HM74 receptor agonists:xanthine derivatives, corresponding pharmaceutical compositions, treatment methods and processes
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.
1. 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 compound according to claim 1 , 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.
3. The compound according to claim 1 , wherein R 1 is hydrogen or methyl.
4. The compound 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.
5. The compound according to claim 4 , wherein R 2 is C 4-6 unsubstituted n-alkyl.
6. The compound according to claim 1 , wherein R 3 is halogen.
7. The compound according to claim 6 , wherein halogen as defined for R 3 is chlorine or bromine.
8. The compound according to claim 7 , wherein R 3 is chlorine.
9. 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.
10. 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.
11. The compound according to claim 10 , R 2 is n-pentyl.
12. The compound according to claim 10 , wherein R 1 is methyl.
13. A compound which is 8-chloro-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 13 which is 8-chloro-1-methyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione.
15. A pharmaceutical formulation comprising a compound according to Formula (I) according to claim 1 and one or more physiologically acceptable diluents, excipients or carriers.
16. 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.