5,7-disubstituted thiazolo[4,5-d]pyrimidines for the selective inhibition of chemokine receptors

Abstract

There are disclosed novel 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one derivatives of formula (I) wherein R 1 , R 2 , R 3 , R 4 and n are as defined in the specification, and pharmaceutically acceptable salts thereof, together with processes for their preparation, pharmaceutical compositions comprising them and their use in therapy. The compounds of formula (I) are CX 3 CR1 receptor antagonists and are thereby particularly useful in the treatment or prophylaxis of neurodegenerative disorders, demyelinating disease, cardio- and cerebrovascular atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis, pulmonary diseases such as COPD, asthma or pain.

1 - 20 . (canceled) 
     
     
         21 . A method of treating, or reducing the risk of neurodegenerative disorders, demyelinating disease, cardio- and cerebrovascular atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis, pulmonary diseases such as COPD, asthma or pain, comprising administering to a person suffering from or susceptible to such a disease or condition, a therapeutically effective amount of a compound of formula (I), 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is CH 3  or CF 3 ; 
 R 2  is halo, CN or C 1-6 alkyl; 
 R 3  is H or CH 3 ; 
 R 4  is H or CH 3 ; and 
 n is 0, 1 or 2, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         22 . A method of treating, or reducing the risk of multiple sclerosis, comprising administering to a person suffering from or susceptible to such a disease or condition, a therapeutically effective amount of a compound of formula (I), 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is CH 3  or CF 3 ; 
 R 2  is halo, CN or C 1-6 alkyl; 
 R 3  is H or CH 3 ; 
 R 4  is H or CH 3 ; and 
 n is 0, 1 or 2, 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         23 . A process for the preparation of a compound of formula (I), as defined in  claim 21 , or a pharmaceutically acceptable salt thereof, comprising:
 a) reacting a compound of formula (II):   
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  are as defined in formula (I); 
         with a compound of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and n are as defined in formula (I) and L 1  represents a leaving group; and 
         where necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting the resultant compound of formula (I) into a further compound of formula (I); and where desired converting the resultant compound of formula (I) into an optical isomer thereof. 
       
     
     
         24 . A process for the preparation of a compound of formula (I), as defined in  claim 21 , or a pharmaceutically acceptable salt thereof, comprising:
 a) hydrolysing a compound of formula (IV)   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4  and n are as defined in formula (I); and 
         where necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting the resultant compound of formula (I) into a further compound of formula (I); and where desired converting the resultant compound of formula (I) into an optical isomer thereof. 
       
     
     
         25 . A method of treating, or reducing the risk of multiple sclerosis, comprising administering to a person suffering from or susceptible to such a disease or condition, a pharmaceutical composition comprising a compound of formula (I), as defined in  claim 22 , as a free base or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier. 
     
     
         26 . A method of treating, or reducing the risk of multiple sclerosis, comprising administering to a person suffering from or susceptible to such a disease or condition, a therapeutically effective amount of a compound that is 5-{[(1S)-1-(5-chloropyridin-2-yl)ethyl]thio}-7-{[(1R)-1(hydroxymethyl)-3-methylbutyl]amino}[1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . A method of treating, or reducing the risk of multiple sclerosis, comprising administering to a person suffering from or susceptible to such a disease or condition, a pharmaceutical composition comprising a compound according to  claim 26 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier.