Adenosine A2a receptor antagonists

Abstract

Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, cycloalkenyl, or heteroaryl; X is alkylene or —C(O)CH 2 —; Y is —N(R 2 )CH 2 CH 2 N(R) 3 )—, —OCH 2 CH 2 N(R 2 )—, —O—, —S—, —CH 2 S—, —(CH 2 ) 2 —NH—, or optionally substituted  m and n are 2-3, and Q is nitrogen or optionally substituted carbon; and Z is optionally substituted phenyl, phenylalkyl or heteroaryl, diphenylmethyl, R 6 —C(O)—, R 6 —SO 2 —, R 6 —OC(O)—, R 7 —N(R 8 )—C(O)—, R 7 —N(R 8 )—C(S)—,  phenyl-CH(OH)—, or phenyl-C(═NOR 2 )—; or when Q is CH, phenylamino or pyridylamino; or Z and Y together are substituted piperidinyl or substituted phenyl; and R 2 , R 3 , R 6 , R 7 , and R 8 are as defined in the specification are disclosed, their use in the treatment of Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them; also disclosed are a processes for preparing intermediates useful for preparing compounds of formula I.

We claim: 
     
       1. A compound having the structural formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R is R 1 -furanyl, R 1 -thienyl, R 1 -pyridyl, R 1 -pyridyl N-oxide, R 1 -oxazolyl, R 10 -phenyl, R 1 -pyrrolyl or C 4 -C 6  cycloalkenyl; 
 X is C 2 -C 6  alkylene or —C(O)CH 2 —; 
 Y is —N(R 2 )CH 2 CH 2 N(R 3 )—, —OCH 2 CH 2 N(R 2 )—, —O—, —S—, —CH 2 S—, —(CH 2 ) 2 —NH—, or 
 
       
         
           
           
               
               
           
         
       
       and
 Z is R 5 -phenyl, R 5 -phenyl(C 1 -C 6 )alkyl, R 5 -heteroaryl, diphenylmethyl, R 6 —C(O)—, R 6 —SO 2 —, R 6 —OC(O)—, R 7 —N(R 8 )—C(O)—, R 7 —N(R 8 )—C(S)—, 
 
       
         
           
           
               
               
           
         
          phenyl-CH(OH)—, or phenyl-C(═NOR 2 )—; or when Q is 
       
       
         
           
           
               
               
           
         
         Z is also phenylamino or pyridylamino; or 
       
       Z and Y together are 
       
         
           
           
               
               
           
         
         R 1  is 1 to 3 substituents independently selected from hydrogen, C 1 -C 6 -alkyl, —CF 3 , halogen, —NO 2 , —NR 12 R 13 , C 1 -C 6  alkoxy, C 1 -C 6  alkylthio, C 1 -C 6  alkylsulfinyl, and C 1 -C 6  alkylsulfonyl; 
         R 2  and R 3  are independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; 
         m and n are independently 2-3; 
         Q is 
       
       
         
           
           
               
               
           
         
         R 1  is 1-2 substituents independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or two R 4  substituents on the same carbon can form ═O; 
         R 5  is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, —CN, di-((C 1 -C 6 )alkyl)amino, —CF 3 , —OCF 3 , acetyl, —NO 2 , hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )alkoxy, di-((C 1 -C 6 )-alkoxy)(C 1 -C 6 )alkoxy, (C 1 -C 6 )-alkoxy(C 1 -C 6 )alkoxy-(C 1 -C 6 )-alkoxy, carboxy(C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkoxy, di-((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkoxy, morpholinyl, (C 1 -C 6 )alkyl-SO 2 -, (C 1 -C 6 )alkyl-SO_-(C 1 -C 6 )alkoxy, tetrahydropyranyloxy, (C 1 -C 6 )alkylcarbonyl(C 1 -C 6 )-alkoxy, (C 1 -C 6 )-alkoxycarbonyl, (C 1 -C 6 )alkylcarbonyloxy(C 1 -C 6 )-alkoxy, —SO 2 NH 2 , phenoxy, 
       
       
         
           
           
               
               
           
         
          or adjacent R 5  substituents together are —O—CH 2 —O—, —O—CH 2 CH 2 —O—, —O—CF 2 —O— or —O—CF 2 CF 2 —O— and form a ring with the carbon atoms to which they are attached; 
         R 6  is (C 1 -C 6 )alkyl, R 5 -phenyl, R 5 -phenyl(C 1 -C 6 )alkyl, thienyl, pyridyl, (C 3 -C 6 )-cycloalkyl, (C 1 -C 6 )alkyl-OC(O)-NH-(C 1 -C 6 )alkyl-, di-((C 1 -C 6 )alkyl)aminomethyl, or 
       
