethyl derivatives 4 are prepared by reaction of 3 with diphenyldiazomethane in acetonitrile. ##STR6## 
     According to Scheme C, derivative 4, where R 3  is hydrogen is reacted with derivative 5 and 1-alkoxycarbonyl-2-alkoxy-1,2-dihydroquinolines in dichloromethane giving derivative 6, where R 1  is as described above and ##STR7## 
     According to Scheme D a cephalosporin t-butyl ester 7 is reacted with trimethylsilyliodide giving 8 which is further reacted with a 1,2,3-thiadiazol-4-thiolate 2, giving 9 which is then deblocked producing cephalosporin derivatives 3. ##STR8## 
     According to Scheme E, cephalosporin 3 is reacted with ##STR9## where R 6  is alkyl and R 7  is alkyl or alkoxy or R 6  and R 7  are cycloalkyl and X is halogen, giving cephalosporins 10. 
     In the above schemes, the 1,2,3-thiadiazol-4-thiolates ##STR10## are the subject of a United States patent application by the same inventors, which was filed on the same date as the parent application of this instant application. The disclosure of such co-pending application, Ser. No. 883,189, now No. 4,803,280 is incorporated by reference. 
     The compounds of the present invention are active antibacterial agents as established in the in vitro agar dilution test using Mueller-Hinton agar. The test compounds were dissolved in a mixture of dimethyl sulfoxide and aqueous sodium bicarbonate and applied as 1 ml of drug solution plus 9 ml of agar per plate. The innoculum was a 5 hour TSB shake culture diluted to 10 -2  with Mueller-Hinton broth and applied to the plates with a Steers&#39; Replicator. 
     The results of this test on representative compounds of this invention (identified by Example Number) against a variety of microorganisms appear in Tables I and II in terms of minimal inhibitory concentration (MIC) in mcg/ml together with Cefotaxime, Cephalothin and Ampicillin as positive controls. 
     
                                           TABLE I                                 
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                    MIC (mcg/ml)                                          
                    Example                                               
                         Example                                          
                              Example                                     
Microorganism       No. 2                                                 
                         No. 1                                            
                              No. 6                                       
                                   Cefotaxime                             
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 Klebsiella STFD 79-6                                                     
                    .06  .5   2    ≦.015, .06                      
Klebsiella  SSC 78-1                                                      
                    .06  .5   1    ≦.015, .06                      
Enterobacter aerogenes                                                    
            STFD 79-14                                                    
                    .5   1    4    .03, .06                               
Enterobacter cloacae                                                      
            K 79-16 2    4    1    .03, .25, .06                          
Serratia    TUL 78-15                                                     
                    32   8    8    1, 2, .25                              
Serratia    QHC 77-2                                                      
                    32   8    8    .5, 1, .12                             
Proteus morganii                                                          
            K 79-25 .5   .5   16   .25, ≦.015, ≦.06         
Proteus rettgheri                                                         
            N 76-1  ≦.03                                           
                         ≦.015                                     
                              --   ≦.015                           
Proteus rettgheri                                                         
            K 77-6  --   --   ≦.12                                 
                                   ≦.06                            
Escherichia coli                                                          
            STFD 79-20                                                    
                    .25  .5   .5   ≦.015, ≦.06              
Escherichia coli                                                          
            311     .25  .5   .5   ≦.015, ≦.06              
Salmonella  SSC 79-57                                                     
                    4    4    8    .25                                    
Salmonella ariz.                                                          
            QHC 77-3                                                      
                    1    1    2    ≦.015, ≦.06              
Acinetobacter                                                             
            STFD 79-17                                                    
                    128  16   32   8, 16                                  
Acinetobacter                                                             
            K 77-1  16   4    32   4, 2, 8                                
Pseudomonas SSC 78-13                                                     
                    &gt;256 128  64   32                                     
Pseudomonas 12-4-4  &gt;256 &gt;128 64   16, 8                                  
Enterococcus                                                              
            OSU 75-1                                                      
                    256  128  256  128, 64, &gt;128                          
Enterococcus                                                              
            SM 77-15                                                      
                    256  64   128  128, 32, 64                            
Staphylococcus                                                            
            SSC 79-18β.sup.-                                         
                    8    1    1    1, 2, .5                               
Staphylococcus                                                            
