Oxidated derivatives of triazolylpurines useful as ligands of the adenosine a2a receptor and their use as medicaments

Abstract

The present invention relates to new triazolyl purine derivatives of formula (I), processes for their preparation, and to pharmaceutical compositions containing them for the treatment of neurological disorders or cerebral ischaemia for which inhibition of adenosine A2A receptor will result at improving the health state of a patient.

1 - 15 . (canceled) 
     
     
         16 . A compound having the general formula I 
       
         
           
           
               
               
           
         
         R 1  is C 1 -C 6  linear or branched alkyl; 
         R 2  is a group of formula: 
         R 9 —(CHR 8 ) p —(CR 6 R 7 ) m —(CR 4 R 5 ) n ; 
         R 4 , R 6  and R 8  are independently H, hydroxyl or ═O with the meaning of carbonyl; 
         R 5 , R 7  and R 9  are independently H or are absent; 
         m, n and p are independently an integer comprised between 0 and 2; 
         m+n+p≧4; 
         R 3  is NH 2  or NHR 10 ; 
         R 10  is linear or branched C 1 -C 6  alkyl; linear or branched C 1 -C 6  hydroxyalkyl; linear or branched (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl; amino(C 1 -C 6 )alkyl, where the amino group is optionally substituted with one or two linear or branched C 1 -C 3  alkyl groups; C 6 -C 14  aryl; or C 6 -C 14  aryl(C 1 -C 6 )alkyl, wherein said C 6 -C 14  aryl group is optionally substituted by one or more substituents, which are the same or different, selected from the group consisting of halogen; hydroxyl; linear or branched, saturated or unsaturated C 1 -C 6  alkoxy; and amino, where the amino group is optionally substituted with one or two linear or branched C 1 -C 6  alkyl groups; 
         or an optically active form, or pharmaceutically acceptable salt thereof; 
         with the proviso that R 4 , R 6  and R 8  are not all H at the same time. 
       
     
     
         17 . The compound according to  claim 16  wherein n=2, m=1 and p≧1. 
     
     
         18 . The compound according to  claim 16 , wherein R 6  is OH or =0 with the meaning of carbonyl. 
     
     
         19 . The compound according to  claim 16  wherein n=1 and R 4  is OH or ═O with the meaning of carbonyl. 
     
     
         20 . The compound according to  claim 16  which is 4-(6-amino-9-methyl-8 [1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol, 1-(6-amino-9-methyl-8 [1,2,3 ]triazol-2-yl-9H-purin-2-yl)butan-1-ol, 4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-one, 4-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl) butan-2-ol, or 1-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-1-one or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The compound of  claim 16  which is 4-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl) butan-2-one or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A pharmaceutical composition comprising at least one compound according to  claim 16  or an optically active form, or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable vehicle and/or excipient. 
     
     
         23 . The pharmaceutical composition according to  claim 22  wherein the compound is 4-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol, 1-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-1-ol, 4-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-2-one, 4-(6-amino-9-methyl-8[1,2,3]triazol-2-yl-9H-purin-2-yl)butan-2-ol, or 1-(6-amino-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-2-yl)-butan-1-one or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The pharmaceutical composition according to  claim 22  which further comprises L-DOPA. 
     
     
         25 . A process for preparing a pharmaceutical composition comprising mixing at least one compound according to  claim 16  or an optically active form, or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable vehicle and/or excipient. 
     
     
         26 . A method for treating a pathological state for which the modulation of A 2A  activity would result at improving the health of a patient which comprises administering an effective amount of compound according to  claim 16  or an optically active form, or a pharmaceutically acceptable salt thereof to a patient in need thereof. 
     
     
         27 . The method according to  claims 26  wherein the pathological state is a motor disorder. 
     
     
         28 . The method according to  claim 27 , wherein said motor disorder is Parkinson's disease, Alzheimer's disease, Huntington's disease, Wilson's disease or Hallervorden-Spatz disease. 
     
     
         29 . The method according to  claim 26  wherein said pathological state is cerebral ischaemia optionally associated with neurodegenerative processes. 
     
     
         30 . A method for treating Parkinson's disease which comprises administering an effective amount of the pharmaceutical composition according to  claim 24  to a patient in need thereof. 
     
     
         31 . A process for synthesizing a compound of  claim 16 , which comprises reacting a compound of the formula II 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is C 1 -C 6  linear or branched alkyl; 
           R 11 is N( R   13 ) 2 ; 
         R 13  is benzyl, p-(Me0)-benzyl, p-(C1)-benzyl or p-(Br)-benzyl; 
         R 12  is Cl; 
       
       with a compound of formula IX 
       
         
           
           
               
               
           
         
         wherein 
         R 14  and R 15  are at each occurrence independently H or OH; 
         V is 2 or 3; 
         in the presence of Hermann's catalyst and sodium acetate in a polar solvent.