Purine derivatives as purinergic receptor antagonists

Abstract

Use of a compound of formula (I) wherein R 1 is selected from alkyl, aryl, alkoxy, aryloxy, 0thioalkyl, thioaryl, CN, halo, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 and NR 4 SO 2 R 7 ; R 2 is selected from N, O or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated carbon atom which is adjacent to one or two N, O or S-heteroatom(s), other than ortho, ortho-disubstituted heteroaryl groups; R 3 is selected from H, alkyl, COR 8 , CONR 9 R 10 , CONR 8 NR 9 R 10 , CO 2 R 11 and SO 2 R 11 ; R 4 , R 5 and R 6 are independently selected from H, alkyl and aryl or where R 5 and R 6 are in an (NR 5 R 6 ) group then R 5 and R 6 may be linked to form a heterocyclic ring; R 7 is selected from alkyl and aryl; R 8 , R 9 and R 10 are independently selected from H, alkyl and aryl, or R 9 and R 10 may be linked to form a heterocyclic ring, or where R 8 , R 9 and R 10 are in a (CONR 8 NR 9 R 10 ) group, R 8 and R 9 may be linked to form a heterocyclic group; and R 1 is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof, 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 as Parkinson's disease or said disorder is depression, cognitive or memory impairment, acute or chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject; compounds of formula (I) for use in therapy; and novel compounds of formula (I) per se.

1 . A method of treating a disorder selected from a group consisting of: 
 (i) movement disorders;    (ii) acute and chronic pain;    (iii) affective disorders;    (iv) central and peripheral nervous system degenerative disorders;    (v) schizophrenia and related psychoses;    (vi) cognitive disorders;    (vii) attention disorders;    (viii) central nervous system injury;    (ix) cerebral ischaemia;    (x) myocardial ischaemia;    (xi) muscle ischaemia;    (xii) sleep disorders;    (xiii) eye disorders selected from retinal ischaemia-reperfusion injury and diabetic neuropathy;    (xiv) cardiovascular disorders; and    (xv) diabetes and its complications;    the method comprising administering to a subject in need of such treatment an effective dose of a compound of formula (I):                          wherein    R 1  is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 , and NR 4 SO 2 R 7 ;    R 2  is selected from the group consisting of N, O, or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated ring carbon atom of said heteroaryl group which is adjacent to one or two N, O, or S-heteroatom(s), other than heteroaryl groups substituted at both positions adjacent the point of attachment of the heteroaryl group to the purine moiety;    R 3  is selected from the group consisting of H, alkyl, COR 8 , CONR 9 R 10 , CONR 8 NR 9 R 10 , CO 2 R 11 , and SO 2 R 11 ;    R 4 , R 5 , and R 6  are independently selected from the group consisting of H, alkyl, and aryl, or where R 5  and R 6  are in an (NR 5 R 6 ) group then R 5  and R 6  may be linked to form a heterocyclic ring;    R 7  is alkyl or aryl;    R 8 , R 9 , and R 10  are independently selected from the group consisting of H, alkyl, and aryl, or R 9  and R 10  may be linked to form a heterocyclic ring, or where R 8 , R 9 , and R 10  are in a (CONR 8 NR 9 R 10 ) group, R 8  and R 9  may be linked to form a heterocyclic group; and    R 11  is alkyl or aryl,    or a pharmaceutically acceptable salt thereof.    
   
   
       2 . The method of  claim 1 , wherein said disorder is a movement disorder.  
   
   
       3 . The method of  claim 2 , wherein the movement disorder is Parkinson's disease.  
   
   
       4 . The method of  claim 3  for treatment of drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning, or post-traumatic Parkinson's disease.  
   
   
       5 . The method of  claim 2 , 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.  
   
   
       6 . The method of  claim 1 , wherein the compound of formula (I) is administered in combination with one or more additional drugs useful in the treatment of movement disorders.  
   
   
       7 . The method of  claim 6 , wherein the components are in the same formulation.  
   
   
       8 . The method of  claim 6 , wherein the components are in separate formulations for administration simultaneously or sequentially.  
   