            FU 79-19-2β.sup.+                                        
                    32   4    16   4, 8                                   
Escherichia coli                                                          
            ESS 22-31                                                     
                    ≦.03                                           
                         ≦.015                                     
                              .5   ≦.015, ≦.06              
Klebsiella pneumoniae                                                     
            AD      .06  .25  .25  ≦.015, ≦.06              
Micrococcus lutea                                                         
            PCI 1001                                                      
                    .06  --   .25  ≦.015, .25                      
Staphylococcus Smith                                                      
                    8    1    2    1, 2                                   
Pseudomonas aeruginosa                                                    
            ATCC 27853                                                    
                    &gt;256 128  128  16, 32                                 
Escherichia coli                                                          
            ATCC 25922                                                    
                    .06  .12  2    ≦.015, ≦.06              
Staphylococcus                                                            
            ATCC 25923                                                    
                    16   2    4    1, .25                                 
Providencia stuarti                                                       
            SSC 80-78                                                     
                    --   --   5    ≦.06                            
Providencia stuarti                                                       
            K 81-29 --   --   1    .25                                    
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                                           TABLE II                                
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                       MIC (mcg/ml)                                       
                       Example                                            
                            Example                                       
Microorganism          No. 10                                             
                            No. 8                                         
                                 Cephalothin                              
                                        Ampicillin                        
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Escherichia coli                                                          
               ATCC 25922                                                 
                       64   64   16     4                                 
Escherichia coli                                                          
               CMC 84-11                                                  
                       128  64   8      4                                 
Escherichia coli                                                          
               CMC 84-16                                                  
                       128  64   16     &gt;256                              
Klebsiella pneumoniae                                                     
               AD (MP) 16   8    1      .25                               
Klebsiella pneumoniae                                                     
               MOR 84-4                                                   
                       64   32   2      32                                
Klebsiella oxytoca                                                        
               MOR 84-28                                                  
                       128  256  &gt;256   32                                
Enterobacter cloacae                                                      
               VGH 84-37                                                  
                       &gt;256 &gt;256 &gt;256   &gt;256                              
Enterobacter cloacae                                                      
               K 84-10 &gt;256 &gt;256 &gt;256   &gt;256                              
Enterobacter aerogenes                                                    
               VGH 84-36                                                  
                       &gt;256 256  &gt;256   256                               
Serratia marcesans                                                        
               K 84-18 &gt;256 &gt;256 &gt;256   64                                
Serratia marcesans                                                        
               F 35 (MP)                                                  
                       &gt;256 &gt;256 &gt;256   &gt;256                              
Proteus rettgheri                                                         
               CMC 84-41                                                  
                       4    2    4      .5                                
Morganella morganii                                                       
               VGH 84-11                                                  
                       &gt;256 &gt;256 &gt;256   &gt;256                              
Morganella morganii                                                       
               CMC 84-37                                                  
                       &gt;256 &gt;256 &gt;256   256                               
Pseudomonas aeruginosa                                                    
               12-4-4 (MP)                                                
                       &gt;256 &gt;256 &gt;256   &gt;256                              
Pseudomonas aeruginosa                                                    
               VGH 84-4                                                   
                       &gt;256 &gt;256 &gt;256   &gt;256                              
