Inflammatory cytokine release inhibitor

Abstract

A medicament having inhibitory activity against NF-κB activation, which comprises a compound represented by the following general formula (I) or a pharmacologically acceptable salt as an active ingredient: wherein X represents a connecting group, A represents hydrogen atom or acetyl group, E represents an aryl group or a heteroaryl group, and ring X represents an arene or a heteroarene.

What is claimed is:  
     
         1 . A method for inhibiting activation of NF-κB, for inhibiting production and release of an inflammatory cytokine or of immune inhibition which comprises administering to a mammal an effective amount for inhibiting activation of NF-κB, for inhibiting production and release of an inflammatory cytokine or for immuno suppression of at least one compound represented by the following formula (I), a pharmacologically acceptable salt, a hydrate, and a solvate thereof:  
       
         
           
           
               
               
           
         
       
       wherein X represents a group represented by the following formula:  
       
         
           
           
               
               
           
         
       
       wherein a bond at the left end binds to ring Z and a bond at the right end binds to E, 
 A represents a hydrogen atom or an acetyl group,  
 E represents an aryl group which may be substituted or a heteroaryl group which may be substituted, ring Z represents an arene which may be substituted in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined above and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined above, or ring Z represents a heteroarene which may be substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined above and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined above, provided that the compounds represented by the following (1) and (2) are excluded:  
 (1) the compounds represented by the aforementioned formula (I) wherein  
 X is a group represented by the following formula:  
                     
 wherein the bond at the left end binds to ring Z and the bond at the right end binds to E,  
 A is a hydrogen atom,  
 E is a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group or a 3-methoxy-5-(trifluoromethyl)phenyl group, ring Z represents a benzene ring which may further have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined above and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined above; and  
 (2) the compounds represented by the aforementioned formula (I), wherein  
 X is a group represented by the following formula:  
                     
 wherein the bond at the left end binds to ring Z and the bond at the right end binds to E,  
 A is a hydrogen atom or an acetyl group,  
 E is a 2,5-bis(trifluoromethyl)phenyl group, a 2-fluoro-5-(trifluoromethyl)phenyl group, a 2-chloro-5-(trifluoromethyl)phenyl group, a 2-nitro-5-(trifluoromethyl)phenyl group, a 2-methyl-5-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, a 2-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, a 2-(1-pyrrolizine)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl group, ring Z represents a benzene ring which may further have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined above and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined above.  
 
     
     
         2 . The method according to  claim 1 , wherein 
 A is a hydrogen atom or an acetyl group, ring Z is a C 6  to C 10  arene which may have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as that defined in the general formula (I) and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined in the general formula (I), E is a phenyl group substituted with two C 1  to C 6  halogenated alkyl groups, wherein said phenyl group may be substituted in addition to the two C 1  to C 6  halogenated alkyl groups or a phenyl group substituted with one C 1  to C 6  halogenated alkyl group wherein said phenyl group may be substituted except with a C 1  to C 6  halogenated alkyl group in addition to the C 1  to C 6  halogenated alkyl group.    
     
     
         3 . The method according to  claim 2 , wherein 
 A is a hydrogen atom or an acetyl group, ring Z is a C 6  to C 10  arene which may have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as defined in the general formula (I) and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined in the general formula (I), E is a 3,5-bis(trifluoromethyl)phenyl group, a 2,5-bis(trifluoromethyl)phenyl group, a 2-fluoro-3-(trifluoromethyl)phenyl group, a 2-chloro-4-(trifluoromethyl)phenyl group, a 2-fluoro-5-(trifluoromethyl)phenyl group, a 2-chloro-5-(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 2-nitro-5-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 2-methyl-5-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, a 3-methoxy-5-(trifluoromethyl)phenyl group, a 4-methoxy-3-(trifluoromethyl)phenyl group, a 2-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, a 2-(1-pyrrolizine)-5-(trifluoromethyl)phenyl group, or a 2-morpholino-5-(trifluoromethyl)phenyl group.    
     
     
         4 . The method according to  claim 3 , wherein A is a hydrogen atom or an acetyl group, ring Z is a C 6  to C 10  arene which may have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as defined in the general formula (I) and the group represented by formula —X-E, wherein each of X and E has the same meaning as defined in the general formula (I), E is a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group or a 3-methoxy-5-(trifluoromethyl)phenyl group.  
     
