5-hydroxy-benzothiazole derivatives having beta-2-adrenoreceptor agonist activity

Abstract

Compounds of formula (I) in free or salt or solvate form, wherein T has the meaning as indicated in the specification, are useful for treating conditions that are prevented or alleviated by activation of the β 2 -adrenoreceptor. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         in free or salt or solvate form, where 
         T is hydrogen or C 1 -C 10 -alkyl optionally substituted at one, two or three positions by C 1 -C 10 -alkoxy, —NR 1 R 2 , a 5- or 6-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, or by a C 3 -C 15 -carbocyclic group, said C 3 -C 15 -carbocyclic group being optionally substituted at one, two or three positions by halo, C 1 -C 10 -alkyl, C 3 -C 10 -cycloalkyl, halo-C 1 -C 10 -alkyl, —NR 3 R 4 , a 5- or 6-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, or by C 1 -C 10 -alkoxy optionally substituted at one, two or three positions by C 6 -C 10 -aryl; 
         or T is a C 3 -C 15 -carbocyclic group optionally substituted at one, two or three positions by halo, C 1 -C 10 -alkyl, C 3 -C 10 -cycloalkyl, halo-C 1 -C 10 -alkyl, —NR 5 R 6 , a 5- or 6-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur, or by C 1 -C 10 -alkoxy optionally substituted at one, two or three positions by C 1 -C 4 -alkyl or C 6 -C 10 -aryl; and 
         R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently hydrogen, C 1 -C 10 -alkyl, C 1 -C 10 -alkoxy, C 3 -C 10 -cycloalkyl or C 6 -C 10 -aryl. 
       
     
     
         2 . A compound according to  claim 1 , where
 T is C 1 -C 10 -alkyl optionally substituted at one, two or three positions by —NR 1 R 2  or a C 5 -C 15 -carbocyclic group, said C 5 -C 15 -carbocyclic group being optionally substituted at one, two or three positions by halo, —NR 3 R 4  or C 1 -C 10 -alkoxy;   or T is a C 5 -C 15 -carbocyclic group optionally substituted at one, two or three positions by C 1 -C 10 -alkyl, C 3 -C 10 -cycloalkyl, —NR 5 R 6  or by C 1 -C 10 -alkoxy optionally substituted at one, two or three positions by C 6 -C 10 -aryl; and   R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently C 1 -C 10 -alkyl or C 6 -C 10 -aryl.   
     
     
         3 . A compound according to  claim 1 , where
 T is C 1 -C 8 -alkyl optionally substituted at one position by —NR 1 R 2  or a C 5 -C 10 -carbocyclic group, said C 5 -C 10 -carbocyclic group being optionally substituted at one or two positions by halo, —NR 3 R 4  or C 1 -C 4 -alkoxy;   or T is a C 5 -C 10 -carbocyclic group optionally substituted at one or two positions by C 1 -C 8 -alkyl, C 3 -C 10 -cycloalkyl, —NR 5 R 6  or by C 1 -C 4 -alkoxy optionally substituted at one position by C 6 -C 8 -aryl, especially phenyl; and   R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently C 1 -C 4 -alkyl or C 6 -C 8 -aryl, especially phenyl.   
     
     
         4 . A compound according to  claim 1  that is also a compound of formula XI 
       
         
           
           
               
               
           
         
         wherein T is as shown in the following table. 
       
       
         
           
                 
               
                     
                 
                   T 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         5 . A compound according to  claim 1  for use as a pharmaceutical. 
     
     
         6 . A compound according to  claim 1  in combination with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound and said drug substance being in the same or different pharmaceutical composition. 
     
     
         7 . A pharmaceutical composition comprising a compound according to  claim 1 , optionally together with a pharmaceutically acceptable carrier. 
     
     
         8 . Use of a compound according to  claim 1  for the preparation of a medicament for the treatment of a condition which is prevented or alleviated by activation of the β 2 -adrenoreceptor. 
     
     
         9 . Use of a compound according to  claim 8  wherein the condition is an obstructive or inflammatory airways disease. 
     
     
         10 . A process for the preparation of a compound of formula I as claimed in  claim 1  in free or salt or solvate form comprising:
 (I) (A) reacting a compound of formula II 
 
       
         
           
           
               
               
           
         
         
           where R a  and R b  are protecting groups and R c  is C 1 -C 4 -alkyl or C 6 -C 10 -aryl, with a compound of formula III
   H 2 N-T  III
 
 
           where T is as defined in  claim 1 ; or 
           (B) reacting a compound of formula IIA 
         
       
       
         
           
           
               
               
           
         
         
           where R a  and R b  are protecting groups, with a compound of formula III, where T is as defined in  claim 1 ; 
         
         (ii) removing the protecting groups; and 
         (iii) recovering the resultant compound of formula I in free or salt or solvate form. 
       
     
     
         11 . A compound of formula II 
       
         
           
           
               
               
           
         
         where R a  and R b  are protecting groups and R c  is C 1 -C 4 -alkyl or C 6 -C 10 -aryl. 
       
     
     
         12 . A compound of formula IIA 
       
         
           
           
               
               
           
         
         where R a  and R b  are protecting groups. 
       
     
     
         13 . A pharmaceutical composition comprising a compound according to  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         14 . A pharmaceutical composition according to  claim 5  further comprising an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance. 
     
     
         15 . A method of treating a condition which is prevented or alleviated by activation of the β 2 -adrenoreceptor in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I according to  claim 1  in free or salt or solvate form. 
     
     
         16 . A method of treating an obstructive or inflammatory airways disease in a subject in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I according to  claim 1  in free or salt or solvate form.