Prodrugs of vancomycin with hydrolysis resistant polymer linkages

Abstract

Vancomycin-polymer conjugates are disclosed. In preferred aspects, polymer residues which are hydrolysis resistant in vitro, are selectively attached to the sugar amino and/or N-methyl amino groups of vancomycin and related compounds. Vancomycin-polymer conjugates made by the methods and methods of treatment using the conjugates are also disclosed.

1 . A compound of the formula (I) 
     
       
         
         
             
             
         
       
       wherein: 
       R 3 -R 5  are each independently selected from among hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  alkenyls, C 3-12  branched alkenyls, C 1-6  alkynyls, C 3-12  branched alkynyls, 
       C 1-6  heteroalkyls, substituted C 1-6  hetero-alkyls, C 1-6  alkoxyalkyl, phenoxyalkyl and C 1-6  heteroalkoxys; 
       R 6  is OH, NH-aryl, NH-aralkyl, or NH—C 1-12  alkyl; 
       w is 1 or 2; 
       Q a  is H or 
     
     
       
         
         
             
             
         
       
       
         wherein: 
         R 1  is a polyalkylene oxide; 
         L 1  is a hydrolysis resistant bifunctional linker; 
         Y 1  is O, S or NR 5 ; 
         q is 0 or a positive integer; and 
         d is 0 or 1. 
       
       Q b  is H or 
     
     
       
         
         
             
             
         
       
       
         wherein: 
         R 2  is a polyalkylene oxide; 
         L 2  is a hydrolysis resistant bifunctional linker; 
         Y 2  is O, S or NR 5 ; 
         s is 0 or a positive integer; and 
         e is 0 or 1. 
       
     
   
   
       2 . The compound of  claim 1 , wherein R 1  further comprises a capping group J selected from the group consisting of OH, NH 2 , SH, CO 2 H and C 1-6  alkyl moieties. 
   
   
       3 . The compound of  claim 1  wherein R 2  further comprises a capping group J selected from the group consisting of OH, NH 2 , SH, CO 2 H and C 1-6  alkyl moieties. 
   
   
       4 . The compound of  claim 1 , wherein:
 Q a  is   
     
       
         
         
             
             
         
       
       Q b  is 
     
     
       
         
         
             
             
         
       
     
   
   
       5 . The compound of  claim 1  wherein:
 Y 1  and Y 2  are independently O;   R 3  and R 4  are each independently hydrogen or CH 3 ;   R 6  is OH or NH-aryl;   q and s are independently 0-2; and   w is 1.   
   
   
       6 . L 1-2  are independently selected from the group consisting of amino acids and
   —[C(O)] v NR 25 (CR 26 R 27 ) t —,     —[C(O)] v (CR 26 R 27 ) t —,     —[C(O)] v NR 25 (CR 26 R 27 O) t —,     —[C(O)] v NR 25 (CR 26 R 27 O) t (CR 28 R 29 ) y O—,     —[C(O)] v NR 25 (CR 26 R 27 O) t (CR 28 R 29 ) y —,     —[C(O)] v NR 25 (CR 26 R 27 ) t O—,     —[C(O)] v NR 25 (CR 26 R 27 ) t (CR 28 CR 29 O) y NR 30 —,     —[C(O)] v O(CR 26 R 27 ) t NR 30 —,     —[C(O)] v O(CR 26 R 27 ) t O—,     —[C(O)] v NR 25 (CR 26 R 27 ) t NR 30 —,     —[C(O)] v NR 25 (CR 26 R 27 ) t (CR 28 CR 29 O) y —,     —[C(O)] v NR 25 (CR 26 CR 27 O) t (CR 28 R 29 ) y NR 30 —,     —[C(O)] v O(CR 26 CR 27 O) t NR 30 —,   
     
       
         
         
             
             
         
       
       
         wherein: 
         R 25 -R 30  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 2-6  alkenyls, C 2-6  alkynyls, C 3-19  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 2-6  substituted alkenyls, C 2-6  substituted alkynyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls, substituted C 1-6  hetero-alkyls, C 1-6  alkoxyalkyl, phenoxyalkyl and C 1-6  heteroalkoxys; 
         R 31  is selected from the group consisting of hydrogen, C 1-6  alkyls, C 2-6  alkenyls, C 2-6  alkynyls, C 3-19  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 2-6  substituted alkenyls, C 2-6  substituted alkynyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  heteroalkyls, substituted 
       
       C 1-6  heteroalkyls, C 1-6  alkoxyalkyl, phenoxyalkyl and C 1-6  heteroalkoxys, NO 2 , haloalkyl and halogen;
 t and y are individually selected positive integers; and 
 v is 0 or 1; 
 
       provided that Q a  and Q b  are both not simultaneously H. 
     
   
   
       7 . The compound of  claim 6 , wherein the amino acid is selected from the group consisting of alanine, valine, leucine, isoleucine, glycine, serine, threonine, methionine, cysteine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, lysine, arginine, histidine and proline. 
   
   
       8 . The compound of  claim 1 , wherein said polyalkylene oxide comprises polyethylene glycol. 
   