     
         5 . The method according to  claim 4 , wherein A is an acetyl group, the following partial structural formula (Iz-1) including ring Z in the general formula (I):  
       
         
           
           
               
               
           
         
       
       represents a group represented by the following formula (Iz-2):  
       
         
           
           
               
               
           
         
       
       wherein 
 R z  represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C 1  to C 6  alkoxy group which may be substituted, a di(C 1  to C 6  alkyl)-amino group, a C 6  to C 10  aryl-carbonyl-amino group, a C 1  to C 6  alkyl group which may be substituted, a C 1  to C 6  halogenated alkyl group which may be substituted, a C 2  to C 6  alkenyl group which may be substituted, a C 2  to C 6  alkynyl group which may be substituted, a C 6  to C 10  aryl group which may be substituted, a C 7  to C 16  aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a C 1  to C 6  alkyl-carbonyl group which may be substituted, a C 1  to C 6  alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, or a diazenyl group which may be substituted,  
 E is a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group or a 3-methoxy-5-(trifluoromethyl)phenyl group.  
 
     
     
         6 . The method according to  claim 5 , wherein A is an acetyl group, R z  is a halogen atom, 
 E is a 3,5-bis(trifluoromethyl)phenyl group, a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group or a 3-methoxy-5-(trifluoromethyl)phenyl group.    
     
     
         7 . The method according to  claim 6 , wherein A is an acetyl group, R z  is a halogen atom, 
 E is a 3,5-bis(trifluoromethyl)phenyl group.    
     
     
         8 . The method according to  claim 3 , wherein A is a hydrogen atom or an acetyl group, the following partial structural formula (Iz-1) including ring Z in the general formula (I):  
       
         
           
           
               
               
           
         
       
       represents a group represented by the following formula (Iz-2):  
       
         
           
           
               
               
           
         
       
       wherein 
 R z  represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C 1  to C 6  alkoxy group which may be substituted, a di(C 1  to C 6  alkyl)-amino group, a C 6  to C 10  aryl-carbonyl-amino group, a C 1  to C 6  alkyl group which may be substituted, a C 1  to C 6  halogenated alkyl group which may be substituted, a C 2  to C 6  alkenyl group which may be substituted, a C 2  to C 6  alkynyl group which may be substituted, a C 6  to C 10  aryl group which may be substituted, a C 7  to C 16  aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a C 1  to C 6  alkyl-carbonyl group which may be substituted, a C 1  to C 6  alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, or a diazenyl group which may be substituted,  
 E is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 2-chloro-4-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.  
 
     
     
         9 . The method according to  claim 8 , wherein A is a hydrogen atom, R z  is a halogen atom, 
 E is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 2-chloro-4-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.    
     
     
         10 . The method according to  claim 2 , wherein A is a hydrogen atom or an acetyl group, ring Z is a C 6  to C 10  arene which may have one or more substituents in addition to the group represented by formula —O-A, wherein A has the same meaning as defined in the general formula (I) and the group represented by formula —X-E, wherein each of X and E has the same meaning as that defined in the general formula (I), E is a heteroaryl group which may be substituted.  
     
     
         11 . The method according to  claim 10 , wherein A is a hydrogen atom or an acetyl group, the following partial structural formula (Iz-1) including ring Z in the general formula (I):  
       
         
           
           
               
               
           
         
       
       represents a group represented by the following formula (Iz-2):  
       
         
           
           
               
               
           
         
       
       wherein 
 R z  represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C 1  to C 6  alkoxy group which may be substituted, a di(C 1  to C 6  alkyl)-amino group, a C 6  to C 10  aryl-carbonyl-amino group, a C 1  to C 6  alkyl group which may be substituted, a C 1  to C 6  halogenated alkyl group which may be substituted, a C 2 l to C   6  alkenyl group which may be substituted, a C 2  to C 6  alkynyl group which may be substituted, a C 6  to C 10  aryl group which may be substituted, a C 7  to C 16  aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a C 1  to C 6  alkyl-carbonyl group which may be substituted, a C 1  to C 6  alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, or a diazenyl group which may be substituted, E is a thiazolyl group which may be substituted.  
 
