Peptides and pharmaceutical compositions for treating eye diseases

Abstract

The present invention relates to novel peptides and a pharmaceutical compositions comprising the same. The peptide compounds and compositions disclosed herein are useful as therapeutic agents for treating eye diseases. When administered to the eyes, the peptide compounds and compositions disclosed herein increase the amount of tear secretion and promotes recovery of a damaged cornea.

1 - 74 . (canceled) 
     
     
         75 . A compound represented by Formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         R 1  and R 2  are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl; 
         R 4 , independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, —OR b , —CH 2 OR b , halo, hydroxyl, and hydroxyalkyl; 
         R b  is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; 
         p is 0, 1, or 2; 
         R 6  is hydrogen or substituted or unsubstituted alkyl; and 
         R 9  is hydrogen or alkyl. 
       
     
     
         76 . The compound of  claim 75 , wherein:
 R 1  and R 2  are each independently H or substituted or unsubstituted alkyl;   R 4  for each occurrence is hydroxyl;   p is 1;   R 6  is alkyl optionally substituted with one occurrence of —C(═O)NH 2 ; and   R 9  is hydrogen.   
     
     
         77 . The compound of  claim 75 , wherein R 1  is substituted or unsubstituted alkyl. 
     
     
         78 . The compound of  claim 75 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         79 . (canceled) 
     
     
         80 . (canceled) 
     
     
         81 . The compound of  claim 75 , wherein R 2  is H. 
     
     
         82 . The compound of  claim 75 , wherein p is 1 and R 4  is hydroxyl. 
     
     
         83 - 86 . (canceled) 
     
     
         87 . The compound of  claim 75 , wherein R 6  is alkyl substituted with one occurrence of —C(═O)NH 2 . 
     
     
         88 . The compound of  claim 75 , wherein R 6  is 
       
         
           
           
               
               
           
         
       
     
     
         89 . (canceled) 
     
     
         90 . (canceled) 
     
     
         91 . The compound of  claim 75 , wherein R 9  is —H. 
     
     
         92 . The compound of  claim 75 , selected from the following: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         93 . (canceled) 
     
     
         94 . A compound represented by Formula (VI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         R 1  and R 2  are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl; 
         R 4 , independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, —OR b , —CH 2 OR b , halo, hydroxyl, and hydroxyalkyl; 
         R b  is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; 
         p is 0, 1, or 2; 
         R 6  is hydrogen or substituted or unsubstituted alkyl; 
         R 7  is hydrogen or alkyl; and 
         R 9  is hydrogen or alkyl. 
       
     
     
         95 - 116 . (canceled) 
     
     
         117 . A compound represented by Formula (VII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: 
         R 1  and R 2  are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl; 
         R 4 , independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocycloalkyl, oxo, —OR b , —CH 2 OR b , halo, hydroxyl, and hydroxyalkyl; 
         R b  is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocycloalkyl; 
         p is 0, 1, or 2; 
         R 6  is hydrogen or substituted or unsubstituted alkyl; 
         R 7  is hydrogen or alkyl; and 
         R 9  is hydrogen or alkyl. 
       
     
     
         118 - 142 . (canceled) 
     
     
         143 . A compound represented by Formula (IX): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein: 
 R 1  and R 2  are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl; 
 R 4 , independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, —OR b , —CH 2 OR b , halo, hydroxyl, and hydroxyalkyl;
 R b  is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; 
 
 p is 0, 1, or 2; 
 R 6  is hydrogen or substituted or unsubstituted alkyl; 
 R 7 , R 8 , and R 9  are each independently hydrogen or alkyl; 
 J is OH or —NR x R y ; and 
 R x  and R y  are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or R x  and R y  taken together with the intervening nitrogen atom form a ring. 
 
     
     
         144 - 174 . (canceled) 
     
     
         175 . A compound represented by Formula (X-am): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         R 1 , R 2 , and R 3  are each independently H or substituted or unsubstituted alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, cycloalkyl, heterocyclyl, or heterocyclylalkyl; 
         R 4 , independently for each occurrence, is selected from substituted or unsubstituted alkyl, aryl, arylalkyl, heterocyclyl, oxo, —OR b , —CH 2 OR b , halo, hydroxyl, and hydroxyalkyl;
 R b  is substituted or unsubstituted alkyl, aryl, arylalkyl, or heterocyclyl; 
 
         p is 0, 1, or 2; 
         R 6  is hydrogen or substituted or unsubstituted alkyl; 
         R 7 , R 8 , and R 9  are each independently hydrogen or alkyl; 
         J is OH or —NR x R y ; and 
         R x  and R y  are each independently selected from H, optionally substituted alkyl, optionally substituted alkoxylalkyl, or R x  and R y  taken together with the intervening nitrogen atom form a ring. 
       
     
     
         176 - 243 . (canceled) 
     
     
         244 . A pharmaceutical composition comprising a compound of  claim 75  and a pharmaceutically acceptable carrier. 
     
     
         245 . The pharmaceutical composition of  claim 244 , wherein the pharmaceutical composition is formulated for topical administration to the eye, e.g., as eye drops. 
     
     
         246 . A method of treating eye disease, comprising administering to a subject in need thereof a compound of  claim 75 . 
     
     
         247 . The method of  claim 246 , wherein the eye disease is selected from retinopathy, keratitis, dry-macular degeneration, wet-macular degeneration, dry eye syndrome, heratoconjunctivitis sicca and keratoconjunctival epithelium disorder. 
     
     
         248 . The method of  claim 246 , wherein administering the compound or composition comprises topical administration to the eye of the subject.