Pyrazole Derivatives

Abstract

A compound of the formula (I): wherein R 1 is hydrogen or lower alkyl; R 2 is lower alkyl, etc.; R 3 is lower alkoxy, etc.; R 4 is hydroxy, etc.; X is O, S, etc.; Y is CH or N; Z is lower alkylene or lower alkenylene; and m is 0 or 1; or salts thereof, which are useful as a medicament.

1 . A compound of the formula (I):  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydrogen or lower alkyl;  
 R 2  is lower alkyl optionally substituted with halogen, hydroxy, lower alkoxyimino or lower alkoxy; lower alkenyl; cycloalkyl; cyano; lower alkanoyl; cycloalkylcarbonyl; N,N-di(lower)alkylcarbamoyl; carbamoyl; N-lower alkoxy-N-lower alkylcarbamoyl; amino; di(lower)alkylamino; lower alkoxycarbonylamino; N,N-di(lower)alkylcarbamoylamino; N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen; hydroxy; carboxy; lower alkoxycarbonyl; aroyl; heterocycliccarbonyl; heterocyclic group; lower alkylsulfonyl; lower alkoxy optionally substituted with lower alkoxy, N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy; lower alkylthio; or lower alkylsufinyl;  
 R 3  is lower alkyl optionally substituted with amino, carbamoylamino or lower alkylsulfonylamino; halogen; cyano; hydroxy; lower alkanoyloxy; lower alkylenedioxy; lower alkoxy optionally substituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino; nitro; amino; hetrocyclic group; lower alkylthio; lower alkylsulfinyl; or lower alkylsufonyl;  
 R 4  is hydrogen; cyano; amino optionally substituted with phthaloyl or lower alkyl; aryl; heterocyclic group; lower alkoxy; hydroxy; lower alkylsulfonyloxy; lower alkanoyloxy; lower alkyl substituted with tritylamino and lower alkoxycarbonyl, amino and lower alkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino and hydroxy; N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyl optionally substituted with halogen; carboxy; lower alkylsulfonyl; sulfo; lower alkylsilyloxy; lower alkoxycarbonyl; sulfamoyl optionally substituted with lower alkyl; carbamoyl optionally substituted with lower alkyl; lower alkylthio; lower alkylsulfinyl; carbamoyloxy; thioureido; or 
 a group of the formula:  
   R 5 -G-J-  in which G is —CO— or —SO 2 —; 
 J is —N(R 6 )— 
   
 (wherein R 6  is hydrogen or lower alkyl); and 
 R 5  is amino optionally substituted with lower alkoxycarbonyl or lower alkyl; lower alkyl optionally substituted with hydroxy, lower alkoxycarbonylamino, lower alkanoyloxy, amino or halogen; lower alkoxy; hydrogen; heterocyclic group; or aryl;  
 
 
 X is O, S, SO or SO 2 ;  
 Y is CH or N;  
 Z is lower alkylene or lower alkenylene; and  
 m is 0 or 1;  
 provided that when R 4  is hydrogen;  
 then R 3  is lower alkyl substituted with amino, carbamoylamino or lower alkylsulfonylamino; or lower alkoxy substituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino;  
 or salts thereof.  
 
   
   
       2 . The compound of  claim 1 , wherein 
 R 1  is hydrogen;    R 2  is lower alkyl optionally substituted with halogen, hydroxy, lower alkyoxyimino or lower alkoxy; cycloalkyl; halogen; lower alkoxy optionally substituted with halogen; or lower alkylthio;    R 3  is lower alkoxy optionally substituted with aryl, hydroxy, cyano, amino, lower alkoxyxcarbonylamino, lower alkylsulfonylamino or carbamoylamino;    R 4  is a group of the formula:      R 5 -G-J-  in which R 5 , G and J are each as defined in  claim 1;       X is O or S; and    Z is lower alkylene.    
   
   
       3 . The compound of  claim 2 , wherein 
 R 2  is lower alkyl optionally substituted with halogen; cycloalkyl; halogen; or lower alkoxy optionally substituted with halogen;    R 3  is lower alkoxy;    R 4  is a group of the formula:      R 5 -G-J-  in which G is —CO— or —SO 2 —, 
 J is —NH— and  
   R 5  is amino or lower alkyl; and      X is O.    
   
   
       4 . The compound of  claim 3 , which is 
 N-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)urea,    N-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide,    N-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea,    N-(2-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea,    N-(2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea,    N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea,    N-(2-{4-[3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea,    N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea,    N-(2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)acetamide, or    N-(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea.    
   
