Thiazolopyrimidines and their use as modulators of chemokine receptor activity

Abstract

The invention provides certain thiazolopyrimidine compounds of formula (I) or a pharmaceutically acceptable salt or solvate there: in which: A is a group of formula (a) or (b): processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.

1 . A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:  
     
       
         
         
             
             
         
       
     
     in which:  
     A is a group of formula (a) or (b):  
     
       
         
         
             
             
         
       
     
     R 1  represents a C 3 -C 7  carbocyclic, C 1 -C 8  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl group, each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , an aryl or heteroaryl group, which last two may themselves be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1 -C 6  alkyl or trifluoromethyl groups;  
     R 2  and R 3  each independently represent a hydrogen atom, or a C 3 -C 7  carbocyclic,  
     C 1 -C 8  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl group, the latter four groups may be optionally substituted by one or more substituent groups independently selected from:  
     (a) halogen atoms, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 ;  
     (b) a 3-8 membered ring optionally containing one or more atoms selected from O, S, NR 8  and itself optionally substituted by C 1 -C 3 -alkyl or halogen; or  
     (c) an aryl group or heteroaryl group each of which may be optionally substituted by one or more substituents independently selected from halogen atoms, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —NR 8 SO 2 R 9 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1 -C 6  alkyl and trifluoromethyl groups;  
     R 4  represents hydrogen, C 1 -C 6  alkyl or a phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 11  and —NR 12 R 13    
     R 5  and R 6  independently represent a hydrogen atom or a C 1 -C 6  alkyl or phenyl group the latter two of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 14  and —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SONR 15 R 16 , NR 15 SO 2 R 16    
     or  
     R 5  and R 6  together with the nitrogen atom to which they are attached form a 4-to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, —OR 14 , —COOR 14 , —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —SONR 15 R 16 , NR 15 SO 2 R 16  or C 1 -C 6  alkyl, itself optionally substituted by one or more substituents independently selected from halogen atoms and —NR 15 R 16  and —OR 17  groups;  
     R 10  represents a C 1 -C 6 -alkyl or a phenyl group, either of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, —OR 17  and —NR 15 R 16 ,  
     X is CH or CCN,  
     Y is N or CR 18 , and  
     each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17  and R 18  independently represents a hydrogen atom or a C 1 -C 6 , alkyl, or a phenyl group.  
   
   
       2 . A compound according to  claim 1 , wherein R represents an optionally substituted benzyl group.  
   
   
       3 . A compound according to claim I or  claim 2 , wherein one of R 2  and R 3  is hydrogen and the other is C 1 - C 8  alkyl substituted by hydroxy and one or more methyl or ethyl groups.  
   
   
       4 . A compound according to any one of  claims 1  to  3  in which A is a group of formula (a).  
   
   
       5 . A compound according to any one of  claims 1  to  3  in which A is a group of formula (b).  
   
   
       6 . A compound according to  claim 5  in which X is CH and Y is N.  
   
   
       7 . A compound according to  claim 1  selected from:  
     -[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-thiazolo[4,5-d]pyrimidine-2(3H)-thione,  
     2-[[(2,3-difluorophenyl)methyl]thio]4[[(1R)-2-hydroxy-1-methylethyl]amino]-7(8H)-pteridinethione,  
     and pharmaceutically acceptable salts thereof.  
   
   
       8 . A process for the preparation of a compound of formula (I) which comprises:  
     (a) treatment of a compound of formula (IIA):  
     
       
         
         
             
             
         
       
     
     where R 1 , R 2  and R 3  are as defined in formula (I) or are protected derivatives thereof and L is a leaving group with a metal hydrosulphide, or  
     (b) treatment of a compound of formula (IIB):  
     
       
         
         
             
             
         
       
     
     where R 1 , R 2  and R 3  are as defined in formula (I) or are protected derivatives thereof with a thiating agent, and optionally thereafter process (a) or (b) and in any order: 
 removing any protecting groups  
 forming a pharmaceutically acceptable salt.  
 
   
   
       9 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of  claims 1  to  7  in association with a pharmaceutically acceptable adjuvant, diluent or carrier.  
   
   
       10 . A process for the preparation of a pharmaceutical composition as claimed in  claim 9  which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of  claims 1  to  7  with a pharmaceutically acceptable adjuvant, diluent or carrier.  
   
   
       11 . A compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of  claims 1  to  7  for use in therapy.  
   
   
       12 . Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of  claims 1  to  7  in the manufacture of a medicament for use in therapy.  
   
   
       13 . A method of treating a chemokine mediated disease wherein the chemokine binds to one or more chemokine, receptors, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of  claims 1  to  7 .  
   
   
       14 . A method according to  claim 13  in which the chemokine receptor belongs to the CXC chemokine receptor subfamily.  
   
   
       15 . A method according to  claim 13  or  14  in which the chemokine receptor is the CXCR2 receptor.  
   
   
       16 . A method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of  claims 1  to  7 .  
   
   
       17 . A method according to  claim 16 , wherein the disease is psoriasis, rheumatoid arthritis or COPD.  
   
   
       18 . A method according to  claim 16 , wherein the disease is rheumatoid arthritis.