N-(3-(4-Substituted-1-piperiding1)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists

Abstract

The present invention provides a method of treatment of a subject suffering from a disease, such as schizophrenia, for which the administration of an NK-3 antagonist is indicated which comprises administering to that subject a therapeutically effective amount of a compound of formula I: wherein, generally, Q is R 1 is benzyl, phenyl, thiophene or imidazolyl optionally substituted with C 1-4 alkyl or halogen, such as methyl, fluorine or bromine; R 2 is hydrogen or C 1-4 alkyl such as methyl; R 3 is phenyl; R 4 is hydrogen; R 5 is hydrogen or C 1-6 alkylcarbonyl such as methylcarbonyl; X is —SO 2 — or —C(O)N(R 2 )SO 2 — where R 2 is preferably hydrogen; Y is a bond, CH 2 or Z 1 where Z 1 is —N(R f )— in which R f is C 1-6 alkylcarbonyl such as ethylcarbonyl; and R 6 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or benzimidazolonyl optionally substituted with one or two groups chosen from C 1-6 alkyl and benzyl, such as methyl, ethyl and benzyl; or a pharmaceutically acceptable salt thereof.

1 - 8 . (canceled)  
   
   
       9 . A compound of the formula I:  
     
       
         
         
             
             
         
       
     
     wherein: 
 Q is  
                     
 R 1  is imidazolyl, which is unsubstituted or substituted with C 1-4 alkyl or halogen;  
 R 2  is hydrogen or C 1-4 alkyl;  
 R 3  is phenyl;  
 R 4  is hydrogen;  
 R 5  is hydrogen or C 1-6 alkylcarbonyl;  
 X is —SO 2 — or —C(O)N(R 2 )SO 2 —;  
 Y is a bond, CH 2  or Z 1  where Z 1  is —N(R f )— in which R f  is C 1-6 alkylcarbonyl; and  
 wherein R 6  is benzimidazolyl, imidazolyl, pyridoimidazolyl, isoxazolyl, oxazolyl, phenyl, pyrazolyl, pyridyl, thiazolyl, imidazothiophenyl, indazolyl, tetrahydropyridoimidazolyl, tetrahydroindazolyl, dihydrothiopyranopyrazolyl, dihydrodioxothiopyranopyrazolyl, dihydropyranopyrazolyl, tetrahydropyridopyrazolyl, or triazolyl; wherein any of which is substituted with from 1 to 5 substituents independently selected from:  
 (a) halo,  
 (b) cyano,  
 (c) —NO 2 ,  
 (d) —CF 3 ,  
 (e) —CHF 2 ,  
 (f) —CH 2 F,  
 (g) —CH 2 OH,  
 (h) —CH 2 OCH 3 ,  
 (i) —(CH 2 ) 1-2 SO 2 —(C 1-2  alkyl)  
 (j) phenyl,  
 (k) C 1-6  alkyl, which is optionally substituted with phenyl, which is optionally substituted with from 1 to 4 substituents independently selected from halo, cyano, —OH, —O—C 1-6  alkyl, —O—C 3-5  cycloalkyl, —CO 2 H, —CO 2 (C 1-6  alkyl), —CF 3 , —OCF 3 , and —SO 2 —(C 1-3  alkyl);  
 (l) —O—C 1-6  alkyl,  
 (m) —C 3-5  cycloalkyl,  
 (n) —CH 2 —(C 3-5  cycloalkyl), and  
 (o) —O—C 3-5  cycloalkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       10 . The compound of  claim 9  wherein: 
 Q is                          R 5  is hydrogen;    R 6  is pyrazole, which is unsubstituted or substituted with with one or two groups chosen from methyl, ethyl and benzyl;    Y is a single bond or CH 2 ;    R 3  is phenyl;    R 4  is hydrogen;    R 2  is hydrogen;    X is —SO 2 — or —C(═O)N(R 2 )SO 2 —; or    R 1  is imidazolyl, which is unsubstituted or substituted with C 1-4 alkyl or halogen; or a pharmaceutically acceptable salt thereof.    
   
   
       11 . The compound of claim  37  wherein R 6  is 1,3-dimethylpyrazol-5-yl or 1-ethyl-3-benzylpyrazol-5yl.  
   
   
       12 . The compound of claim  37  wherein Y is a single bond.  
   
   
       13 . The compound of claim  37  wherein X is —C(═O)N(R 2 )SO 2 — where R 2  is hydrogen.  
   
   
       14 . The compound of claim  37  wherein R 1  is imidazolyl, which is unsubstituted or substituted with methyl.  
   
   
       15 . A compound which is: 
 1-methyl-1H-imidazole-4-sulfonic acid {3-[4-(2-ethyl-5-methyl-2H-pyrazol-3-yl)-piperidin-1-yl]-1-phenylpropyl}amide;    or a pharmaceutically acceptable salt thereof.    
   
   
       16 . A pharmaceutical composition comprising the compound of  claim 9  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.  
   
   
       17 . A method for treating schizophrenia in a human patient in need thereof which comprises administering to the patient an effective amount of the compound of  claim 9  or a pharmaceutically acceptable salt thereof.