Pyrazole compound and pharmaceutical use thereof

Abstract

A compound of the following general Formula [Ib]: wherein each symbol is the same as defined in the description; or a pharmaceutically acceptable salt thereof.

1 - 20 . (canceled) 
     
     
         21 : A compound of formula [2b]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; and 
 
 m is 0, 1, 2, 3, or 4. 
 
       
     
     
         22 : A compound of formula [2c]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; 
 
 R 4a  is a C 1-6  alkyl group; and 
 m is 0, 1, 2, 3, or 4. 
 
       
     
     
         23 : A method of preparing a compound of formula [2b]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; and 
 
 m is 0, 1, 2, 3, or 4, 
 
         the method comprising reducing a compound of formula [29]: 
       
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; and 
 
 m is 0, 1, 2, 3, or 4, 
 
         by catalytic hydrogenation in a solvent in the presence of a metal catalyst under a hydrogen atmosphere. 
       
     
     
         24 : The method of  claim 23 , wherein
 the metal catalyst is selected from the group consisting of palladium on carbon, alumina-supported rhodium, Raney nickel, and Adam's catalyst;   the solvent is selected from the group consisting of an alcoholic solvent, an ether solvent, an ester solvent, water, and a mixed solvent of any of the foregoing; and   the catalytic hydrogenation is carried out at a temperature of between about 25° C., and about 80° C.   
     
     
         25 : The method of  claim 23 , wherein the compound of formula [29] or salt thereof is obtained by reacting a compound of formula [28]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; and 
 
 m is 0, 1, 2, 3, or 4, 
 
         with bromine, followed by a base, in a solvent. 
       
     
     
         26 : The method of  claim 25 , wherein
 the base is selected from the group consisting of potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, and triethylamine;   the solvent is selected from the group consisting of a halogenated hydrocarbon solvent and water; and   the reacting is carried out at a temperature of between about 0° C., and about 100° C.   
     
     
         27 : A method of preparing a compound of formula [2c]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; 
 
 R 4a  is a C 1-6  alkyl group; and 
 m is 0, 1, 2, 3, or 4; 
 
         the method comprising removing a group P C3  from a compound of formula [35]: 
       
       
         
           
           
               
               
           
         
         wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; 
 
 R 4a  is a C 1-6  alkyl group; 
 m is 0, 1, 2, 3, or 4; and 
 P 3C  is a protecting group of a carboxy group; 
 
         via a deprotection reaction. 
       
     
     
         28 : The method of  claim 27 , wherein
 the group P 3C  is a tert-butyl group; and   the deprotection reaction comprises the treatment of compound [35] with a solvent under acidic conditions.   
     
     
         29 : The method of  claim 28 , wherein
 the acidic conditions comprise an acid selected from the group consisting of hydrochloric acid, sulfuric acid, and trifluoroacetic acid;   the solvent is selected from the group consisting of an ether solvent, a halogenated hydrocarbon solvent, an ester solvent, an alcoholic solvent, and a mixed solvent of any of the foregoing; and   the deprotection reaction is carried out at a temperature of between about 0° C., and about 80° C.   
     
     
         30 : The method of  claim 27 , wherein the compound of formula [35] is obtained by removing a group P N4  from a compound of formula [34]: 
       
         
           
           
               
               
           
         
         wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; 
 
 R 4a  is a C 1-6  alkyl group; 
 m is 0, 1, 2, 3, or 4; and 
 P 3C  is a protecting group of a carboxy group; and 
 P N4  is a protecting group of an amino group; 
 
         via a deprotection reaction. 
       
     
     
         31 : The method of  claim 30 , wherein
 the group P N4  is a benzyloxycarbonyl group; and   the deprotection reaction comprises reducing the compound of formula [34] by catalytic hydrogenation in a solvent in the presence of a palladium catalyst under a hydrogen atmosphere.   
     
     
         32 : The method of  claim 31 , wherein
 the palladium catalyst is selected from the group consisting of palladium on carbon and palladium (II) hydroxide;   the solvent is selected from the group consisting of an alcoholic solvent, an ether solvent, an ester solvent, and a mixed solvent of any of the foregoing; and   the deprotection reaction is carried out at a temperature of between about 25° C., and about 80° C.   
     
     
         33 : The method of  claim 30 , wherein the compound of formula [34] is obtained by rearranging the group P N4  in a compound of formula [32]: 
       
         
           
           
               
               
           
         
         wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; 
 
 m is 0, 1, 2, 3, or 4; and 
 P 3C  is a protecting group of a carboxy group; and 
 P N44  is a protecting group of an amino group, 
 
         followed by reacting the resulting compound with R 4a -L in a solvent in the presence of a base,
 wherein R 4a  is a C 1-6  alkyl group; and 
 L is a leaving group. 
 
       
     
     
         34 : The method of  claim 33 , wherein
 the base is sodium hydride;   the solvent is selected from the group consisting of an ether solvent, a polar solvent, and a mixed solvent of any of the foregoing; and   the reacting with R 4a -L occurs at a temperature between about 0° C., and about 80° C.   
     
     
         35 : The method of  claim 33 , wherein the compound of formula [32] is obtained by introducing a group P C3  into a carboxy group of a compound of formula [31]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; 
 
 m is 0, 1, 2, 3, or 4; and 
 P N4  is a protecting group of an amino group, 
 
         via a protection reaction. 
       
     
     
         36 : The method of  claim 35 , wherein
 the group P C3  is a tert-butyl group; and   the compound of formula [31] is converted into an acid chloride thereof in a solvent and then reacted with tert-butyl alcohol in the presence of a base.   
     
     
         37 : The method of  claim 36 , wherein
 the acid chloride is obtained by reacting the compound of formula [31] or salt thereof with a reagent selected from the group consisting of thionyl chloride, oxalyl chloride, and phosphorous oxychloride;   the base is selected from the group consisting of an organic amine and an alkali metal carbonate;   the solvent is selected from the group consisting of a hydrocarbon solvent, an ether solvent, a halogenated hydrocarbon solvent, and a mixture of any of the foregoing; and   the conversion into the acid chloride and the reacting with tert-butyl alcohol are carried out at a temperature of between about 0° C., and about 130° C.   
     
     
         38 : The method of  claim 35 , wherein the compound of formula [31] or the salt thereof is obtained by subjecting a compound of formula [30]: 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein
 each carbon with * is optionally substituted with
 (1) a C 1-6  alkyl group or 
 (2) a hydroxy C 1-6  alkyl group; 
 
 m is 0, 1, 2, 3, or 4; and 
 P N4  is a protecting group of an amino group, 
 
         to a Hofmann rearrangement reaction in the presence of a base and bromine, followed by an intramolecular cyclization reaction in a solvent. 
       
     
     
         39 : The method of  claim 38 , wherein
 the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, and sodium methoxide;   the solvent is selected from the group consisting of an alcoholic solvent, an ether solvent, water, and a mixture of any of the foregoing; and   the Hofmann rearrangement reaction is carried out at a temperature of between about −78° C. to about 100° C.