Novel substituted xanthine derivatives

Abstract

The present invention relates to compounds of formula Ia process for their manufacture, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment of conditions having an association with TRPC5 containing ion channels. R1, R2, R3, R4 and R5 have meanings given in the description.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents ethyl, isopropyl, isobutyl, cyclobutyl; 
         R 2  represents 
       
       
         
           
           
               
               
           
         
         R 3  represents hydrogen, fluoro, C 1 -C 3 -alkyl optionally substituted with one or more fluorine atoms; 
         R 4  represents hydrogen or fluoro; 
         R 5  represents 
       
       
         
           
           
               
               
           
         
         which groups are optionally substituted with one or more fluorine atoms and/or one or more C 1 -C 3 -alkyl fluorinated with one or more fluorine atoms. 
       
     
     
         2 . The compound according to  claim 1  wherein
 R 1  represents ethyl, isopropyl, isobutyl, cyclobutyl; 
 R 2  represents 
 
       
         
           
           
               
               
           
         
         R 3  represents hydrogen, fluoro, methyl, ethyl, —CF 3 ; 
         R 4  represents hydrogen or fluoro; 
         R 5  represents 
       
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound according to  claim 1 , namely a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . A pharmaceutically acceptable salt of the compound according to  claim 1 . 
     
     
         5 . (canceled) 
     
     
         6 . A pharmaceutical composition comprising the compound according to  claim 1 . 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . A method for treating a TRPC5 mediated disorder in a subject, the method comprising administering to the subject an effective amount of the compound of  claim 1 . 
     
     
         10 . The method according to  claim 9 , wherein the TRPC5 mediated disorder is a psychiatric, neurological or neurodegenerative condition. 
     
     
         11 . The method according to  claim 10 , wherein the psychiatric, neurological or neurodegenerative condition is selected from the group consisting of diseases associated with dysregulated emotional processing (e.g. borderline personality disorder or depressive disorders like major depression, major depressive disorder, psychiatric depression, dysthymia, and postpartum depression, and bipolar disorders), anxiety and fear-related disorders (e.g. post-traumatic stress disorder, panic disorder, agoraphobia, social phobias, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive compulsive disorder, and separation anxiety), memory disorders (e.g. Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleeping disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke, and Wernicke-Korsakoff syndrome), disorders associated with impaired impulse control and addiction as well as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and other brain disorders caused by trauma or other insults including aging. 
     
     
         12 . The method according to  claim 9 , wherein for the compound of formula (I):
 R 1  represents ethyl, isopropyl, isobutyl, cyclobutyl;   R 2  represents   
       
         
           
           
               
               
           
         
         R 3  represents hydrogen, fluoro, methyl, ethyl, —CF 3 ; 
         R 4  represents hydrogen or fluoro; 
         R 5  represents 
       
       
         
           
           
               
               
           
         
       
     
     
         13 . The method according to  claim 9 , wherein the compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A method for treating a TRPC5 mediated disorder in a subject, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt of the compound according to formula (I): 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents ethyl, isopropyl, isobutyl, cyclobutyl; 
         R 2  represents 
       
       
         
           
           
               
               
           
         
         R 3  represents hydrogen, fluoro, C 1 -C 3 -alkyl optionally substituted with one or more fluorine atoms; 
         R 4  represents hydrogen or fluoro; 
         R 5  represents 
       
       
         
           
           
               
               
           
         
         which groups are optionally substituted with one or more fluorine atoms and/or one or more C 1 -C 3 -alkyl fluorinated with one or more fluorine atoms. 
       
     
     
         15 . The method of  claim 14 , wherein the pharmaceutically acceptable salt is a salt of a compound of formula (I) wherein:
 R 1  represents ethyl, isopropyl, isobutyl, cyclobutyl;   R 2  represents   
       
         
           
           
               
               
           
         
         R 3  represents hydrogen, fluoro, methyl, ethyl, —CF 3 ; 
         R 4  represents hydrogen or fluoro; 
         R 5  represents 
       
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 14 , wherein the pharmaceutically acceptable salt is a salt of a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The method according to  claim 14 , wherein the TRPC5 mediated disorder is a psychiatric, neurological or neurodegenerative condition. 
     
     
         18 . The method according to  claim 17 , wherein the psychiatric, neurological or neurodegenerative condition is selected from the group consisting of diseases associated with dysregulated emotional processing (e.g. borderline personality disorder or depressive disorders like major depression, major depressive disorder, psychiatric depression, dysthymia, and postpartum depression, and bipolar disorders), anxiety and fear-related disorders (e.g. post-traumatic stress disorder, panic disorder, agoraphobia, social phobias, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive compulsive disorder, and separation anxiety), memory disorders (e.g. Alzheimer's disease, amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleeping disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke, and Wernicke-Korsakoff syndrome), disorders associated with impaired impulse control and addiction as well as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and other brain disorders caused by trauma or other insults including aging.