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 inflammatory diseases or conditions of joint, gastrointestinal tract, lung, heart, nervous tissue, pancreas, kidney, skin, eye, transplanted organs, multi-organ diseases, inflammatory sequelae of viral or bacterial infections, or inflammatory conditions associated with atherosclerosis and following hypoxic or ischaemic insults, which comprises 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 the inflammatory diseases or conditions of:
 the joint is arthritis selected from rheumatoid arthritis, osteoarthritis or prosthetic joint failure;   the gastrointestinal tract is selected from ulcerative colitis, Crohn's disease, other inflammatory bowel and gastrointestinal diseases, gastritis and mucosal inflammation resulting from infection, or enteropathy provoked by non-steroidal anti-inflammatory drugs;   the lung is selected from adult respiratory distress syndrome, asthma, cystic fibrosis, or chronic obstructive pulmonary disease;   the heart is selected from myocarditis;   the nervous tissue is selected from multiple sclerosis;   the pancreas is selected from inflammation associated with diabetes melitus and complications thereof;   the kidney is selected from glomerulonephritis;   the skin is selected from dermatitis, psoriasis, eczema, urticaria, or burn injury;   the eye is selected from glaucoma;   the transplanted organs is selected from rejection;   the multi-organ diseases is selected from systemic lupus erythematosis or sepsis;   the inflammatory sequelae of viral or bacterial infections and inflammatory conditions associated with atherosclerosis and following hypoxic or ischaemic insults with or without reperfusion is selected from in brain or in ischaemic heart disease.   
     
     
         3 . A method for treating inflammatory diseases or conditions of skin, which comprises 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. 
 
 
     
     
         4 . The method according to  claim 3 , wherein the inflammatory diseases or conditions of skin is selected from dermatitis, psoriasis, eczema, urticaria, or burn injury. 
     
     
         5 . The method according to  claim 4 , wherein the inflammatory diseases or conditions of skin is psoriasis. 
     
     
         6 . A method for treating psoriasis, which comprises 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. 
 
 
     
     
         7 . The method for treating psoriasis according to  claim 6 , wherein:
 R 1  is hydrogen, C 1-4  alkyl, CH 2 CN or (CH 2 ) 3 CF 3 ;   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; and   R 3  is halogen or CN.   
     
     
         8 . The method for treating psoriasis according to  claim 7 , wherein R 1  is hydrogen or C 1-4  alkyl is methyl. 
     
     
         9 . The method for treating psoriasis according to  claim 7 , 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. 
     
     
         10 . The method according to  claim 9 , wherein R 2  is C 4-6  unsubstituted n-alkyl. 
     
     
         11 . The method for treating psoriasis according to  claim 7 , wherein R 3  is halogen. 
     
     
         12 . The method for treating psoriasis according to  claim 11 , wherein halogen as defined for R 3  is chlorine or bromine. 
     
     
         13 . The method for treating psoriasis according to  claim 12 , wherein R 3  is chlorine. 
     
     
         14 . A method for treating psoriasis, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound which 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-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;   8-chloro-3-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione; or   
       a pharmaceutically acceptable salt thereof. 
     
     
         15 . A method for treating psoriasis, which comprises administering to a subject in need thereof a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen or methyl; 
 R 2  is C 4-6  unsubstituted n-alkyl; and 
 R 3  is chlorine; or 
 
       a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method for treating psoriasis according to  claim 15  wherein R 2  is n-pentyl. 
     
     
         17 . The method for treating psoriasis according to  claim 15 , wherein R 1  is methyl. 
     
     
         18 . A method for treating psoriasis, which comprises administering to a subject in need thereof a compound which is 8-chloro-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method for treating psoriasis according to  claim 18 , which comprises administering to a subject in need thereof a compound which is 8-chloro-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione. 
     
     
         20 . A method for treating psoriasis, which comprises administering to a subject in need thereof a pharmaceutical formulation comprising a compound according to Formula (I) according to  claim 1  and one or more physiologically acceptable diluents, excipients or carriers. 
     
     
         21 . A method for treating psoriasis, which comprises administering to a subject in need thereof a pharmaceutical formulation comprising:
 (i) a compound according to Formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof;   (ii) one or more active ingredients selected from statins, bile-acid binding resins and nicotinic acid; and   (iii) one or more physiologically acceptable diluents, excipients or carriers.   
     
     
         22 . A method for treating psoriasis, which comprises administering to a subject in need thereof a pharmaceutical formulation comprising a compound which is 8-chloro-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof.