Uridine nucleoside derivatives, compositions and methods of use

Abstract

This disclosure relates to uridine nucleoside derivatives, compositions comprising therapeutically effective amounts of those nucleoside derivatives and methods of using those nucleoside derivatives or compositions in treating disorders that are responsive to ligands, such as agonists, of P2Y6 receptor, e.g., neuronal disorders, including neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease) and traumatic CNS injury, pain, Down Syndrome (DS), glaucoma and inflammatory conditions.

1 .- 225 . (canceled) 
     
     
         226 . A method for treating glaucoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         A is a bicyclic aromatic ring having up to 4 heteroatoms selected from N, O and S, wherein the bicyclic aromatic ring is independently and optionally substituted with one or more R 7 ; 
         X is selected from:
 H, —C(O)R 5 , and —C(O)OR 5 ; 
 
         Y is a bond or a (C1-C5)-aliphatic group independently and optionally substituted with one or more R 4 ; 
         Z and W are each independently selected from ═O, ═S, ═N(R 5 ), and ═NOR 5 ; 
         R 1  is selected from:
 —H, halogen, —OR 5 , —CN, —CF 3 , —OCF 3  and a (C1-C6)-aliphatic group optionally substituted with one or more R 7 ; 
 
         R 2  and R 3  are each independently selected from OR 5 , —SR 5 , —NR 5 R 6 , —OC(O)R 5 , —OC(O)NR 5 R 6 , and —OC(O)OR 5 ; 
         each occurrence of R 4  is independently selected from:
 halogen, —OR 5 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 5 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 5 ) 2 , —SR 5 , —SOR 5 , —SO 2 R 5 , —SO 2 N(R 5 ) 2 , —SO 3 R 5 , —C(O)R 5 , —C(O)C(O)R 5 , —C(O)CH 2 C(O)R 5 , —C(S)R 5 , —C(S)OR 5 , —C(O)OR 5 , —C(O)C(O)OR 5 , —C(O)C(O)N(R 5 ) 2 , —OC(O)R 5 , —C(O)N(R 5 ) 2 , —OC(O)N(R 5 ) 2 , —C(S)N(R 5 ) 2 , —(CH 2 ) 0-2 NHC(O)R 5 , —N(R 5 )N(R 5 )COR 5 , —N(R 5 )N(R 5 )C(O)OR 5 , —N(R 5 )N(R 5 )CON(R 5 ) 2 , —N(R 5 )SO 2 R 5 , —N(R 5 )SO 2 N(R 5 ) 2 , —N(R 5 )C(O)OR 5 , —N(R 5 )C(O)R 5 , —N(R 5 )C(S)R 5 , —N(R 5 )C(O)N(R 5 ) 2 , —N(R 5 )C(S)N(R 5 ) 2 , —N(COR 5 )COR 5 , —N(OR 5 )R 5 , —C(═NH)N(R 5 ) 2 , —C(O)N(OR 5 )R 5 , —C(═NOR 5 )R 5 , —OP(O)(OR 5 ) 2 , —P(O)(R 5 ) 2 , —P(O)(OR 5 ) 2 , and —P(O)(H)(OR 5 ); 
 
         each occurrence of R 5  is independently selected from:
 H-, 
 (C1-C12)-aliphatic-, 
 (C3-C10)-cycloalkyl- or -cycloalkenyl-, 
 [(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-, 
 (C6-C10)-aryl-, 
 (C6-C 10)-aryl-(C1-C12)aliphatic-, 
 (C3-C10)-heterocyclyl-, 
 (C6-C10)-heterocyclyl-(C1-C12)aliphatic-, 
 (C5-C10)-heteroaryl-, and 
 (C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
 wherein two R 5  groups bound to the same atom optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, O, S, SO, and SO 2 , wherein the ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl; and 
 wherein each R 5  group is independently and optionally substituted with one or more R 7 ; 
 
