Oxazole derivatives of tetracyclines

Abstract

This invention provides compounds of the formula: wherein A″, X and Y are defined in the specification. These compounds are useful as antibacterial agents.

1 - 28 . (canceled) 
     
     
         29 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
       wherein:
 X is selected from hydrogen, amino, NR 11 R 12 , alkyl of 1 to 12 carbon atoms optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, vinyl, optionally substituted, alkynyl of 2 to 12 carbon atoms optionally substituted and halogen: 
 R 1  and R 2  are each independently H or alkyl of 1 to 12 carbon atoms or 
 R 1  and R 2  when optionally taken together with the nitrogen atom to which each is attached form a 3 to 7 membered saturated hydrocarbon ring; 
 R 11  and R 12  are each independently H or alkyl of 1 to 12 carbon atoms or 
 R 11  and R 12  when optionally taken together with the nitrogen atom to which each is attached form a 3 to 7 membered saturated hydrocarbon ring; 
 Y is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, alkenyl of 2 to 12 carbon atoms optionally substituted vinyl, alkynyl of 2 to 12 carbon atoms optionally substituted and halogen; 
 produced by the process comprising the steps: 
 a. reacting 7-(substituted)-8-(substituted)-9-amino-6-demethyl-6-deoxytetracycline of the formula 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof 
         with 2-chlorotrimethoxyethane in an aprotic solvent to afford a chloro compound of the formula 
       
       
         
           
           
               
               
           
         
       
       b. reacting the chloro compound with an amine R 1 R 2 NH to form a substituted amine of the formula 
       
         
           
           
               
               
           
         
         c. hydrolyzing the substituted amine with acid to give a compound of the formula 
       
       
         
           
           
               
               
           
         
         d. isolating the compound or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . The product produced by the process according to  claim 29  wherein X is N(CH 3 ) 2 . 
     
     
         31 . The product produced by the process according to  claim 29  wherein the amine R 1 R 2 NH is t-butyl amine. 
     
     
         32 . The product produced by the process according to  claim 29  wherein the aprotic solvent is N,N-dimethylformamide. 
     
     
         33 . The product produced by the process according to  claim 29  which is [4S-(4α,4aα,5aα, 12aα)]-4,7-Bis(dimethylamino)-9-[2-(1,1-dimethylethylamino)acetylamino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-11-dioxo-2-naphthacenecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein:
 X is selected from hydrogen, amino, NR 11 R 12 , alkyl of 1 to 12 carbon atoms optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, vinyl optionally substituted, alkynyl of 2 to 12 carbon atoms optionally substituted and halogen; 
 R 1  and R 2  are each independently H or alkyl of 1 to 12 carbon atoms or 
 R 1  and R 2  when optionally taken together with the nitrogen atom to which each is attached form a 3 to 7 membered saturated hydrocarbon ring; 
 R 11  and R 12  are each independently H or alkyl of 1 to 12 carbon atoms or 
 R 11  and R 12  when optionally taken together with the nitrogen atom to which each is attached form a 3 to 7 membered saturated hydrocarbon ring; 
 Y is selected from hydrogen, alkyl of 1 to 12 carbon atoms optionally substituted, aryl of 6, 10 or 14 carbon atoms optionally substituted, alkenyl of 2 to 12 carbon atoms optionally substituted, vinyl, alkynyl of 2 to 12 carbon atoms optionally substituted and halogen; 
 or a pharmaceutically acceptable salt thereof 
 produced by the process comprising the steps: 
 a. reacting 7-(substituted)-8-(substituted)-9-amino-6-demethyl-6-deoxytetracycline of the formula 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof 
         with 2-chlorotrimethoxyethane in an aprotic solvent to afford a chloro compound of the formula 
       
       
         
           
           
               
               
           
         
         b. reacting the chloro compound with acid to give 9-(2-chloromethylcarbonylamino)substituted-6-demethyl-6-deoxytetracycline of the formula 
       
       
         
           
           
               
               
           
         
         c. reacting the 9-(2-chloromethylcarbonylamino)substituted-6-demethyl-6-deoxytetracycline with amine R 1 R 2 NH to give a compound of the formula 
       
       
         
           
           
               
               
           
         
         d. isolating the compound or a pharmaceutically acceptable salt thereof. 
       
     
     
         35 . The product prepared by the process according to  claim 34  wherein X is N(CH 3 ) 2 . 
     
     
         36 . The product prepared by the process according to  claim 34  wherein the amine R 1 R 2 NH is t-butyl amine. 
     
     
         37 . The product prepared by the process according to  claim 34  wherein the aprotic solvent is N,N-dimethylformamide. 
     
     
         38 . The product prepared by the process according to  claim 34  which is [4S-(4α,4aα,5aα,12aα)]-4,7-Bis(dimethylamino)-9-[2-(1,1-dimethylethylamino)acetylamino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         39 - 40 . (canceled)