   
       9 . The compound of  claim 8 , wherein said polyalkylene oxide is selected from the group consisting of:
   A-O—(CH 2 CH 2 O) x —     A-O—(CH 2 CH 2 O)—CH 2 C(O)—O—,     A-O—(CH 2 CH 2 O) x —CH 2 CH 2 NR 7 —,     A-O—(CH 2 CH 2 O) x —CH 2 CH 2 SH,   wherein:   A is a capping group selected from the group consisting of OH, NH 2 , SH, CO 2 H and C 1-6  alkyl moieties; and   x is an integer of from about 10 to about 2,300.   
   
   
       10 . The compound of  claim 1 , wherein said polyalkylene oxide has a total number average molecular weight of from about 5,000 to about 100,000 daltons. 
   
   
       11 . The compound of  claim 10 , wherein said polyalkylene oxide has a total number average molecular weight of from about 10,000 to about 80,000 daltons. 
   
   
       12 . The compound of  claim 10 , wherein said polyalkylene oxide has a total number average molecular weight of from about 20,000 to about 40,000 daltons. 
   
   
       13 . A compound of  claim 1 , wherein:
 Q a  is   
     
       
         
         
             
             
         
       
       
         wherein: 
         R 1  is A-O—(CH 2 CH 2 O) x —CH 2 C(O)—O—, wherein A is a capping group selected from the group consisting of OH, NH 2 , SH, CO 2 H and C 1-6  alkyl moieties and x is an integer of from about 10 to about 2,300; 
         Y 1  is O 
         q is 0-2; 
         d is 0 or 1; 
       
       Q b  is hydrogen; 
       R 3  and R 4  are each independently hydrogen or CH 3 , 
       R 6  is OH or NH-aryl; and 
       w is 1. 
     
   
   
       14 . A compound of  claim 1 , wherein:
 Q b  is   
     
       
         
         
             
             
         
       
       
         wherein: 
         R 2  is A-O—(CH 2 CH 2 O) x —CH 2 C(O)—O—, wherein A is a capping group selected from the group consisting of OH, NH 2 , SH, CO 2 H and C 1-6  alkyl moieties and x is an integer of from about 10 to about 2,300; 
         Y 2  is O; 
         s is 0-2; 
         e is 0 or 1; 
       
       Q a  is hydrogen; 
       R 3  and R 4  are each independently hydrogen or CH 3 ; 
       R 6  is OH or NH-aryl- and 
       w is 1. 
     
   
   
       15 . A process for preparing a compound of  claim 1  comprising, reacting a vancomycin compound of the formula: 
     
       
         
         
             
             
         
       
       wherein 
       R 3  and R 4  are independently selected from the group consisting of hydrogen, C 1-6  alkyls, C 3-12  branched alkyls, C 3-8  cycloalkyls, C 1-6  substituted alkyls, C 3-8  substituted cycloalkyls, aryls, substituted aryls, aralkyls, C 1-6  hetero-alkyls, substituted C 1-6  hetero-alkyls, C 1-6  alkoxyalkyl, phenoxyalkyl and C 1-6  heteroalkoxys; 
       R 6  is OH, NH-aryl, NH-aralkyl, or NH—C 1-12  alkyl; and 
       w is 1 or 2; 
     
     with a polymer residue containing at least one leaving group capable of reacting with the sugar amino group of said vancomycin compound in the presence of at least about a twenty-fold molar excess of triethylamine and a sufficient amount of dimethylformamide. 
   
   
       16 . The process of  claim 15 , further comprising reacting said sugar amino compound with a second activated polymer residue containing at least one leaving group capable of reacting with the N-methyl-amino group of said conjugate in the presence of at least about a 5 fold molar excess of dimethylaminopyridine and a sufficient amount of a solvent mixture of dichloromethane and dimethylformamide. 
   
   
       17 . The process of  claim 16 , wherein said solvent mixture comprises about equal parts dichloromethane and dimethylformamide. 
   
   
       18 . A method of treating a bacterial infection in a mammal comprising administering an effective amount of a compound of  claim 1 , to a mammal in need of such treatment, whereby the compound of  claim 1  undergoes degradation and releases vancomycin in vivo. 
   
   
       19 . A method of treating a bacterial infection in a mammal comprising administering an effective amount of a compound of  claim 13 , to a mammal in need of such treatment, whereby the compound of  claim 13  undergoes degradation and releases vancomycin in vivo. 
   
   
       20 . A method of treating a bacterial infection in a mammal comprising administering an effective amount of a compound of  claim 14 , to a mammal in need of such treatment, whereby the compound of  claim 14  undergoes degradation and releases vancomycin in vivo. 
   
   
       21 . A method of treating a bacterial infection in a mammal comprising administering to a mammal in need of such treatment, an effective amount of a combination of vancomycin or a pharmaceutically acceptable salt thereof and a compound of  claim 1 . 
   
   
       22 . A kit comprising in separate containers in a single package, pharmaceutical compositions for use in combination to treat a bacterial infection which comprises in one container a therapeutically effective amount of vancomycin or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier and in a second container a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.