US2003109484A1PendingUtilityA1

Novel 2'-halomethylidene, 2'-ethenylidene and 2'ethynyl cytidine, uridine and guanosine derivatives

Priority: Nov 15, 1988Filed: Jun 6, 2002Published: Jun 12, 2003
Est. expiryNov 15, 2008(expired)· nominal 20-yr term from priority
C07H 19/06C07H 19/16
54
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Claims

Abstract

This invention relates to certain novel 2′-halomethylidene, 2′-ethenylidene and 2′-ethynyl cytidine, uridine and guanosine derivatives, and compositions thereof, which are useful in the treatment of patients afflicted with neoplastic or viral disease states.

Claims

exact text as granted — not AI-modified
1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 V is oxy, methylene, or thio,  
 X 1  and X 2  are each independently hydrogen or halogen, with the proviso that at least one of X 1  and X 2  is halogen,  
 B is a radical of the formula  
                     
 wherein Y 1  is nitrogen, a CH group, a CCl group, a CBr group or a CNH 2  group; Y 2  and Y 3  are each independently nitrogen or a CH group; Y 4  is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy or halogen; Y 5  is amino or C 1 -C 4  alkoxy; and Z is hydrogen, halogen, or NH 2 ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 V is oxy, methylene, or thio,  
 R is hydrogen or C 1 -C 4  alkyl,  
 B is a radical of the formula  
                     
 wherein Y 1  is nitrogen, a CH group, a CCl group, a CBr group or a CNH 2  group; Y 2  and Y 3  are each independently nitrogen or a CH group; Y 4  is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy or halogen; Y 5  is amino or C 1 -C 4  alkoxy; and Z is hydrogen, halogen, or NH 2 ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 V is oxy, methylene, or thio,  
 A 1  and A 2  are each independently hydrogen or a —C CR group, wherein R is hydrogen or C 1 -C 4  alkyl, with the proviso that where A 1  is hydrogen A 2  is a —C CR group, and where A 1  is a —C CR group A 2  is hydrogen,  
 B is a radical of the formula  
                     
 wherein Y 1  is nitrogen, a CH group, a CCl group, a CBr group or a CNH 2  group; Y 2  and Y 3  are each independently nitrogen or a CH group; Y 4  is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy or halogen; Y 5  is amino or C 1 -C 4  alkoxy; and Z is hydrogen, halogen, or NH 2 ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         4 . A compound of  claim 1  wherein X 1  is fluoro and X 2  is hydrogen.  
     
     
         5 . A compound of  claim 1  wherein X 1  is hydrogen and X 2  is fluoro.  
     
     
         6 . A compound of  claim 2  or  3  wherein R is hydrogen.  
     
     
         7 . A compound of  claim 1 ,  2  or  3  wherein V is oxy.  
     
     
         8 . A compound of  claim 1 ,  2  or  3  wherein Z is hydrogen.  
     
     
         9 . A compound of  claim 1 ,  2  or  3  wherein Y 1  is a CH group.  
     
     
         10 . A compound of  claim 1 ,  2  or  3  wherein Y 2  is nitrogen.  
     
     
         11 . A compound of  claim 1 ,  2  or  3  wherein Y 3  is nitrogen.  
     
     
         12 . A compound of  claim 1 ,  2  or  3  wherein Z is hydrogen.  
     
     
         13 . A compound of  claim 1 ,  2  or  3  wherein Y 2  is a CH group.  
     
     
         14 . A method of treating a patient afflicted with a neoplastic disease state comprising the administration thereto of a therapeutically effective antineoplastic amount of a compound of  claim 1 ,  2  or  3 .  
     
     
         15 . A method of treating a patient afflicted with a viral infection comprising the administration thereto of a therapeutically effective antiviral amount of a compound of  claim 1 ,  2  or  3 .  
     
     
         16 . A method of controlling the growth of a neoplasm in a patient afflicted with a neoplastic disease state comprising administration thereto of a therapeutically effective antineoplastic amount of a compound of  claim 1 ,  2  or  3 .  
     
     
         17 . A method of controlling a viral infection in a patient afflicted therewith comprising administration thereto of a therapeutically effective antiviral amount of a compound of  claim 1 ,  2  or  3 .  
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 ,  2  or  3  in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.  
     
     
         19 . A compound of  claim 1  wherein the compound is 2′-deoxy-2′-difluoromethylidene-cytidine.  
     
     
         20 . The compound of  claim 1  wherein the compound is 2′-deoxy-2′-difluoromethylidene-uridine.  
     
     
         21 . The compound of  claim 1  wherein the compound is 2′-deoxy-2′-difluoromethylidene-guanosine.  
     
     
         22 . A compound of  claim 1  wherein the compound is (E)-2′-deoxy-2′-fluoromethylidene-cytidine.  
     
     
         23 . A compound of  claim 1  wherein the compound is (Z)-2′-deoxy-2′-fluoromethylidene-cytidine.  
     
     
         24 . A compound of  claim 1  wherein the compound is (Z) or (E)-2′-deoxy-2′-fluoromethylidene-uridine.  
     
     
         25 . A compound of  claim 1  wherein the compound is (z) or (E) 2′-deoxy-2′-fluoromethylidene-guanosine.  
     
     
         26 . The compound of  claim 2  wherein the compound is 2′-deoxy-2′-ethenylidene-cytidine.  
     
     
         27 . The compound of  claim 2  wherein the compound is 2′-deoxy-2′-ethenylidene-uridine.  
     
     
         28 . A compound of  claim 2  wherein the compound is 2′-deoxy-2′-ethenylidene-guanosine.  
     
     
         29 . A compound of  claim 3  wherein the compound is 2′-deoxy-2′ (R or S)-ethynyl-cytidine.  
     
     
         30 . A compound of  claim 3  wherein the compound is 2′-deoxy-2′ (R or S)-ethynyl-uridine.  
     
     
         31 . A compound of  claim 3  wherein the compound is 2′-deoxy-2′ (R or S)-ethynyl-guanosine.  
     
     
         32 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 V is oxy, methylene, or thio,  
 X HAL  is halogen,  
 Ar is a C 6 -C 12  aryl group,  
 B is a radical of the formula  
                     
 wherein Y 1  is nitrogen, a CH group, a CCl group, a CBr group or a CNH 2  group; Y 2  and Y 3  are each independently nitrogen or a CH group; Y 4  is hydrogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy or halogen; Y 5  is amino or C 1 -C 4  alkoxy; and Z is hydrogen, halogen, or NH 2 .  
 
     
     
         33 . A compound of  claim 32  wherein Ar is phenyl.  
     
     
         34 . A compound of  claim 33  wherein X HAL  is fluorine.  
     
     
         35 . A composition comprising a compound of  claim 1 ,  2 ,  3 , or  32  in admixture or otherwise in association with an inert carrier.

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