Pharmaceutical agents

Abstract

This invention relates to compounds of formula (1) wherein B is optionally substituted aryl; R 1 and R 2 are the same or different and are independently selected from hydrogen or C 1-3 alkyl; n is 1 or 2, preferably n is 1; m is 0 or 1; R 3 is hydrogen or acyl; R 4 and R 5 are the same or different and are independently selected from amino, alkylamino, dialkylamino, arylamino and C 2 -C 8 cycloalkylamino; X and Y are independently selected from C, H or N provided at least one of X and Y is N; and salts thereof, solvates thereof, pharmaceutically acceptable derivatives thereof, prodrugs thereof, tautomers thereof and/or isomers thereof; and processes for their preparation and methods of treatment, pharmaceutical formulations and uses involving them.

1 . Compounds of formula (1)  
       
         
           
           
               
               
           
         
       
       wherein 
 B is optionally substituted aryl;  
 R 1  and R 2  are the same or different and are independently hydrogen or C 1-3  alkyl;  
 n is 1 or 2;  
 m is 0 or 1;  
 R 3  is hydrogen or acyl;  
 R 4  and R 5  are the same or different and are independently selected from amino, alkylamino, dialkylamino, arylamino and C 2-8  cycloalkylamino;  
 X and Y are independently selected from C H or N provided at least one of X and Y is N;  
 or salts thereof, solvates thereof, pharmaceutically acceptable derivatives thereof, prodrugs thereof, tautomers thereof or isomers thereof.  
 
     
     
         2 . A compound of formula (1) according to  claim 1  wherein B is selected from optionally substituted phenyl, indolyl, thiophenyl, thiazolyl and pyridyl.  
     
     
         3 . A compound of formula (1) according to  claim 2  where B is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       where the arrow indicates the point of attachment.  
     
     
         4 . A compound of formula (1) according to  claim 1  wherein X is CH, and Y is N and m is 0.  
     
     
         5 . A compound of formula (1) according to  claim 1  wherein 
 B is optionally substituted phenyl;    R 1  is hydrogen and R 2  is selected from hydrogen and C 1-3  alkyl;    n is 1;    m is 0 or 1;    R 3  is hydrogen; and    R 4  and R 5  are the same; and    one of X and Y is n and the other is C H    
     
     
         6 . A compound of formula (1) according to  claim 1  wherein 
 B is optionally substituted phenyl;    R 1  and R 2  are hydrogen;    n is 1;    m is 0;    R 4  and R 5  are the same;    X is CH and Y is N.    
     
     
         7 . A method for the prophylatic or therapeutic treatment of one or more disorders related to neuronal damage of the central nervous system comprising administering to a subject in need thereof an effective amount of a compound of formula (1) as claimed in  claim 1 .  
     
     
         8 . The method according to  claim 7  wherein said disorder related to neuronal damage of the central nervous system is associated with acute events leading to ischaemia or other form of hypoxia.  
     
     
         9 . The method according to  claim 8  wherein said acute event is head trauma, stroke, cardiac arrest, ischaemia, hypoxia, hypoglycaemia or epilepsy.  
     
     
         10 . The method according to  claim 7  wherein said disorder related to neuronal damage of the central nervous system is associated with a neurodengenerative disease.  
     
     
         11 . A The method according to  claim 10  wherein said neurodegenerative disorder is Alzheimer's disease, Parkinson's disease or Huntington's disease, lateral amyotropic sclerosis or variants thereof, or schizophrenia.  
     
     
         12 . A method for the prophylactic or therapeutic treatment of one or more disorders related to neuronal damage of the peripheral nervous system comprising administering to a subject in need thereof an effective amount of a compound of formula (1) as claimed in  claim 1 .  
     
     
         13 . The method according to  claim 12  wherein said disorder is neuropathic pain or diabetic perpheral neuropathy.  
     
     
         14 . A method for the prophylactic or therapeutic treatment of one or more conditions related to N-methyl-D-aspartate (NMDA) receptors comprising administering to a subject in need thereof an effective amount of a compound of formula (1) as claimed in  claim 1 .  
     
     
         15 . The method according to  claim 14  wherein said condition is pain, depression, anxiety, migraine, headache, neurogenic bladder, irritative bladder disturbancy, drug dependency or emesis.  
     
     
         16 . A method for the prophylactic or therapeutic treatment of one or more conditions related to sodium channels comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as claimed in  claim 1 .  
     
     
         17 . The method according to  claim 16  wherein said condition is eplilepsy or epileptic psychotic symptoms, hypertension, diabetic peripheral neuropathy, intractable cough, or pain.  
     
     
         18 . (canceled)  
     
     
         19 . A pharmaceutical or veterinary composition comprising a compound of formula (1) as claimed in  claim 1  in association with a pharmaceutically acceptable carrier, diluent, adjuvant and/or excipient.  
     
     
         20 . A process for the preparation of a compound of formula (1) as claimed in  claim 1  where m is 0 comprising: 
 reacting a compound of the formula                          with a compound of the formula (2)                          B is optionally substituted aryl;    R 1  and R 2  are the same or different and are independently hydrogen or C 1-3  alkyl    n is 1 or 2;    R 4  and R 5  are the same or different and are independently selected from amino,    alkylamino, dialkylamino, arylamino and C 2-8  cycloalklamino;    X and Y are independently selected from CH, or N provided at least one of X and Y is N;    and L is a leaving group and Z is a group capable of being converted to hydroxyl.    
     
     
         21 . A process for the preparation of a compound of formula (1) as claimed in  claim 1  wherein m is 1 comprising: 
 (i) reacting a compound of formula                          with a compound of formula (3)                          (ii) reacting product of step (i) with appropriate amine(s) to afford a compound of formula (1) by substitution of Hal, wherein    B is optionally substituted aryl;    R 1  and R 2  are the same or different and are independently hydrogen or C 1-3  alkyl:    n is 1 or 2:    Hal is a halogen or halogen like substituent; and    X and Y are independently selected from CH, or N provided at least one of X and Y is N.    
     
     
         22 . The compound of Formula I selected from compounds Nos. 1-108 in Table 1.  
     
     
         23 . (canceled)  
     
     
         24 . The compound according to  claim 1  wherein n is 1.  
     
     
         25 . A method for the therapeutic treatment of an ischmeic disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         26 . A method for the therapeutic treatment of a disease selected from the group consisting of head trauma, stroke, cardiac arrest, ischemia, hypoxia, hypoglycemia and epilepsy comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to  claim 1.