Hydantoin derivative

Abstract

wherein R1, R2, R3, and R4 are as defined in the claims.

1 . A compound represented by general formula (1) below or a pharmacologically acceptable salt, or a hydrate or a solvate thereof: 
       
         
           
           
               
               
           
         
         (wherein, 
         when R1 and R2 are not both hydrogens, R1 and R2 are independently: 
         1) hydrogen; 
         2) halogen atom; 
         3) an alkyl group comprising one or two carbons that may be substituted with one to five fluorine atoms; or 
         4) an alkoxy group comprising one or two carbons that may be substituted with one to five fluorine atoms; or 
         R1 and R2 bond with each other to form a group represented by the formula below: 
       
       
         
           
           
               
               
           
         
         (wherein each * indicates the position of bonding with the phenyl portion); and
 R3 and R4 are independently a methyl group that may be substituted with one to three fluorine atoms; or 
 R3 and R4, together with a bound carbon atom, form a three- to six-membered carbocyclic ring (wherein, one of the carbon atoms forming the ring may be replaced with an oxygen atom, a sulfur atom, or a methyl-substituted or unsubstituted nitrogen atom). 
 
       
     
     
         2 . The compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1 , wherein R1 and R2 are selected from the combinations below:
 1) R1 is a hydrogen atom or a halogen atom, and R2 is a hydrogen atom, a trifluoromethyl group, or a trifluoromethoxy group (provided that R1 and R2 are not both hydrogen atoms);   2) R1 is a trifluoromethyl group or a trifluoromethoxy group, and R2 is a hydrogen atom or a halogen atom;   3) R1 and R2 bond with each other to form a group represented by the formula below:   
       
         
           
           
               
               
           
         
       
       (wherein, each * indicates the position of bonding with the phenyl portion); and
 R3 and R4 are methyl groups; or 
 R3 and R4, together with a bound carbon atom, form a ring selected from below: 
 
       
         
           
           
               
               
           
         
       
       (wherein * indicates the position of bonding with the imidazolidine-2,4-dione portion). 
     
     
         3 . The compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1 , wherein R1 and R2 are selected from the combinations below:
 1) R1 is a trifluoromethoxy group and R2 is a fluorine atom;   2) R1 is a bromine atom and R2 is a hydrogen atom;   3) R1 is a trifluoromethoxy group and R2 is a fluorine atom;   4) R1 is a fluorine atom and R2 is a trifluoromethoxy group;   5) R1 is a trifluoromethyl group and R2 is a hydrogen atom;   6) R1 is a hydrogen atom and R2 is a trifluoromethoxy group;   7) R1 and R2 bond with each other to form a group represented by the formula below:   
       
         
           
           
               
               
           
         
       
       (wherein each * indicates the position of bonding with the phenyl portion); and
 R3 and R4 are methyl groups; or 
 R3 and R4, together with a bound carbon atom, form a ring selected from below: 
 
       
         
           
           
               
               
           
         
       
       (wherein * indicates the position of bonding with the imidazolidine-2,4-dione portion). 
     
     
         4 . The compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1 , wherein R3 and R4 are methyl groups. 
     
     
         5 . The compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1 , wherein R3 and R4, together with a bound carbon atom, form a ring selected from below: 
       
         
           
           
               
               
           
         
       
       (wherein * indicates the position of bonding with the imidazolidine-2,4-dione portion). 
     
     
         6 . The compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1 , wherein the compound is selected from the group consisting of:
 1-(4-(2-((2-(4-fluoro-3-(trifluoromethoxy)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione;   1-(4-(2-((2-(3-bromophenyl)-4-oxo-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione;   1-(4-(2-((2-(4-fluoro-3-(trifluoromethyl)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione;   1-(4-(2-((2-(3-fluoro-4-(trifluoromethoxy)phenyl)-4-oxo-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione;   1-(4-(2-((2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-4-oxo-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione;   1-(3,5-dimethyl-4-(2-((4-oxo-2-(3-(trifluoromethyl)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl) sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione;   1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione);   1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)phenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione;   1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)phenyl)-8-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione;   5-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)phenyl)-2-oxa-5,7-diazaspiro[3.4]octane-6,8-dione; and   4-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)phenyl)-4,6-diazaspiro[2.4]heptane-5,7-dione.   
     
     
         7 . The compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1 , wherein the compound is 1-(3,5-dimethyl-4-(2-((4-oxo-2-(3-(trifluoromethyl)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl) sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione 
     
     
         8 . The compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1 , wherein the compound is 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione. 
     
     
         9 . The compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1 , wherein the compound is 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)ethyl)phenyl)-1,3-diazaspiro[4.4]nonane-2,4-dione. 
     
     
         10 . A pharmaceutical composition, which comprises the compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1  as an active ingredient. 
     
     
         11 . The pharmaceutical composition of  claim 10 , which is for use in oral administration. 
     
     
         12 . A pharmaceutical composition for activating intracellular cAMP response, which comprises the compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1  as an active ingredient. 
     
     
         13 . A stem cell-mobilizing agent, or an agent for preventing or treating osteoporosis, fracture, adynamic bone disease, achondroplasia, hypochondroplasia, osteomalacia, osteoarthritis, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, which comprises the compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1  as an active ingredient. 
     
     
         14 . A method for prevention or treatment of osteoporosis, fracture, adynamic bone disease, achondronplasia, hypochondroplasia, osteomalacia, osteoarthritis, arthritis, thrombocytopenia, hypoparathyroidism, hyperphosphatemia or tumoral calcinosis, or stem cell mobilization, wherein the method comprises administering a pharmaceutically effective amount of a composition comprising the compound or pharmacologically acceptable salt, or a hydrate or a solvate thereof of  claim 1  to a patient in need of the prevention or treatment of the disease or stem cell mobilization.