   
       9 . The method of  claim 6 , wherein said one or more additional drugs useful in the treatment of movement disorders are drugs useful in the treatment of Parkinson's disease.  
   
   
       10 . The method of  claim 6 , wherein the one or more additional drugs is L-DOPA or a dopamine agonist.  
   
   
       11 . The method of  claim 1 , wherein said disorder is selected from the group consisting of depression, cognitive impairment, memory impairment, acute pain, chronic pain, ADHD, and narcolepsy.  
   
   
       12 . The method of  claim 11 , wherein said cognitive or memory impairment disorder is Alzheimer's disease.  
   
   
       13 . The method of  claim 1 , wherein the subject is human.  
   
   
       14 . The method of  claim 1 , wherein the compound of formula (I) is selected from the group consisting of: 
 N,N-Dimethyl-6-(2-furyl)-1H-purine-2-amine;    6-(2-Furyl)-1H-purine-2-amine;    6-(2-Furyl)-2-methylthio-1H-purine;    2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-carboxamide;    2-Amino-N-n-butyl-6-(2-furyl)-9H-purine-9-carboxamide;    2-Amino-6-(2-furyl)-N-(4-methoxybenzyl)-9H-purine-9-carboxamide;    2-Amino-6-(2-furyl)-N-(4-methylbenzyl)-9H-purine-9-carboxamide;    2-Amino-N-(2-chlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;    (1S)-2-Amino-6-(2-furyl)-N-(1-phenylethyl)-9H-purine-9-carboxamide;    2-Amino-6-(2-furyl)-N-(3-methylbenzyl)-9H-purine-9-carboxamide;    2-Amino-6-(2-furyl)-N-n-pentyl-9H-purine-9-carboxamide;    6-(2-Furyl)-9-(1-phenyl-1-propene-3-yl)-9H-purine-2-amine;    6-(2-Furyl)-9-(3-phenylpropyl)-9H-purine-2-amine;    2-Amino-N-(4-fluorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;    2-Amino-N-(3,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;    6-(2-Furyl)-9-(4-isopropylbenzyl)-9H-purine-2-amine;    2-Amino-6-(2-furyl)-N-(2-phenylethyl)-9H-purine-9-carboxamide;    2-Amino-N-(2,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide;    Benzyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate;    N-Benzyl-2-methoxy-6-(2-furyl)-9H-purine-9-carboxamide;    2-Amino-N-benzyl-6-(2-furyl)-N-methyl-9H-purine-9-carboxamide;    9-(3-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine;    6-(2-Furyl)-9-(3-methylbenzyl)-9H-purine-2-amine;    6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-amine;    2-Amino-N-(3-chlorophenyl)-6-(2-furyl)-9H-purine-9-acetamide;    9-(2-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine;    6-(2-Furyl)-9-(4-trifluoromethylbenzyl)-9H-purine-2-amine;    9-(4-Bromophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine;    6-(2-Furyl)-9-(2-phenylethenyl)sulphonyl-9H-purine-2-amine;    6-(2-Furyl)-9-(3-(3-pyridyl)propyl)-9H-purine-2-amine;    9-(3-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine;    6-(2-Furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine;    2-Amino-6-(2-furyl)-N-(2-furylmethyl)-9H-purine-9-carboxamide;    2-Amino-6-(2-furyl)-N-(2-thienylmethyl)-9H-purine-9-carboxamide;    9-(4-Methylbenzyl)-6-(5-methyl-2-furyl)-9H-purine-2-amine;    9-(2,6-Difluorobenzyl)-6-(2-furyl)-9H-purine-2-amine;    6-(2-Furyl)-9-(6-methyl-2-pyridyl)methyl-9H-purine-2-amine;    6-(2-Furyl)-9-(2-(1-methyl-1H-imidazol-4-ylsulphonylamino)benzyl)-9H-purine-2-amine;    9-(5-Chloro-2-thienylmethyl)-6-(2-furyl)-9H-purine-2-amine;    9-(2-Fluorobenzyl)-6-(4-methyl-2-thiazolyl)-9H-purine-2-amine; and    9-(2-Fluoro-5-nitrobenzyl)-6-(2-furyl)-9H-purine-2-amine.    
   