   
       5 . A process of preparing a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is hydrogen or lower alkyl;  
 R 2  is lower alkyl optionally substituted with halogen, hydroxy, lower alkoxyimino or lower alkoxy; lower alkenyl; cycloalkyl; cyano; lower alkanoyl; cycloalkylcarbonyl; N,N-di(lower)alkylcarbamoyl; carbamoyl; N-lower alkoxy-N-lower alkylcarbamoyl; amino; di(lower)alkylamino; lower alkoxycarbonylamino; N,N-di(lower)alkylcarbamoylamino; N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen; hydroxy; carboxy; lower alkoxycarbonyl; aroyl; heterocycliccarbonyl; heterocyclic group; lower alkylsulfonyl; lower alkoxy optionally substituted with lower alkoxy, N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy; lower alkylthio; or lower alkylsufinyl;  
 R 3  is lower alkyl optionally substituted with amino, carbamoylamino or lower alkylsulfonylamino; halogen; cyano; hydroxy; lower alkanoyloxy; lower alkylenedioxy; lower alkoxy optionally substituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino; nitro; amino; hetrocyclic group; lower alkylthio; lower alkylsulfinyl; or lower alkylsufonyl;  
 R 4  is hydrogen; cyano; amino optionally substituted with phthaloyl or lower alkyl; aryl; heterocyclic group; lower alkoxy; hydroxy; lower alkylsulfonyloxy; lower alkanoyloxy; lower alkyl substituted with tritylamino and lower alkoxycarbonyl, amino and lower alkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino and hydroxy; N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyl optionally substituted with halogen; carboxy; lower alkylsulfonyl; sulfo; lower alkylsilyloxy; lower alkoxycarbonyl; sulfamoyl optionally substituted with lower alkyl; carbamoyl optionally substituted with lower alkyl; lower alkylthio; lower alkylsulfinyl; carbamoyloxy; thioureido; or 
 a group of the formula:  
   R 5 -G-J-  in which G is —CO— or —SO 2 —; 
 J is —N(R 6 )— 
   
 (wherein R 6  is hydrogen or lower alkyl); and 
 R 5  is amino optionally substituted with lower alkoxycarbonyl or lower alkyl; lower alkyl optionally substituted with hydroxy, lower alkoxycarbonylamino, lower alkanoyloxy, amino or halogen; lower alkoxy; hydrogen; heterocyclic group; or aryl;  
 
 
 X is O, S, SO or SO 2 ;  
 Y is CH or N;  
 Z is lower alkylene or lower alkenylene; and  
 m is 0 or 1;  
 provided that when R 4  is hydrogen;  
 then R 3  is lower alkyl substituted with amino, carbamoylamino or lower alkylsulfonylamino; or lower alkoxy substituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino;  
 or salts thereof,  
 which comprises,  
 1) reacting a compound of the formula:  
                     or its salt with a compound of the formula:                          or its salt in the acidic condition to provide a compound of the formula:                          or its salt, in the above formulas,    R 1 , R 2 , R 3 , R 4 , X, Y, Z and m are each as defined above, or    
 2) reacting a compound of the formula:  
                     
 or its salt with a compound (V) of the formula:  
   R 4 -Z-Q  (V)  
 or its salt to provide a compound of the formula:  
                     
 or its salt, in the above formulas:  
 R 1 , R 2 , R 3 , R 4 , Y and Z are each as defined above,  
 Xa is O or S, and  
 Q is hydroxy or an acid residue.  
 
   
   
       6 . A pharmaceutical composition comprising the compound of  claim 1 , as an active ingredient, in association with a pharmaceutically non-toxic carrier or excipient.  
   
   
       7 . A compound of  claim 1  for use as a medicament  
   
   
       8 . A method for treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegenerative diseases which comprises administering an effective amount of the compound of  claim 1  to human beings or animals.  
   
   
       9 . Use of the compound of  claim 1  for the manufacture of a medicament for treatment and/or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegenerative diseases in human beings or animals.  
   
   
       10 . The analgesic agent comprising the compound of  claim 1 , which is usable for treating and/or preventing pains caused by or associated with acute or chronic inflammations without causing gastrointestinal disorders.  
   
   
       11 . The analgesic agent of  claim 10 , which is usable for treating or preventing pains caused by or associated with rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, gouty arthritis, or juvenile arthritis; lumbago; cervico-omo-brachial syndrome; scapulohumeral periarthritis; pain and tumescence after operation or injury without causing gastrointestinal disorders.  
   
   
       12 . A commercial package comprising the pharmaceutical composition containing the compound (I) identified in  claim 1  and a written matter associated therewith, wherein the written matter states that the compound (I) can or should be used for preventing or treating inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immunity diseases, analgesic, thrombosis, cancer or neurodegenerative diseases.