Acinetobacter calcoaceticus                                               
               MOR 84-43                                                  
                       &gt;256 &gt;256 &gt;256   32                                
Staphylococcus aureus                                                     
               ATCC 25923                                                 
                       .5   .5   .25    ≦.12                       
Staphylococcus aureus                                                     
               Smith (MP)                                                 
                       ≦.12                                        
                            ≦.12                                   
                                 ≦.12                              
                                        ≦.12                       
Staphylococcus aureus                                                     
               CMC 83-128                                                 
                       1    1    ≦.12                              
                                        ≦.12                       
Staphylococcus epidermidis                                                
               CMC 83-135                                                 
                       ≦.12                                        
                            ≦.12                                   
                                 ≦.12                              
                                        ≦.12                       
Staphylococcus epidermidis                                                
               IO 83-58                                                   
                       2    2    .25    16                                
Staphylococcus saprophyticus                                              
               VGH 84-50                                                  
                       1    1    .25    ≦.12                       
Enterococcus   VGH 84-65                                                  
                       32   32   32     1                                 
Escherichia coli                                                          
               No. 311(Parent)                                            
                       64   32   8      2                                 
Escherichia coli                                                          
               No. 311 N.A.                                               
                       64   32   8      2                                 
Staphylococcus aureus                                                     
               CMC 83-131                                                 
                       32   32   32     2                                 
Staphylococcus aureus                                                     
               CMC 83-132                                                 
                       32   32   32     1                                 
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     EXAMPLE 1 
     (Z)-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-3-[[(5-phenyl-1,2,3-thiadiazol-4-yl)thio]mehtyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     A mixture of 0.5 g of 3-[(acetyloxy)methyl]-7β-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt (Cefotaxime, sodium salt), 0.4 g of 5-phenyl-1,2,3-thiadiazole-4-thiol, sodium salt and 10 ml of water was stirred and heated at 55°-60° C. for 5.5 hours with acid adjustment to pH 6.5 every hour. The mixture was then chilled overnight and filtered through diatomaceous earth. The filtrate was adjusted to pH 5 with dilute hydrochloric acid and then extracted twice with ethyl acetate. The aqueous remainder was filtered through diatomaceous earth, readjusted to pH 5 and added to a 50 ml column of Amberlite® XAD-2 ion exchange resin. The column was washed with water, then with methanol. The methanolextract was evaporated, giving 150 mg of the desired product as a cream colored solid: IR(KBr) 1760 cm -1  (β-lactam --C═O). 
     EXAMPLE 2 
     (Z)-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazol-4-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 
     A mixture of 0.5 g of Cefotaxime, sodium salt, 0.4 g of 5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazole-4-thiol, potassium salt and 16 ml of water was heated at 70° C. for 5.5 hours with pH adjustment to 6.8-7.2, then cooled and filtered. The filtrate was adjusted to pH 5 and extracted with 30 ml of ethyl acetate. The aqueous remainder was filtered through diatomaceous earth and adjusted to pH 2.5 with 2N hydrochloric acid. The resulting solid was collected, washed with water and dried, giving 86 mg of the desired product as a light orange solid [α] D   26  =-10°+2 (0.885 DMSO): IR(KBr) 1770 cm -1  (β-lactam --C═O). 
     EXAMPLE 3 
     7-Amino-3-[[[5-(1,1-dimethylethyl)-1,2,3-thiadiazol-4-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     A mixture of 3.55 g of 3-[(acetyloxy)methyl]-7β-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (7-aminocephalosporanic acid), 2.55 g of 5-(1,1-dimethylethyl)-1,2,3-thiadiazole-4-thiol, sodium salt, 1.11 g of sodium bicarbonate, 65 ml of water and 30 ml of acetone was stirred at reflux for 2 hours, then cooled and filtered. The filtrate was treated with activated charcoal, then filtered through diatomaceous earth. This filtrate was acidified to pH 3.4 with 2N hydrochloric acid. The solid was collected, washed with water and dried, giving 1.5 g of the desired product as a beige solid: IR(KBr) 1780 cm -1  (β-lactam --C═O). 
     EXAMPLE 4 
     7-Amino-3-[[[5-(1,1-dimethylethyl)-1,2,3-thiadiazol-4-yl]thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester 
     A mixture of 1.4 g of 7β-amino-3-[[[5-(1,1-dimethylethyl)-1,2,3-thiadiazol-4-yl]thio]methyl]-8-oxo-5-thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 3.0 g of diphenyldiazomethane in 50 ml of acetonitrile was stirred for 48 hours, then filtered and the filtrate evaporated to an oil. This oil was purified by repeated chromatography on preparative TLC plates, eluting with ethyl acetate:hexane (1:2), giving 914 mg of the desired product as a beige solid: IR(KBr) 1775 cm -1  (β-lactam --C═O). 