   
       15 . A method of neuroprotection comprising administering to a subject in need of such treatment an effective dose of a compound of formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 , and NR 4 SO 2 R 7 ;  
 R 2  is selected from the group consisting of N, O, or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated ring carbon atom of said heteroaryl group which is adjacent to one or two N, O, or S-heteroatom(s), other than heteroaryl groups substituted at both positions adjacent the point of attachment of the heteroaryl group to the purine moiety;  
 R 3  is selected from the group consisting of H, alkyl, COR 8 , CONR 9 R 10 , CONR 8 NR 9 R 10 , CO 2 R 11 , and SO 2 R 11 ;  
 R 4 , R 5 , and R 6  are independently selected from the group consisting of H, alkyl, and aryl, or where R 5  and R 6  are in an (NR 5 R 6 ) group then R 5  and R 6  may be linked to form a heterocyclic ring;  
 R 7  is alkyl or aryl;  
 R 8 , R 9 , and R 10  are independently selected from the group consisting of H, alkyl, and aryl, or R 9  and R 10  may be linked to form a heterocyclic ring, or where R 8 , R 9 , and R 10  are in a (CONR 8 NR 9 R 10 ) group, R 8  and R 9  may be linked to form a heterocyclic group; and  
 R 11  is alkyl or aryl,  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       16 . The method of  claim 15 , wherein said method is for neuroprotection in a subject suffering from or at risk from a neurodegenerative disorder.  
   
   
       17 . The method of  claim 16 , wherein said neurodegenerative disorder is a movement disorder.  
   
   
       18 . The method of  claim 17 , wherein said movement disorder is selected from the group consisting of Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning, post traumatic Parkinson's disease, 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.  
   
   
       19 . The method of  claim 15 , wherein the subject is human.  
   
   
       20 . A method of treating a disorder in which the blocking of adenosine A 2A  receptors is beneficial selected from the group consisting of: 
 (i) movement disorders;    (ii) acute and chronic pain;    (iii) affective disorders;    (iv) central and peripheral nervous system degenerative disorders;    (v) schizophrenia and related psychoses;    (vi) cognitive disorders;    (vii) attention disorders;    (viii) central nervous system injury;    (ix) cerebral ischaemia;    (x) myocardial ischaemia;    (xi) muscle ischaemia;    (xii) sleep disorders;    (xiii) eye disorders selected from retinal ischaemia-reperfusion injury and diabetic neuropathy;    (xiv) cardiovascular disorders; and    (xv) diabetes and its complications;    the method comprising administering to a subject in need of such treatment an effective dose of a compound of formula (I):                          wherein    R 1  is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7 , and NR 4 SO 2 R 7 ;    R 2  is selected from the group consisting of N, O, or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated ring carbon atom of said heteroaryl group which is adjacent to one or two N, O, or S-heteroatom(s), other than heteroaryl groups substituted at both positions adjacent the point of attachment of the heteroaryl group to the purine moiety;    R 3  is selected from the group consisting of H, alkyl, COR 8 , CONR 9 R 10 , CONR 8 NR 9 R 10 , CO 2 R 11 , and SO 2 R 1 ;    R 4 , R 5 , and R 6  are independently selected from the group consisting of H, alkyl, and aryl, or where R 5  and R 6  are in an (NR 5 R 6 ) group then R 5  and R 6  may be linked to form a heterocyclic ring;    R 7  is alkyl or aryl;    R 8 , R 9 , and R 10  are independently selected from the group consisting of H, alkyl, and aryl, or R 9  and R 10  may be linked to form a heterocyclic ring, or where R 8 , R 9 , and R 10  are in a (CONR 8 NR 9 R 10 ) group, R 8  and R 9  may be linked to form a heterocyclic group; and    R 11  is alkyl or aryl,    or a pharmaceutically acceptable salt thereof.    
   
   
       21 . The method of  claim 20 , wherein the disorder is caused by hyperfunctioning of the adenosine receptors.