Pyrimidine Derivatives And Their Use As CB2 Modulators

Abstract

This relates to novel pyrimidine derivatives, pharmaceutical compositions containing these compounds and their use in the treatment of diseases, particularly pain, which diseases are caused directly or indirectly by an increase or decrease in activity of the cannabinoid receptor.

1 . A compound of formula (I): 
     
       
         
         
             
             
         
       
       wherein: 
       Y is phenyl, optionally substituted with one, two or three substituents; 
       R 1  is selected from hydrogen, C 1-6  alkyl C 3-6  cycloalkyl and halosubstitutedC 1-6  alkyl; 
       R 2  is (CH 2 ) m R 3  where m is 0 or 1; 
       or R 1  and R 2  together with N to which they are attached form an optionally substituted 4- to 8-membered non-aromatic heterocyclyl ring; 
       R 3  is an optionally substituted 4- to 8-membered non-aromatic heterocyclyl group, an optionally substituted C 3-8  cycloalkyl group, an optionally substituted straight or branched C 1-10  alkyl a C 5-7  cycloalkenyl or R 5 ; 
       R 4  is selected from hydrogen, C 1-6  alkyl C 3-6  cycloalkyl, or halosubstitutedC 1-6  alkyl COCH 3 , and SO 2 Me; 
       R 5  is 
     
     
       
         
         
             
             
         
       
       wherein p is 0, 1 or 2 and X is CH 2  or O; 
       R 6  is methyl, chloro or CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to 3; 
       R 7  is OH, C 1-6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ; 
       R 8a  is H or C 1-6 alkyl; 
       R 8b  is H or C 1-6 alkyl; 
       R 9  is C 1-6 alkyl; 
       q is 0, 1 or 2; 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       2 . A compound as claimed in  claim 1  wherein Y is a substituted phenyl. 
   
   
       3 . A compound of formula (Ia): 
     
       
         
         
             
             
         
       
       wherein: 
       R 1  is selected from hydrogen, C 1-6  alkyl, C 3-6  cycloalkyl and halosubstitutedC 1-6  alkyl; 
       R 2  is (CH 2 ) m R 3  where m is 0 or 1; 
       or R 1  and R 2  together with N to which they are attached form a 4- to 8-membered non-aromatic ring selected from azetidinyl, pyrrolidinyl, morpholinyl, piperizinyl, piperidinyl, tetrahydropyridinyl, azapine, oxapine, azacyclooctanyl, azaoxacyclooctanyl and azathiacyclooctanyl any of which can be unsubstituted or substituted by one, two or three substituents selected from C 1-6  alkyl, C 1-6  alkoxy, a hydroxy group, a cyano group, halo, sulfonyl group, methylsulfonyl, NR 8a R 8b  NHCOCH 3 , (═O), and —CONHCH 3 . 
       R 3  is 2- or 3-azetidinyl, oxetanyl, thioxetanyl, thioxetanyl-s-oxide, thioxetanyl-s,s-dioxide, dioxalanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiomorpholinyl, thiomorpholinyl-s,s-dioxide, tetrahydropyridinyl, azapine, oxapine, azacyclooctanyl, azaoxacyclooctanyl, azathiacyclooctanyl, oxacylcooctanyl, thiacyclooctanyl, a C 3-8  cycloalkyl group, a straight or branched C 1-10  alkyl, a C 5-7  cycloalkenyl or R 5 , any of which can be unsubstituted or substituted by one, two or three substituents selected from C 1-6  alkyl, C 1-6  alkoxy, a hydroxy group, a cyano group, halo, sulfonyl group, methylsulfonyl, NR 8a R 8b , NHCOCH 3 , (═O), and —CONHCH 3 ; 
       R 10  is selected from C 1-6  alkyl, halosubstitutedC 1-6  alkyl, C 1-6  alkoxy, a hydroxy group, a cyano group, halo, a C 1-6 alkyl sulfonyl group, —CONH 2 , —NHCOCH 3 , —COOH, halosubstitutedC 1-6  alkoxy, SC 1-6 alkyl and SO 2 NR 8a R 8b ; 
       R 4  is selected from hydrogen, C 1-6  alkyl, C 3-6  cycloalkyl, or halosubstitutedC 1-6  alkyl, COCH 3 , and SO 2 Me; 
       R 5  is 
     
     
       
         
         
             
             
         
       
       wherein p is 0, 1 or 2 and X is CH 2  or O; 
       R 6  is methyl, chloro or CHxFn wherein n is 1, 2, or 3, x is 0, 1 or 2 and n and x add up to 3; 
       R 7  is OH, C 1-6 alkoxy, NR 8a R 8b , NHCOR 9 , NHSO 2 R 9 , SOqR 9 ; 
       R 8a  is H or C 1-6 alkyl; 
       R 8b  is H or C 1-6 alkyl; 
       R 9  is C 1-6 alkyl; 
       q is 0, 1 or 2; 
       d is 0, 1, 2 or 3 
       or a pharmaceutically acceptable salt thereof. 
     
   
   
       4 . A compound as claimed in  claim 1  wherein R 4  is C 1-6 alkyl or hydrogen. 
   
   
       5 . A compound as claimed in  claim 1  wherein R 6  is CF 3 . 
   
   
       6 . A compound as claimed in  claim 1  selected from any one of Examples 1 to 265 or a pharmaceutically acceptable derivative thereof. 
   
   
       7 . A compound as claimed in  claim 1  in nanoparticulate form. 
   
   
       8 . A pharmaceutical composition comprising a compound as claimed in  claim 1 . 
   
   
       9 . A pharmaceutical composition as claimed in  claim 8  further comprising a pharmaceutical carrier or diluent thereof. 
   
   
       10 . A method of treating a human suffering from a condition which is mediated by the activity of cannabinoid 2 receptors which comprises administering to said subject a therapeutically effective amount of a compound as claimed in  claim 1 . 
   
   
       11 . A method of treatment as claimed in  claim 10  wherein the condition is an immune disorder, an inflammatory disorder, pain, rheumatoid arthritis, multiple sclerosis, osteoarthritis or osteoporosis. 
   
   
       12 . The method as claimed in  claim 10 , wherein said animal is a human.