Novel compounds

Abstract

The present invention relates to therapeutically active xanthine derivative compounds of Formula (I): corresponding processes for manufacture of said derivatives, pharmaceutical formulations containing and uses of such compounds in therapy, particularly in treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial.

What is claimed is: 
     
         1 . A method for treating an inflammatory disease or condition of nervous tissue or inflammatory sequelae of a viral or bacterial infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen or C 1-4  alkyl which optionally is substituted with one or more groups selected from CN or CF 3 ; 
 R 2  is C 3-10  unsubstituted alkyl, C 1-10  alkyl substituted with one or more groups selected from fluorine, CN, C 5  alkenyl, unbranched C 4  alkenyl, or C 1-4  alkyl substituted with cycloalkyl; and 
 R 3  is halogen or CN; or 
 
       a pharmaceutically acceptable salt thereof; and
 provided that: 
 (i) when R 3  is Cl, and R 1  is ethyl, R 2  is other than propyl; 
 (ii) when R 3  is Br, and R 1  is propyl, R 2  is other than propyl; 
 (iii) when R 3  is Cl or Br, and R 1  is butyl, R 2  is other than butyl; and 
 (iv) when R 1  is C 1-4  alkyl, CH 2 CN, or (CH 2 ) 3 CF 3 , R 2  is other than branched alkyl. 
 
     
     
         2 . The method according to  claim 1 , wherein said method treats the inflammatory disease or condition of nervous tissue, and wherein the disease or condition is multiple sclerosis. 
     
     
         3 . The method according to  claim 1 , wherein said method treats inflammatory sequelae of a viral or bacterial infection. 
     
     
         4 . The method according to  claim 1 , wherein R 1  is hydrogen, C 1-4  alkyl, CH 2 CN or (CH 2 ) 3 CF 3 ; and R 2  is C 3-10  unsubstituted alkyl, (CH 2 ) 1-5 CN, C 2-5  alkyl substituted with one or more fluorine substitutions, unbranched C 5  alkenyl, or C 1-4  alkyl substituted with cycloalkyl. 
     
     
         5 . The method according to  claim 1 , wherein R 1  is hydrogen or methyl. 
     
     
         6 . The method according to  claim 1 , wherein R 2  is C 4-6  unsubstituted n-alkyl, (CH 2 ) 1-3 CN, C 3-4  alkyl with one or more fluorine substitutions or C 5  alkenyl. 
     
     
         7 . The method according to  claim 1 , wherein R 2  is C 4-6  unsubstituted n-alkyl. 
     
     
         8 . The method according to  claim 1 , wherein R 3  is chlorine or bromine. 
     
     
         9 . The method according to  claim 1 , wherein R 3  is chlorine. 
     
     
         10 . The method according to  claim 1 , wherein the compound of Formula (I) is selected from:
 (8-chloro-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)acetonitrile;   3-butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione;   8-bromo-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(3,3,3-trifluoropropyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-1-propyl-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione;   3-butyl-8-chloro-1-methyl-3,7-dihydro-1H-purine-2,6-dione;   (3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile;   8-chloro-3-(2-cyclopropylethyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-1,3-bis(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione;   4-(8-chloro-1-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)butanenitrile;   8-chloro-1-ethyl-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione;   1-methyl-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile;   8-chloro-3-propyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(3-methylbutyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-propyl-3,7-dihydro-1H-purine-2,6-dione;   3-butyl-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile;   8-chloro-3-(4-penten-1-yl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-hexyl-3,7-dihydro-1H-purine-2,6-dione;   4-(8-chloro-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)butanenitrile;   8-chloro-3-hexyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione;   3-butyl-8-chloro-1-ethyl-3,7-dihydro-1H-purine-2,6-dione;   [8-chloro-3-(2-cyclopropylethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl]acetonitrile;   (8-chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile;   8-chloro-1-(4,4,4-trifluorobutyl)-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione;   2,2′-(8-chloro-2,6-dioxo-6,7-dihydro-1H-purine-1,3(2H)-diyl)diacetonitrile;   8-chloro-1-methyl-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(2-cyclohexylethyl)-3,7-dihydro-1H-purine-2,6-dione;   1,3-dibutyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-carbonitrile;   1,3-dibutyl-8-iodo-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(4-methylpentyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(6-methylheptyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-octyl-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-decyl-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(cyclohexylmethyl)-3,7-dihydro-1H-purine-2,6-dione;   (+/−)-8-chloro-3-(3-methylpentyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(2-cyclopentylethyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(cyclopropylmethyl)-3,7-dihydro-1H-purine-2,6-dione;   (+/−)-8-chloro-3-(2-methylbutyl)-3,7-dihydro-1H-purine-2,6-dione;   (+/−)-8-chloro-3-(2-methylpentyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(cyclobutylmethyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(cyclopentylmethyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(3-cyclopropylpropyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(2-cyclobutylethyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(4-fluorobutyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(3-fluoropropyl)-3,7-dihydro-1H-purine-2,6-dione;   8-chloro-3-(5-fluoropentyl)-3,7-dihydro-1H-purine-2,6-dione;   4-(8-chloro-1-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)butanenitrile;   3-(3-buten-1-yl)-8-chloro-3,7-dihydro-1H-purine-2,6-dione;   6-(8-chloro-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)-2,2-dimethylhexanenitrile;   8-chloro-3-(6-fluorohexyl)-3,7-dihydro-1H-purine-2,6-dione; and   8-chloro-3-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione;   or a pharmaceutically acceptable salt thereof.   
     
     
         11 . The method according to  claim 1 , wherein R 1  is hydrogen or methyl; R 2  is C 4-6  unsubstituted n-alkyl; and R 3  is chlorine. 
     
     
         12 . The method according to  claim 1 , wherein R 2  is n-pentyl. 
     
     
         13 . The method according to  claim 1 , wherein R 1  is hydrogen. 
     
     
         14 . The method according to  claim 1 , comprising treating multiple sclerosis by administering 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof, to said subject. 
     
     
         15 . The method according to  claim 1 , comprising treating multiple sclerosis by administering 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione to said subject. 
     
     
         16 . The method according to  claim 1 , comprising treating inflammatory sequelae by administering 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof, to said subject. 
     
     
         17 . The method according to  claim 1 , comprising treating inflammatory sequelae by administering 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione to said subject. 
     
     
         18 . A method for treating an inflammatory disease or condition of nervous tissue or inflammatory sequelae of a viral or bacterial infection comprising administering to a subject in need thereof a pharmaceutical formulation comprising the compound of Formula (I), or pharmaceutically acceptable salt thereof, according to  claim 1 , and one or more physiologically acceptable diluents, excipients or carriers. 
     
     
         19 . The method according to  claim 18 , wherein the pharmaceutical formulation comprises 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method according to  claim 18 , wherein the pharmaceutical formulation comprises 8-chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione.