Therapeutic agents and methods of use thereof for the modulation of angiogenesis

Abstract

The present invention provides angiogenesis inhibitor compounds comprising a MetAP-2 inhibitory core coupled to a peptide, as well as pharmaceutical compositions comprising the angiogenesis inhibitor compounds and a pharmaceutically acceptable carrier. The present invention also provides methods of treating an angiogenic disease, e.g., cancer, in a subject by administering to the subject a therapeutically effective amount of one or more of the angiogenesis inhibitor compounds of the invention.

1 . A compound of Formula I,  
       
         
           
           
               
               
           
         
         wherein  
         A is a Met-AP2 inhibitory core;  
         W is O or NR 2 ;  
         R 1  and R 2  are each, independently, hydrogen or alkyl;  
         X is alkylene or substituted alkylene;  
         n is 0 or 1;  
         R 3  and R 4  are each, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 3  and R 4 , together with the carbon atom to which they are attached, form a carbocyclic or heterocyclic group; or R 3  and R 4  together form an alkylene group;  
         Z is —C(O)— or alkylene-C(O)—; and  
         P is a peptide comprising from 1 to about 100 amino acid residues attached at its amino terminus to Z or a group OR 5  or N(R 6 )R 7 , wherein 
 R 5 , R 6  and R 7  are each, independently, hydrogen, alkyl, substituted alkyl, azacycloalkyl or substituted azacycloalkyl; or R 6  and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring structure;  
 
         or  
         Z is —O—, —NR 8 —, alkylene-O— or alkylene-NR 8 —, where R 8  is hydrogen or alkyl; and  
         P is hydrogen, alkyl or a peptide consisting of from 1 to about 100 amino acid residues attached at its carboxy terminus to Z.  
       
     
     
         2 . The compound of  claim 1 , wherein at least one of R 1 , R 3  and R 4  is a substituted or unsubstituted alkyl group.  
     
     
         3 . The compound of  claim 2 , wherein at least one of R 1 , R 3  and R 4  is a substituted or unsubstituted normal, branched or cyclic C 1 -C 6  alkyl group.  
     
     
         4 . The compound of  claim 3 , wherein at least one of R 1 , R 3  and R 4  is a normal or branched C 1 -C 4  alkyl group.  
     
     
         5 . The compound of  claim 1 , wherein one of R 3  and R 4  is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroarylalkyl group, or a substituted or unsubstituted aryl alkyl group.  
     
     
         6 . The compound of  claim 5 , wherein one of R 3  and R 4  is selected from the group consisting of phenyl, naphthyl, indolyl, imidazolyl, pyridyl, benzyl, naphthylmethyl, indolylmethyl, imidazolylmethyl and pyridylmethyl.  
     
     
         7 . The compound of  claim 1 , wherein n is 1 and X is C 1 -C 6 -alkylene.  
     
     
         8 . The compound of  claim 7 , wherein X is methylene or ethylene.  
     
     
         9 . The compound of  claim 1 , wherein Z is C 1 -C 6 -alkylene-C(O)—.  
     
     
         10 . The compound of  claim 9 , wherein Z is methylene-C(O)— or ethylene-C(O)—.  
     
     
         11 . The compound of  claim 1 , wherein at least one of R 6  and R 7  is alkyl, substituted alkyl, substituted or unsubstituted azacycloalkyl or substituted or unsubstituted azacycloalkyl.  
     
     
         12 . The compound of  claim 11 , wherein at least one of R 6  and R 7  is an azacycloalkyl group having an N-alkyl substituent.  
     
     
         13 . The compound of  claim 12 , wherein the N-alkyl substituent is a C 1 -C 4 -alkyl group.  
     
     
         14 . The compound of  claim 13 , wherein the N-alkyl substituent is a methyl group.  
     
     
         15 . The compound of  claim 1 , wherein R 6  and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted five or six-membered aza- or diazacycloalkyl group.  
     
     
         16 . The compound of  claim 15 , wherein R 6  and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted five or six-membered diazacycloalkyl group which includes an N-alkyl substituent.  
     
     
         17 . The compound of  claim 16 , wherein the N-alkyl substituent is a C 1 -C 4 -alkyl group.  
     
     
         18 . The compound of  claim 17 , wherein the N-alkyl substituent is a methyl group.  
     
     
         19 . The compound of  claim 1 , wherein P is NH 2  or one of the groups shown below:  
       
         
           
           
               
               
           
         
       
     
     
         20 - 63 . (canceled)  
     
     
         64 . A method of treating an angiogenic disease in a subject, comprising administering to the subject a therapeutically effective amount of an angiogenesis inhibitor compound comprising the structure  
       
         
           
           
               
               
           
         
         wherein  
         A is a Met-AP2 inhibitory core;  
         W is O or NR 2 ;  
         R 1  and R 2  are each, independently, hydrogen or alkyl;  
         X is alkylene or substituted alkylene;  
         n is 0 or 1;  
         R 3  and R 4  are each, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 3  and R 4 , together with the carbon atom to which they are attached, form a carbocyclic or heterocyclic group; or R 3  and R 4  together form an alkylene group;  
         Z is —C(O)— or alkylene-C(O)—; and  
         P is a peptide comprising from 1 to about 100 amino acid residues attached at its amino terminus to Z or a group OR 5  or N(R 6 )R 7 , wherein 
 R 5 , R 6  and R 7  are each, independently, hydrogen, alkyl, substituted alkyl, azacycloalkyl or substituted azacycloalkyl; or R 6  and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring structure;  
 
         or  
         Z is —O—, —NR 8 —, alkylene-O— or alkylene-NR 8 —, where R 8  is hydrogen or alkyl; and  
         P is hydrogen, alkyl or a peptide consisting of from 1 to about 100 amino acid residues attached at its carboxy terminus to Z.  
       
     
     
         65 - 73 . (canceled)