Di-, tri-, and tetra-peptides having antiangiogenic activity

Abstract

Compounds having the formula (SEQ ID NO: 1), which are useful for treating conditions that arise from or are exacerbated by angiogenesis, are described. Also disclosed are pharmaceutical compositions comprising these compounds, methods of treatment using these compounds, and methods of inhibiting angiogenesis.

1 . A compound of formula (I)  
       
         
           
                 
                 
               
                     
                     
                 
                     
                   (I) Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 , (SEQ ID NO:1) 
                 
                     
                     
                 
             
                
                
                
               
            
           
         
       
       or a therapeutically acceptable salt thereof, wherein 
 Xaa 1  is selected from the group consisting of hydrogen and R—(CH 2 ) n —C(O)—, wherein n is an integer from 0 to 8 and R is selected from the group consisting of alkoxy, alkyl, amino, aryl, carboxyl, cycloalkenyl, cycloalkyl, and heterocycle;  
 Xaa 2  is selected from the group consisting of alanyl, D-alanyl, arginyl, asparaginyl, aspartyl, citrullyl, glutaminyl, histidyl, alloisoleucyl, isoleucyl, D-isoleucyl, leucyl, D-leucyl, lysyl(N-epsilon acetyl), D-lysyl(N-epsilon acetyl), lysyl(N-epsilon-nicotinyl), N-methylisoleucyl, methionyl, norleucyl, norvalyl, ornithyl, phenylalanyl, prolyl, D-prolyl, homoseryl, seryl, allothreonyl, and threonyl;  
 Xaa 3  is selected from the group consisting of arginyl, D-arginyl, citrullyl, histidyl, homoarginyl, lysyl, lysyl(N-epsilon isopropyl), ornithyl, and 3-(3-pyridyl)alanyl;  
 provided that when Xaa 3  is arginyl or D-arginyl then Xaa 2  is other than arginyl;  
 Xaa 4  is absent or selected from the group consisting of N-methyl-D-alanyl, 2-aminobutyryl, 2-aminoisobutyryl, D-glutaminyl, homoprolyl, hydroxyprolyl, leucyl, phenylalanyl, prolyl, and D-prolyl; and  
 Xaa 5  is selected from the group consisting of hydroxyl, D-alanylamide, azaglycylamide, glycylamide, D-lysyl(N-epsilon acetyl)amide, —NHCH(CH 3 ) 2 , a group represented by the formula —NH—(CH 2 ) n —CHR 1 R 2 , and a group represented by the formula —NHR 3 , wherein n is an integer from 0 to 8; R 1  is selected from the group consisting of hydrogen, alkyl, cycloalkenyl, and cycloalkyl; R 2  is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle, and hydroxyl, with the proviso that when n is 0, R 2  is other than alkoxy or hydroxyl; and R 3  is selected from the group consisting of hydrogen, cycloalkenyl, cycloalkyl, and hydroxyl.  
 
     
     
         2 . The compound of  claim 1  wherein 
 Xaa 1  is R—(CH 2 ) n —C(O)—;    n is 0;    R is selected from the group consisting of alkyl and heterocycle, wherein the alkyl is selected from the group consisting of methyl and n-butyl, and wherein the heterocycle is 6-methylpyridinyl;    Xaa 2  is selected from the group consisting of D-alanyl, arginyl, asparaginyl, aspartyl, citrullyl, glutaminyl, histidyl, isoleucyl, D-isoleucyl, D-leucyl, D-lysyl(N-epsilon acetyl) lysyl(N-epsilon acetyl), lysyl(N-epsilon-nicotinyl), methionyl, norleucyl, ornithyl, prolyl, homoseryl, seryl, allothreonyl, and threonyl;    Xaa 3  is selected from the group consisting of arginyl and citrullyl;    Xaa 4  is absent or prolyl; and    Xaa 5  is selected from the group consisting of D-alanylamide, —NHCH 2 CH 3 , and —NHCH(CH 3 ) 2 .    
     
