Polymer-conjugated metap2 inhibitors, and therapeutic methods of use thereof

Abstract

One aspect of the invention provides polymer conjugated MetAP2 inhibitors. While not being bound by any particular theory, it is believed that coupling the MetAP2 inhibitory core via the linkers described herein provides compounds with superior efficacy to the parent small molecules and superior pharmacokinetic profiles. In one aspect of the invention, the polymer conjugated MetAP2 inhibitors are useful in methods of treating disease, comprising administering to a subject in need thereof a therapeutically effective amount of a polymer conjugated MetAP2 inhibitor.

1 . A method of preparing poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexyl)carbamoylfumagillol]: 
       
         
           
           
               
               
           
         
         the method comprising contacting p-nitrophenyl fumagill-6-yl carbonate: 
       
       
         
           
           
               
               
           
         
         with poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexylamine.HCl)]: 
       
       
         
           
           
               
               
           
         
         
           to form a mixture; 
           wherein x is between 1 and about 450, y is between 1 and about 30, and n is between 1 and about 50, wherein the p-nitrophenyl fumagill-6-yl carbonate is contacted with the poly [HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexylamine.HCl)] in the presence of N, N-diisopropylethylamine. 
         
       
     
     
         2 .- 20 . (canceled) 
     
     
         21 . A compound or pharmaceutically acceptable salt thereof, comprising: 
       
         
           
           
               
               
           
         
         wherein, independently for each occurrence,
 R 4  is H or —C 1 -C 6  alkyl; 
 R 5  is H or —C 1 -C 6  alkyl; 
 R 6  is C 2 -C6 hydroxyalkyl; 
 Z is -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-L or —NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Q-X—Y—C(O)—W; 
 AA 1  is glycine, alanine, or H 2 N(CH 2 ) m CO 2 H, wherein m is 2, 3, 4 or 5; 
 AA 2  is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; 
 AA 3  is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; 
 AA 4  is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine; 
 AA 5  is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine; 
 AA 6  is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H 2 N(CH 2 ) m CO 2 H, wherein m is 2, 3, 4 or 5; 
 L is —OH, —O-succinimide, —O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, —NH 2 , —NH(C 2 -C 6  hydroxyalkyl), halide or perfluoroalkyloxy; 
 Q is NR, O, or S; 
 X is M-(C(R) 2 ) p -M-J-M-(C(R) 2 ) p -M-V; 
 M is a bond, or C(O); 
 J is a bond, or ((CH 2 ) q Q) r , C 5 -C 8  cycloalkyl, aryl, heteroaryl, NR, O, or S; 
 Y is NR, O, or S; 
 R is H or alkyl; 
 V is a bond or 
 
       
       
         
           
           
               
               
           
         
         
           R 9  is alkyl, aryl, aralkyl, or a bond; or R 9  taken together with Y forms a heterocyclic ring; 
           R 10  is amido or a bond; 
           R 11  is H or alkyl; 
           W is a MetAP2 inhibitor moiety or alkyl; 
           x is in the range of 1 to about 450; 
           y is in the range of 1 to about 30; 
           n is in the range of 1 to about 50; 
           p is 0 to 20; 
           q is 2 or 3; 
           r is 1, 2, 3, 4, 5, or 6; and 
           the compound has a molecular weight of less than about 60 kDa. 
         
       
     
     
         22 . The compound of  claim 21 , wherein R 4  is C 1 -C 6  alkyl. 
     
     
         23 . The compound of  claim 22 , wherein R 4  is methyl. 
     
     
         24 . The compound of  claim 21 , wherein R 5  is C 1 -C 6  alkyl. 
     
     
         25 . The compound of  claim 24 , wherein R 5  is methyl. 
     
     
         26 . The compound of  claim 21 , wherein R 6  is 2-hydroxyethyl, 2- hydroxypropyl or 3-hydroxypropyl. 
     
     
         27 . The compound of  claim 21 , wherein the molecular weight is less than about 45 kDa. 
     
     
         28 . The compound of  claim 21 , wherein the ratio of x toy is in the range of about 30:1 to about 3:1, about 20:1 to about 4:1, or about 15:1 to about 6:1. 
     
     
         29 . The compound of  claim 21 , wherein Z is —NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C(O)-L. 
     
     
         30 . The compound of  claim 21 , wherein L is methoxy, ethoxy, pentafluorophenyloxy, phenyloxy, acetoxy, fluoride, chloride, methoxycarbonyloxy; ethoxycarbonyloxy, phenyloxycarbonyloxy, 4- nitrophenyloxy, trifluoromethoxy, pentafluoroethoxy, or trifluoroethoxy. 
     
     
         31 . The compound of  claim 21 , wherein Z is —NH-AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -C(O)-Q-X—Y—C(O)—W. 
     
     
         32 . The compound of  claim 21 , wherein AA 1 , AA 3  and AA 5  are glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine. 
     
     
         33 . The compound of  claim 21 , wherein AA 2 , AA 4  and AA 6  are glycine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, threonine, or tyrosine. 
     
     
         34 . The compound of  claim 21 , wherein AA 2  is a bond; and AA 3  is a bond. 
     
     
         35 . The compound of  claim 21 , wherein W is 
       
         
           
           
               
               
           
         
       
     
     
         36 . A pharmaceutical composition, comprising the compound of  claim 21 , and a pharmaceutically acceptable carrier or excipient. 
     
     
         37 . A method of treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 21 , wherein the disease is a solid tumor, lymphoma, leukemia, multiple myeloma, coronary artery disease, pulmonary fibrosis, stroke, or chronic wounds. 
     
     
         38 . A method of treating an angiogenic disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 21 . 
     
     
         39 . A method of treatment or inhibition of an undesirable proliferation of cells comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 21 .