2-Aminocarbonyl-9H-purine derivatives

Abstract

The present invention relates to compounds of the formula: and pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such compounds.

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein  
       R 1  is H, C 1 -C 6  alkyl or fluorenyl, said C 1 -C 6  alkyl being optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo or cyano;  
       (A) R 2  is H or C 1 -C 6  alkyl, R 15  is H or C 1 -C 6  alkyl, and X is either (i) unbranched C 2 -C 3  alkylene optionally substituted by C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl, or (ii) a group of the formula:  
         —(CH 2 ) n —W—(CH 2 ) p — 
       where W is C 5 -C 7  cycloalkylene optionally substituted by C 1 -C 6  alkyl, n is 0 or 1 and p is 0 or 1, or  
       (B) R 15  is H or —C 1 -C 6  alkyl, and R 2  and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C 1 -C 6  alkyl, or  
       (C)R 2  is H or C 1 -C 6  alkyl, and R 15  and X, taken together with the nitrogen atom to which they are attached, represent azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C 1 -C 6  alkyl;  
       either, R 3  and R 4 , taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl or homopiperazinyl, each being optionally substituted on a ring nitrogen or carbon atom by C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by —NR 6 R 7 ,  
       or, R 3  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or benzyl and R 4  is  
       (a) azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, benzyl or het, or  
       (b) —(C 2 -C 6  alkylene)-R 8 ,  
       (c) —(C 1 -C 6  alkylene)-R 13 , or  
       (d) C 1 -C 6  alkyl or C 3 -C 8  cycloalkyl;  
       R 5  is CH 2 OH or CONR 14 R 14 ;  
       R 6  and R 7  are either each independently H or C 1 -C 6  alkyl or, taken together with the nitrogen atom to which they are attached, represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl, pyrrolidinyl and piperidinyl being optionally substituted by C 1 -C 6  alkyl;  
       R 8  is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-yl or tetrahydroisoquinolin-1-yl, each being optionally substituted on a ring carbon atom by C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, C 1 -C 6  alkoxy-(C 1 -C 6 )-alkyl, R 9 R 9 N—(C 1 -C 6 )-alkyl, fluoro-(C 1 -C 6 )-alkyl, —CONR 9 R 9 , —COOR 9  or C 2 -C 5  alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C 1 -C 6 )-alkoxy, halo, —OR 9 , cyano, —S(O) m R 10 , —NR 9 R 9 , —SO 2 NR 9 R 9 , —NR 9 COR 10  or —NR 9 SO 2 R 10 , and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to the C 2 -C 6  alkylene group by C 1 -C 6  alkyl, phenyl, C 1 -C 6  alkoxy-(C 2 -C 6 )-alkyl, R 9 R 9 N—(C 2 -C 6 )-alkyl, fluoro-(C 1 -C 6 )-alkyl, C 2 -C 5  alkanoyl, —COOR 10 , C 3 -C 8  cycloalkyl, —SO 2 R 10 , —SO 2 NR 9 R 9  or —CONR 9 R 9 , or (ii) NR 11 R 12 ;  
       R 9  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
       R 10  is C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or phenyl;  
       R 11  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl or benzyl;  
       R 12  is H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, benzyl, fluoro-(C 1 -C 6 )-alkyl, —CONR 9 R 9 , —COOR 10 , C 2 -C 5  alkanoyl or —SO 2 NR 9 R 9 ;  
       R 13  is (a) phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each being optionally substituted by C 1 -C 6  alkyl, C 1 -C 6  alkoxy, —(C 1 -C 3  alkylene)-(C 1 -C 6  alkoxy), halo, cyano, —(C 1 -C 3  alkylene)-CN, —CO 2 H, —(C 1 -C 3  alkylene)-CO 2 H, —CO 2 (C 1 -C 6  alkyl), —(C 1 -C 3  alkylene)-CO 2 (C 1 -C 6  alkyl), —(C 1 -C 3  alkylene)-NR 14 R 14 , —CONR 14 R 4  or —(C 1 -C 3  alkylene)-CONR 14 R 14 , or (b) azetidin-2-yl, azetidin-3-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, homopiperidin-2-yl, homopiperidin-3-yl or homopiperidin-4-yl, each being optionally substituted by C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, phenyl, benzyl or het;  
       R 14  is H or C 1 -C 6  alkyl optionally substituted by cyclopropyl;  
       m is 0, 1 or 2;  
       Y is CO, CS, SO 2  or C═N(CN); and  
       “het”, used in the definition of R 4  and R 3 , is a C-linked, 4- to 6-membered ring, heterocycle having either from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen or 1 sulphur ring heteroatom, optionally substituted by C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 6  alkoxy, C 3 -C 8  cycloalkoxy, hydroxy, oxo or halo.  
     
   
   
       2 - 44 . (canceled)  
   
   
       45 . A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, diluent or carrier.  
   
   
       46 - 56 . (canceled)  
   
   
       57 . A method of agonising an A2a receptor in a mammal, comprising administering to said mammal in need thereof an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       58 . A method of treating an inflammatory disease in a mammal, comprising administering to said mammal in need of such treatment an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       59 . A method of treating a respiratory disease in mammal, comprising administering to said mammal in need of such treatment an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       60 . The method of  claim 59  where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis.  
   
   
       61 . A method of treating septic shock, male erectile dysfunction, male factor infertility, female factor infertility, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease,  Helicobacter pylori  gastritis, non- Helicobacter pylori  gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing, in a mammal comprising administering to said mammal in need of such treatment with an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       62 - 78 . (canceled)