     EXAMPLE 5 
     (Z)-3-[[[5-(1,1-Dimethylethyl)-1,2,3-thiadiazol-4-yl]-thio]methyl]-7-[[(methoxyimino)[2-[(triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 
     A mixture of 444 mg of 2-(2-tritylaminothiazol-4-yl)-2-[Z]-methoximinoacetic acid, 553 mg of 7β-amino-3-[[[5-(1,1-dimethylethyl)-1,2,3-thiadiazol-4-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 247 mg of 2-ethoxy-1(2H)-quinolinecarboxylic acid, ethyl ester and 15 ml of dichloromethane was stirred at room temperature overnight. The solution was extracted with 0.5N, hydrochloric acid, water, saturated aqueous sodium bicarbonate and brine, then evaporated, giving 808 mg of the desired product as a yellow glass: IR(KBr) 1785 cm -1  (β-lactam --C═O). 
     EXAMPLE 6 
     (Z)-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[5-(1,1-dimethylethyl)-1,2,3-thiadiazol-4-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     A 750 mg portion of (Z)-3-[[[5-(1,1-dimethylethyl)-1,2,3-thiadiazol-4-yl]thio]methyl]-7β-[[(methoxyimino)[(triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester and 5 drops of anisole were dissolved in 10 ml of dichloromethane in an ice bath. A 2 ml portion of trifluoroacetic acid was added, the mixture was stirred for 3 hours at room temperture, then evaporated at reduced pressure and triturated with ether. The resulting solid was collected, washed with ether, dried in vacuo and then stirred with 5 ml of 80% formic acid for 2 hours. The mixture was diluted with 5 ml of water and filtered. The filtrate was treated with activated charcoal, refiltered and evaporated to dryness. The residue was triturated with ether giving 260 mg of the desired product as a solid: IR(KBr) 1770 cm -1  (β-lactam --C═O). 
     EXAMPLE 7 
     (6R-trans)-3-[[(5-Methyl-1,2,3-thiadiazol-4-yl)thio]methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester 
     A solution of 2.60 g of t-butyl 7β-(thienylacetylamino)-3-iodomethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, 800 mg of 5-methyl-1,2,3-thiadiazole-4-thiol, sodium salt and 75 ml of dry ethanol was stirred for 2 hours. The solvent was evaporated in vacuo, the residue taken up in dichloromethane, filtered and then chromatographed over Bio-Sil A (40×400 mm) eluting with a gradient of 0% to 2% methanol in dichloromethane. The desired fractions were combined, evaporated and crystallized from ethanol, giving 1.75 g of the desired compound, mp 155°-157° C. &#39;H NMR (300 MHz, CDCl 3 ): δ 1.49 (s, 9H, t-butyl); 2.57 (s, 3H, CH 3 ); 3.65 (AB quartet, 2H, 4-CH 2 ); 3.85 (s, 2H, CH 2  CO); 4.18 (AB quartet, 2H, CH 2  S); 4.93 (d, 1H, J=4.9  Hz, 6-H); 5.80 (dd, 1H, J=9.2 Hz, 4.9 Hz, 7-H); [6.97 (m, 2H) and 7.26 (m, 1H)(thienyl)]. 
     EXAMPLE 8 
     (6R-trans)-3-[[(5-Methyl-1,2,3-thiadiazol-4-yl)thio]methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     A cold (0° C.) solution of 2.62 g of the product of Example 7 in 20 ml of dry anisole and 25 ml of dichloromethane was treated with 20 ml of trifluoroacetic acid. After evaporation the residue was chromatographed as described in Example 7, giving 950 mg of the desired product. &#39;H NMR (300 MHz, CDCl 3 ): δ 2.57 (s, 3H); 3.70 (AB quartet, 2H, 4-CH 2 ); 3.87 (s, 2H); 4.17 (AB quartet, 2H, CH 2  S--); 4.97 (d, 1H, J=4.8 Hz, 6-H); 5.76 (dd, 1H, J=9.24 Hz, 4.8 Hz, 7-H); [6.98 (m, 2H) and 7.24 (m, 1H)(thienyl)]. 