     
         3 . The compound of  claim 1  wherein Xaa 3  is arginyl.  
     
     
         4 . The compound of  claim 3  wherein Xaa 2  is isoleucyl.  
     
     
         5 . The compound of  claim 4  selected from the group consisting of 
 N-Ac-Ile-Arg-Pro-NHCH 2 CH 3 ;    N-(6-methylnicotinyl)-Ile-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Ile-Arg-Pro-NHCH(CH 3 ) 2 ;    N-Valeryl-Ile-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Ile-Arg-Pro-D-AlaNH 2 ;    N-Ac-Ile-Arg-NHCH 2 CH 3 ;    N-Ac-Ile-Arg-NHCH(CH 3 ) 2 ;    N-(6-Me-nicotinyl)-Ile-Arg-NHCH 2 CH 3 ; and    N-Valeryl-Ile-Arg-NHCH 2 CH 3 .    
     
     
         6 . The compound of  claim 3  wherein Xaa 2  is D-isoleucyl.  
     
     
         7 . The compound of  claim 6  selected from the group consisting of 
 N-(6-methylnicotinyl)-D-Ile-Arg-Pro-NHCH 2 CH 3 ; and    N-Ac-D-Ile-Arg-Pro-NHCH 2 CH 3 .    
     
     
         8 . The compound of  claim 3  wherein Xaa 2  is selected from the group consisting of prolyl, D-lysyl(N-epsilon acetyl), lysyl(N-epsilon acetyl), and lysyl(N-epsilon-nicotinyl).  
     
     
         9 . The compound of  claim 8  selected from the group consisting of 
 N-Ac-Pro-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-D-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Lys(Ac)-Arg-NHCH 2 CH 3 ;    N-Ac-Lys(Nic)-Arg-NHCH 2 CH 3 ;    N-(6-Me-nicotinyl)-Lys(Ac)-Arg-NHCH 2 CH 3 ;    N-Valeryl-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ; and    N-Ac-Lys(Ac)-Arg-Pro-D-AlaNH 2 .    
     
     
         10 . The compound of  claim 3  wherein Xaa 2  is selected from the group consisting of D-alanyl, citrullyl, and D-leucyl.  
     
     
         11 . The compound of  claim 10  selected from the group consisting of 
 N-Ac-D-Ala-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-D-Leu-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Cit-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Cit-Arg-NHCH 2 CH 3 ; and    N-Ac-Cit-Arg-Pro-D-AlaNH 2 .    
     
     
         12 . The compound of  claim 3  wherein Xaa 2  is selected from the group consisting of arginyl, asparaginyl, methionyl, norleucyl, ornithyl, aspartyl, glutaminyl, homoseryl, histidyl, seryl, allothreonyl, and threonyl.  
     
     
         13 . The compound of  claim 12  selected from the group consisting of 
 N-Ac-Thr-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Ser-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Nle-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Orn-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Asp-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Gln-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Asn-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Met-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-Hser-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-alloThr-Arg-Pro-NHCH 2 CH 3 ;    N-Ac-His-Arg-Pro-NHCH 2 CH 3 ;    N-Valeryl-alloThr-Arg-NHCH 2 CH 3 ; and    N-Ac-alloThr-Arg-Pro-D-AlaNH 2 .    
     
     
         14 . The compound of  claim 1  wherein Xaa 3  is citrullyl.  
     
     
         15 . The compound of  claim 14  wherein Xaa 2  is selected from the group consisting of arginyl and lysyl(N-epsilon acetyl).  
     
     
         16 . The compound of  claim 15  selected from the group consisting of 
 N-Ac-Arg-Cit-Pro-NHCH 2 CH 3 ; and    N-Ac-Lys(Ac)-Cit-NHCH 2 CH 3 .    
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 1 , or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.  
     
     
         18 . A method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of  claim 1  or a therapeutically acceptable salt thereof.  
     
     
         19 . A method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of  claim 1  or a therapeutically acceptable salt thereof.