 
         R 6  is selected from:
 —R 5 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 5 ) 2  and —S(O) 2 R 5 ; 
 
         each occurrence of R 7  is independently selected from:
 halogen, —OR 8 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 8 , oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 8 ) 2 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 N(R 8 ) 2 , —SO 3 R 8 , —C(O)R 8 , —C(O)C(O)R 8 , —C(O)CH 2 C(O)R 8 , —C(S)R 8 , —C(S)OR 8 , —C(O)OR 8 , —C(O)C(O)OR 8 , —C(O)C(O)N(R 8 ) 2 , —OC(O)R 8 , —C(O)N(R 8 ) 2 , —OC(O)N(R 8 ) 2 , —C(S)N(R 8 ) 2 , —(CH 2 ) 0-2 NHC(O)R 8 , —N(R 8 )N(R 8 )COR 8 , —N(R 8 )N(R 8 )C(O)OR 8 , —N(R 8 )N(R 8 )CON(R 8 ) 2 , —N(R 8 )SO 2 R 8 , —N(R 8 )SO 2 N(R 8 ) 2 , —N(R 8 )C(O)OR 8 , —N(R 8 )C(O)R 8 , —N(R 8 )C(S)R 8 , —N(R 8 )C(O)N(R 8 ) 2 , —N(R 8 )C(S)N(R 8 ) 2 , —N(COR 8 )COR 8 , —N(OR 8 )R 8 , —C(═NH)N(R 8 ) 2 , —C(O)N(OR 8 )R 8 , —C(═NOR 8 )R 8 , —OP(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , —P(O)(OR 8 ) 2 , and —P(O)(H)(OR 8 ); 
 
         each occurrence of R 8  is independently selected from:
 H- and (C1-C6)-aliphatic-; 
 
         and a pharmaceutically acceptable carrier, adjuvant or excipient. 
       
     
     
         227 . The method of  claim 226 , wherein the glaucoma is marked by elevated intraocular pressure. 
     
     
         228 . The method of  claim 226 , wherein the glaucoma is selected from the group consisting of open-angle glaucoma, angle-closure glaucoma, congenital glaucoma, and secondary glaucoma. 
     
     
         229 . The method of  claim 228 , wherein the glaucoma is open-angle glaucoma or angle-closure glaucoma. 
     
     
         230 . The method of  claim 229 , wherein the open-angle glaucoma or angle-closure glaucoma is selected from the group consisting of secondary glaucoma, pigmentary glaucoma, pseudoexfoliative glaucoma, traumatic glaucoma, neovascular glaucoma, and iridocorneal endothelial syndrome (ICE). 
     
     
         231 . The method of  claim 226 , wherein the glaucoma is low-tension or normal-pressure glaucoma. 
     
     
         232 . The method of  claim 226 , wherein the subject in need thereof has glaucoma or ocular hypertension. 
     
     
         233 . The method of  claim 226 , wherein the composition is administered by an ophthalmic route. 
     
     
         234 . The method of  claim 226 , wherein A of the compound of Formula I is selected from: 
       
         
           
           
               
               
           
         
         wherein A is optionally further substituted with one or more R 7    
       
     
     
         235 . The method of  claim 226 , wherein A of the compound of Formula I is 
       
         
           
           
               
               
           
         
         wherein A is optionally further substituted with one or more R 7 . 
       
     
     
         236 . The method of  claim 226 , wherein X of the compound of Formula I is —H. 
     
     
         237 . The method of  claim 226 , wherein R 1  is —H. 
     
     
         238 . The method of  claim 226 , wherein Z is ═O. 
     
     
         239 . The method of  claim 226 , wherein W is ═O. 
     
     
         240 . The method of  claim 226 , wherein Y is —CH 2 —. 
     
     
         241 . The method of  claim 226 , wherein both occurrences of R 4  are —F or —CH 3 . 
     
     
         242 . The method of  claim 226 , wherein R 2  is —OH. 
     
     
         243 . The method of  claim 226 , wherein R 3  is —OH. 
     
     
         244 . The method of  claim 226 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         245 . The method of  claim 226 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.