     
     
         12 . The method according to  claim 11 , wherein A is a hydrogen atom, R z  is a halogen atom, E is a 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, 5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 5-phenyl-4-(trifluoromethyl)thiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-ethylthiazol-2-yl group, a 5-methyl-4-phenylthiazol-2-yl group, a 4-isopropyl-5-phenylthiazol-2-yl group, a 4-benzyl-5-phenylthiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group, a 5-acetyl-4-phenylthiazol-2-yl group, a 5-benzoyl-4-phenylthiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(ethoxycarbonyl)thiazol-2-yl group, a 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, a 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(4-phenylpiperidin-1-yl)thiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(4-methylpiperidin-1-yl)thiazol-2-yl group, a 4,5-diphenylthiazol-2-yl group, a 4-phenylthiazol-2-yl group, a 4,5-dimethyl thiazol-2-yl group, a 2-thiazolyl group, a 5-methylthiazol-2-yl group, a 4-ethyl-5-phenylthiazol-2-yl group, a 5-carboxymethyl-4-phenylthiazol-2-yl group, a 5-methylcarbamoyl-4-phenylthiazol-2-yl group, a 5-ethyl carbamoyl-4-phenylthiazol-2-yl group, a 5-isopropylcarbamoyl-4-phenyl thiazol-2-yl group, a 5-(2-phenethyl)carbamoyl-4-phenylthiazol-2-yl group, a 4-(n-butyl)-5-phenylthiazol-2-yl group, a 4-methyl-5-[(3-trifluoromethyl)phenyl]thiazol-2-yl group, or a 5-(4-fluorophenyl)-4-methylthiazol-2-yl group.  
     
     
         13 . The method according to  claim 12 , wherein A is a hydrogen atom, R z  is a halogen atom, E is a 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group.  
     
     
         14 . The method according to  claim 1 , which is an inhibitor against expression of a gene for one or more substances selected from the following substance group 6 comprising a tumor necrosis factor (TNF), interleukin-1, interleukin-2, interleukin-6, interleukin-8, a granulocyte colony-stimulating factor, interferon β, cell adhesion factor ICAM-1, VCAM-1, ELAM-1, a nitricoxide synthetase, major histocompatibility antigen family class I, major histocompatibility antigen family class II, P2-microglobulin, a immunoglobulin light chain, serum amyloid A, angiotensinogen, complement B, complement C4, c-myc, a transcript derived from a HIV gene, a transcript derived from a HTLV gene, a transcript derived from a simian virus 40 gene, a transcript derived from a cytomegalovirus gene, and a transcript derived from a adenovirus gene.  
     
     
         15 . The method according to  claim 1 , wherein the inhibiting activation of NF-κB, inhibiting production and release of an inflammatory cytokine or of immune inhibition comprises inhibiting activation of NF-κB and administering to the mammal an effective amount of the at least one compound for inhibiting activation of NF-κB.  
     
     
         16 . The method according to  claim 15 , wherein the mammal is a human.  
     
     
         17 . The method according to  claim 1 , wherein the inhibiting activation of NF-κB or inhibiting production and release of an inflammatory cytokine comprises inhibiting production and release of an inflammatory cytokine and administering to the mammal an effective amount of the at least one compound for inhibiting production and release of an inflammatory cytokine.  
     
     
         18 . The method according to  claim 17 , wherein the mammal is a human.  
     
     
         19 . The method according to  claim 1 , wherein the inhibiting activation of NF-κB, inhibiting production and release of an inflammatory cytokine or of immune inhibition comprises immune inhibition and administering to the mammal an effective amount of the at least one compound for immuno suppression.  
     
     
         20 . The method according to  claim 19 , wherein the mammal is a human.  
     
     
         21 . A compound represented by the following general formula (I-1) or a salt thereof, or a hydrate thereof or a solvate thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 Z 1  represents a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position, E 1  represents a phenyl group substituted with two C 1  to C 6  halogenated alkyl groups wherein said phenyl group may be substituted in addition to the two C 1  to C 6  halogenated alkyl groups,  
 provided that the compounds represented by the following (1) and (2) are excluded:  
 (1) the compounds represented by the aforementioned formula (I-1), wherein E 1  is a 2,5-bis(trifluoromethyl)phenyl group; and  
 (2) the following compounds:  
 N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxybenzamide,  
 N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,  
 N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide,  
 N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide,  
 N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-nitrobenzamide, and  
 2-hydroxy-N-[2,3,5-tris(trifluoromethyl)phenyl]benzamide.  
 