     EXAMPLE 9 
     (6R-trans)-3-[[(5-Ethyl-1,2,3-thiadiazol-4-yl)thio]methyl]-8-oxo-7-[2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester 
     A solution of 2.62 g of 7β-(thienylacetylamino)-3-iodomethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester, 900 mg of 5-ethyl-1,2,3-thiadiazo-4-ylthiol, sodium salt and 75 ml of dry ethanol was stirred for 2 hours, then the solvent was removed in vacuo. The residue was taken up in dichloromethane, filtered and chromatographed on Bio-Sil A (40×400 mm), eluting with a 0% to 2% gradient of methanol in dichloromethane. The desired fractions were combined and crystallized from ethyl acetate-hexane, giving 2.3 g of the desired compound, mp 167.5°-169° C. &#39;H NMR (300 MHz, CDCl 3 ): δ 1.35 (t, 3H); 1.56 (s, 9H); 2.95 (q, 2H); 3.65 (AB quartet, 2H, 4-CH 2 ); 3.85 (s, 2H); 4.18 (AB quartet, 2H, CH 2  S); 4.93 (d, 1 H, J=4.9 Hz, 6-H); 5.80 (dd, 1H, J=9.2 Hz, 4.9 Hz, 7-H; [6.98 (m, 2H) and 7.26 (m, 1H) (thienyl)]. 
     EXAMPLE 10 
     (6R-trans)-3-[[(5-Ethyl-1,2,3-thiadiazol-4-yl)thio]methyl]-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     A cold (0° C.) solution of 1.08 g of the product of Example 9 in 5 ml of dry anisole and 25 ml of dichloromethane was treated with 10 ml of trifluoroacetic acid. After 30 minutes the solvents were removed in vacuo and the crude acid was dissolved in ethyl acetate and extracted twice with 5 % aqueous sodium bicarbonate. The alkaline extracts were combined, acidified to pH 3 and extracted three times with ethyl acetate. These extracts were combined, dried and concentrated in vacuo giving a light orange foam. This foam was suspended in diethyl ether and collected, giving 650 mg of the desired product. &#39;H NMR (300 MHz, CDCl 3 ): δ 1.32 (t, 3H); 2.95 (q, 2H); 3.68 (AB quartet, 2H, 4-CH 2 ); 3.86 (s, 2H); 4.19 (AB quartet, 2H, CH 2  S); 4.98 (d, 1H, J=4.8 Hz, 6-H); 5.79 (dd, 1H, J=9.2 Hz, 4.8 Hz, 7-H); [6.98 (m, 2H) and 7.25 (m, 1H)(thienyl)]. 
     EXAMPLE 11 
     (6R-trans)-7-[[[(2-Triphenylmethylamino)-4-thiazolyl]-(methoxyimino)acetyl]amino]-3-[[(5-methyl-1,2,3-thiadiazol-4-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester 
     A solution of 2.06 g of (Z)-7β-[[[(2-triphenylmethylamino)-4-thiazolyl](methoxyimino)acetyl]amino]-3-iodomethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 750 mg of 5-methyl-1,2,3-thiadiazole-4-thiol, sodium salt and 50 ml of ethanol was stirred for one hour and then concentrated in vacuo. The oily residue was taken up in dichloromethane, filtered and chromatographed over a Bio-Sil A column (40×400 mm), eluting with a gradient of 0% to 5% methanol in dichloromethane. The desired fractions were combined, concentrated in vacuo to give an orange foam which was triturated with hexane and the amorphous solid collected, giving 1.1 g of the desired product. &#39;H NMR (300 MHz, CDCl 3 ): δ 1.50 (s, 9H); 2.58 (s, 3H); 3.70 (AB quartet, 2H, 4-H); 4.07 (s, 3H); 4.19 (AB quartet, 2H, (CH 2  S); 5.02 (d, 1 H, J=4.9 Hz, 6-H); 5.93 (dd, 1H, J=9.2 Hz, 4.9 Hz, 7-H); 6.73 (s, 1H, thiazole H); 6.85 (d, NH); 7.29 (bs, 15H). 