       
         
           
           
               
               
           
         
         R 7  is (C 1 -C 6 )alkyl, R 5 -phenyl or R 5 -phenyl(C 1 -C 6 )alkyl; 
         R 8  is hydrogen or C 1 -C 6  alkyl; or R 7  and R 8  together are —(CH 2 ) p —A—(CH 2 ) q , wherein p and q are independently 2 or 3 and A is a bond, —CH 2 —, —S— or —O—, and form a ring with the nitrogen to which they are attached; 
         R 9  is 1-2 groups independently selected from hydrogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, halogen, —CF 3  and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy; 
         R 10  is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, —CN, —NH 2 , C 1 -C 6 alkylamino, di-((C 1 -C 6 )alkyl)amino, —CF 3 , —OCF 3  and —S(O) 0-2 (C 1 -C 6 )alkyl; 
         R 11  is H, C 1 -C 6  alkyl, phenyl, benzyl, C 2 -C 6  alkenyl, C 1 -C 6  alkoxy(C 1 -C 6 )alkyl, di-((C 1 -C 6 )alkyl)amino(C 1 -C 6 )alkyl, pyrrolidinyl(C 1 -C 6 )alkyl or piperidino(C 1 -C 6 )alkyl; 
         R 12  is H or C 1 -C 6  alkyl; and 
         R 13  is (C 1 -C 6 )alkyl-C(O)- or (C 1 -C 6 )alkyl-SO 2 —; 
       
       wherein heteroaryl is a single ring or benzofused heteroaromatic group, or an N-oxide thereof, of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, provided that the rings do not include adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms. 
     
     
       2. A compound of  claim 1  wherein R is R 1 -furanyl. 
     
     
       3. A compound of  claim 1  wherein X is C 2 -C 6  alkylene. 
     
     
       4. A compound of  claim 1  wherein Y is 
       
         
           
           
               
               
           
         
       
     
     
       5. A compound of  claim 4  wherein Q is 
       
         
           
           
               
               
           
         
       
     
     
       6. A compound of  claim 5  wherein m and n are each 2, and R 4  is H. 
     
     
       7. A compound of  claim 1  wherein Z is R 5 -phenyl, R 5 -heteroaryl, R 6 —C(O)— or R 6 —SO 2 —. 
     
     
       8. A compound of  claim 7  wherein R 5  is H, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkoxy, or R 6  is R 5 -phenyl. 
     
     
       9. A compound of  claim 1  wherein R is R 1 -furanyl, X is C 2 -C 6  alkylene, Y is 
       
         
           
           
               
               
           
         
       
       Q is 
       
         
           
           
               
               
           
         
       
       m and n are each 2, R 4  is H, Z is R 5 -phenyl, R 5 -heteroaryl, R 6 —C(O)— or R 6 —SO 2 —, R 5  is H, halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy(C 1 -C 6 )alkoxy or (C 1 -C 6 )alkoxy (C 1 -C 6 )alkoxy, and R 6  is R 5 -phenyl. 
     
     
       10. A compound of  claim 1  selected from the group consisting of compounds of the formula 
       
         
           
           
               
               
           
         
       
       wherein R and Z—Y are as defined in the following table: 
       
         
           
                 
                 
               
                     
                 
                   Z—Y— 
                   R 
                 
                     
                 
                     
                 
                 
                 
               
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       11. A compound of  claim 1  wherein Z is R 5 -heteroaryl and heteroaryl is selected from the group consisting of pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl, triazolyl, indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl, benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl, or an N-oxide thereof. 
     
     
       12. A compound of  claim 11  wherein heteroaryl is selected from the group consisting of pyridyl, pyridyl N-oxide, thiazolyl, pyrazinyl, pyrimidyl, quinolyl and benzimidazolyl. 
     
     
       13. The compound having the structure 
       
         
           
           
               
               
           
         
       
     
     
       14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  in a pharmaceutically acceptable carrier. 
     
     
       15. A method of treating central nervous system diseases or stroke, comprising administering an effective amount of a compound of formula I claim 1, or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment. 
     
     
       16. A method of  claim 15  for treating depression, cognitive diseases and neurodegenerative diseases. 
     
     
       17. A method of  claim 16  for treating Parkinson's disease, senile dementia or psychoses of organic origin. 
     
     
       18. A pharmaceutical composition of claim 14 wherein said compound has the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       19. The method of claim 15 wherein said compound, or pharmaceutically acceptable salt thereof, is a compound having the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       20. The method of claim 19 wherein said central nervous system disease is Parkinson's disease, senile dementia, or psychoses of organic origin. 
     
     
       21. A pharmaceutically acceptable salt of a compound having the structure: