Thieno(3,2-d)pyrimidines and furano(3,2-d)pyramidines and their use as purinergic receptor antagonists

Abstract

A compound of formula (I), wherein X is S or O; R 1 is selected from H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR 5 , CO 2 R 5 , CONR 5 R 7 , CONR 5 NR 6 R 7 , NR 6 R 7 , NR 5 CONR 6 R 7 , NR 5 COR 6 , NR 5 CO 2 R 8 , and NR 5 SO 2 R 8 ; R 2 is selected from aryl attached via an unsaturated carbon atom; R 3 is selected from H, alkyl, hydroxy, alkoxy, halogen, CN and NO 2 ; R 3 is selected from H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO 2 , COR 5 , CO 2 R 5 , CONR 6 R 7 , CONR 5 NR 6 R 7 , NR 6 R 7 , NR 5 CONR 6 R 7 , NR 5 COR 6 , NR 5 CO 2 R 8 and NR 5 SO 2 R 8 ; R 5 , R 6 and R 7 are independently selected from H, alkyl and aryl or where R 6 and R 7 are in an (NR 6 R 7 ) group, R 6 and R 7 may be linked to form a heterocyclic group, or where R 5 , R 6 and R 7 are in a (CONR 5 NR 6 R 7 ) group, R 5 and R 6 may be linked to form a heterocyclic group; and R 8 is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof, and the use thereof in therapy and in the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A 2A receptors, may be beneficial, particularly wherein said disorder is a movement disorder such a Parkinson's disease or said disorder is depression, cognitive or memory impairment, acute or chronic pain, ADHD or narcolepsy, or wherein said medicament is for neuroprotection in a subject.

1 .- 49 . (canceled) 
     
     
         50 . A method for blocking a purine receptor in a subject, comprising administering to said subject an effective dose of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is S or O; 
 R 1  is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR 5 , CO 2 R 5 , CONR 6 R 7 , CONR 5 NR 6 R 7 , NR 6 R 7 , NR 5 CONR 6 R 7 , NR 5 COR 6 , NR 5 CO 2 R 8 , and NR 5 SO 2 R 8 ; 
 R 2  is selected from aryl attached via an unsaturated carbon atom; 
 R 3  is selected from the group consisting of H, alkyl, hydroxy, alkoxy, halogen, CN and NO 2 ; 
 R 4  is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO 2 , COR 5 , CO 2 R 5 , CONR 6 R 7 , CONR 5 NR 6 R 7 , NR 6 R 7 , NR 5 CONR 6 R 7 , NR 5 COR 6 , NR 5 CO 2 R 8  and NR 5 SO 2 R 8 ; 
 R 5 , R 6  and R 7  are independently selected from the group consisting of H, alkyl and aryl, or where R 6  and R 7  are in an (NR 6 R 7 ) group, R 6  and R 7  may be linked to form a heterocyclic group, or where R 5 , R 6  and R 7  are in a (CONR 5 NR 6 R 7 ) group, R 5  and R 6  may be linked to form a heterocyclic group; and 
 R 8  is selected from alkyl and aryl, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         51 . The method according to  claim 50 , wherein the purine receptor is an adenosine receptor. 
     
     
         52 . The method according to  claim 51 , wherein the adenosine receptor is an A 2A  receptor. 
     
     
         53 . The method according to  claim 50 , wherein the subject is human. 
     
     
         54 . A method for treating a subject suffering from or at risk of a condition selected from the group consisting of:
 (i) a movement disorder;   (ii) an affective disorder;   (iii) a central or peripheral nervous system degenerative disorder;   (iv) schizophrenia or a related psychosis;   (v) a cognitive disorder;   (vi) an attention disorder;   (vii) a central nervous system injury;   (viii) cerebral ischaemia;   (ix) myocardial ischaemis;   (x) muscle ischaemia;   (xi) a sleep disorder;   (xii) an eye disorder selected from the group consisting of retinal ischaemia-reperfusion injury and diabetic neuropathy;   (xiii) a cardiovascular disorder;   (xiv) memory impairment;   (xv) ADHD;   (xvi) narcolepsy; and   (xvii) diabetes and its complications,   
       the method comprising administering to said subject an effective dose of a compound of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 X is S or O; 
 R 1  is selected from the group consisting of _H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, COR 5 , CO 2 R 5 , CONR 6 R 7 , CONR 5 NR 6 R 7 , NR 6 R 7 , NR 5 CONR 6 R 7 , NR 5 COR 6 , NR 5 CO 2 R 8 , and NR 5 SO 2 R 8 ; 
 R 2  is selected from aryl attached via an unsaturated carbon atom; 
 R 3  is selected from the group consisting of H, alkyl, hydroxy, alkoxy, halogen, CN and NO 2 ; 
 R 4  is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, aryloxy, thioalkyl, thioaryl, halogen, CN, NO 2 , COR 5 , CO 2 R 5 , CONR 6 R 7 , CONR 5 NR 6 R 7 , NR 6 R 7 , NR 5 CONR 6 R 7 , NR 5 COR 6 , NR 5 CO 2 R 8  and NR 5 SO 2 R 8 ; 
 R 5 , R 6  and R 7  are independently selected from the group consisting of H, alkyl and aryl, or where R 6  and R 7  are in an (NR 6 R 7 ) group, R 6  and R 7  may be linked to form a heterocyclic group, or where R 5 , R 6  and R 7  are in a (CONR 5 NR 6 R 7 ) group, R 5  and R 6  may be linked to form a heterocyclic group; and 
 R 8  is selected from alkyl and aryl, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         55 . The method according to  claim 54 , wherein the movement disorder is Parkinson's disease. 
     
     
         56 . The method according to  claim 55 , wherein the Parkinson's disease is selected from the group consisting of drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning and post-traumatic Parkinson's disease. 
     
     
         57 . The method according to  claim 54 , wherein the movement disorder is selected from the group consisting of progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, and other disorders of the basal ganglia which result in dyskinesias. 
     
     
         58 . The method according to  claim 54 , wherein the compound of formula (I) is administered in combination with one or more additional drugs useful in the treatment of movement disorders, and wherein the compound of formula (I) and the one or more additional drugs are in the same formulation or in separate formulations for simultaneous or sequential administration. 
     
     
         59 . The method according to  claim 58 , wherein the one or more additional drugs are effective in treating Parkinson's disease. 
     
     
         60 . The method according to  claim 58 , wherein the one or more additional drugs are selected from the group consisting of L-DOPA and a dopamine agonist. 
     
     
         61 . The method according to  claim 54 , wherein the subject is human.