     EXAMPLE 12 
     [6R-[6α,7β(Z)]]-7-[[(2-Amino-4-thiazolyl(methoxyimino)acetyl]amino]-3-[[(5-methyl-1,2,3-thiadiazol-4-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     A cold (0° C.) solution of 840 mg of the product of Example 11 in 2 ml of anisole and 10 ml of dry dichloromethane was treated with 5 ml of trifluoroacetic acid. After 30 minutes the solvents were removed in vacuo and the crude acid triturated with diethyl ether. The resulting crude acid was dissolved in an excess of 5% aqueous sodium bicarbonate, filtered and reacidified to pH 3. The resulting orange precipitate was collected, washed with water and dried in vacuo giving the desired product. &#39;H NMR (300 MHz, CD 3  SOCD 3 ): δ 2.45 (s, 3H); 3.55 (AB quartet, 2H, 4-H); 3.85 (s, 3H); 4.20 (AB quartet, 2H, CH 2  S); 5.05 (d, 1H, J=4.9Hz, 6-H); 5.65 (dd, 1H, J=9.2Hz, 4.9 Hz, 7-H); 6.75 (s, 1H, thiazole H); 7.21 (bs, NH 2 ); 9.60 (d, NH). Infrared absorption (MBr pellet) 1770 cm -1 . 
     EXAMPLE 13 
     (6R-trans)-7-[[[(2-Triphenylmethylamino)-4-thiazolyl](methoxyimino)acetyl]amino]-3-[[[ 5-ethyl-1,2,3-thiadiazol-4-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester 
     A solution of 7.0 g of 7β-[[[(2-triphenylmethylamino)-4-thiazolyl](methoxyimino)acetyl]amino]-3-iodomethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester, 1.68 g of 5-ethyl-1,2,3-thiadiazole-4-thiol, sodium salt and 100 ml of dry ethanol was stirred for 2 hours and then concentrated in vacuo. The residue was takenup in 75 ml of dichloromethane, applied to a 60×560 mm column of Bio-Sil A and eluted with a gradient of 0% to 5% methanol in dichloromethane. The desired fractions were combined and concentrated in vacuo, giving 4.5 g of the desired compound as a light yellow foam. &#39;H NMR (300 MHz, CDCl 3 ): δ 1.34 (t, 3H); 1.55 (s, 9H); 2.94 (q, 2H); 3.70 (AB quartet, 2H-4H); 4.06 (s, 3H); 4.18 (AB quartet, 2H, CH 2  S); 5.02 (d, 1H, J=4.8 Hz, 6-H); 5.91 (dd, 1H, J=9.2 Hz, 4.8 Hz, 7-H); 6.75 (s, 1H, thiazole H); 6.81 (d, NH); 7.28 (bs, 15H). 
     EXAMPLE 14 
     [6R-[6α,7β(Z)]]-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[(5-ethyl-1,2,3-thiadiazol-4-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 
     The produce of Example 12 was repeated using the product of Example 13, giving the desired product. &#39;H NMR (300 MHz, CD 3  SOCD 3 ): δ 1.30 (t, 3H); 2.90 (q, 2H); 3.55 (AB quartet, 2H, 4-H); 3.86 (s, 3H); 4.16 (AB quartet, 2H, CH 2  S); 5.03 (d, 1H, J=4.8 Hz, 6-H); 5.71 (dd, 1H, J=9.2 Hz, 4.8 Hz, 7-H); 6.76 (s, 1H, thiazole H) 7.20 (bs, NH 2 ); 9.60 (d, NH). 
     EXAMPLE 15 
     (Z)-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[5-ethyl-1,2,3-thiadiazol-4-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, acetoxymethyl ester 
     A cold (0° C.) solution of 200 mg of (Z)-7β-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[5-ethyl-1,2,3-thiadiazol-4-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt in 10 ml of dry dimethylformamide was treated with 200 mg of iodomethyl acetate. After 2 hours at 0° C. the mixture was diluted with ice water and extracted with ethyl acetate. The organic extract was dried and concentrated in vacuo to a foam which was taken up in dichloromethane and chromatographed over a Bio-Sil A column, eluting with a gradient of 0% to 5% methanol in dichloromethane. The desired fractions were concentrated giving a foam which was triturated with ether, giving 50 mg of the desired ester. Infrared spectrum (KBr pellet) 1775 cm -1 . 
     EXAMPLE 16 
     (Z)-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[5-ethyl-1,2,3-thiadiazol-4-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, ethoxycarbonylethoxy ester 
     The procedure of Example 15 is repeated using α-iodoethyl ethyl carbonate instead of iodomethyl acetate, giving the desired compound.