     
     
         22 . The compound according to  claim 21  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z 1  represents a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position, E 1  is a 3,5-bis(trifluoromethyl)phenyl group.  
     
     
         23 . The compound according to  claim 22  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z 1  is a group represented by the following formula:  
       
         
           
           
               
               
           
         
       
       wherein A 1  represents a hydrogen atom or an acetyl group, R 1z  represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group which may be substituted, an amino group which may be substituted, a hydrocarbon group which may be substituted, a heteroring group which may be substituted, an acyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, a diazenyl group which may be substituted, E 1  is a 3,5-bis(trifluoromethyl)phenyl group.  
     
     
         24 . The compound according to  claim 23  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A 1  is a hydrogen atom or an acetyl group, R 1z  is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a C 1  to C 6  alkoxy group which may be substituted, a di(C 1  to C 6  alkyl)-amino group, a C 6  to C 10  aryl-carbonyl-amino group, a C 1  to C 6  alkyl group which may be substituted, a C 1  to C 6  halogenated alkyl group which may be substituted, a C 2  to C 6  alkenyl group which may be substituted, a C 2  to C 6  alkynyl group which may be substituted, a C 6  to C 10  aryl group which may be substituted, a C 7  to C 16  aralkyl group which may be substituted, a 5 to 6 membered heteroaryl group which may be substituted, a carbamoyl group which may be substituted, a sulfamoyl group which may be substituted, a C 1  to C 6  alkyl-carbonyl group which may be substituted, a C 1  to C 6  alkoxy-carbonyl group which may be substituted, a 5-membered heteroaryl-sulfonyl group which may be substituted, a 6-membered nonaromatic heterocyclic-sulfonyl group which may be substituted, an ureido group which may be substituted, a thioureido group which may be substituted, or a diazenyl group which may be substituted, E 1  is a 3,5-bis(trifluoromethyl)phenyl group.  
     
     
         25 . The compound according to  claim 24  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A 1  is a hydrogen atom or an acetyl group, R 1z  is a halogen atom, E 1  is a 3,5-bis(trifluoromethyl)phenyl group.  
     
     
         26 . A compound represented by the following general formula (I-2) or a salt thereof, or a hydrate thereof or a solvate thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 Z 2  represents a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position,  
 E 2  represents a phenyl group whose 3-position or 5-position is substituted with a C 1  to C 6  halogenated alkyl group wherein said phenyl group may be substituted except when a substituent is a C 1  to C 6  halogenated alkyl group in addition to the C 1  to C 6  halogenated alkyl group in the 3-position or 5-position,  
 provided that the compounds represented by the following (1) and (2) are excluded:  
 (1) the compounds represented by the aforementioned formula (I-2), wherein E 2  is a 2-fluoro-5-(trifluoromethyl)phenyl group, a 2-chloro-5-(trifluoromethyl)phenyl group, a 2-nitro-5-(trifluoromethyl)phenyl group, a 2-methyl-5-(trifluoromethyl)phenyl group, a 2-methoxy-5-(trifluoromethyl)phenyl group, a 2-(methylsulfanyl)-5-(trifluoromethyl)phenyl group, a 2-(1-pyrrolizine)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl group; and  
 (2) the following compounds:  
 5-chloro-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide,  
 5-bromo-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide,  
 5-hydroxy-5-iodo-N-[3-(trifluoromethyl)phenyl]benzamide,  
 5-chloro-N-[4-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,  
 5-chloro-N-[5-chloro-3-(trifluoromethyl)phenyl]-2-hydroxybenzamide,  
 5-chloro-2-hydroxy-N-[4-nitro-3-(trifluoromethyl)phenyl]benzamide,  
 5-fluoro-2-hydroxy-N-[2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)phenyl]benzamide,  
 5-fluoro-2-hydroxy-N-[2-(6,6,6-trifluorohexyloxy)-5-(trifluoromethyl)phenyl]benzamide,  
 5-chloro-2-hydroxy-N-(3-trifluoromethyl-4-{[4-(trifluoromethyl)sulfanyl]phenoxy}phenyl)-benzamide,  
 N-[4-(benzothiazole-2-yl)sulfanyl-3-(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide,  
 5-chloro-N-[2-(4-chlorophenoxy)-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,  
 5-chloro-2-hydroxy-N-[2-(4-methylphenoxy)-5-(trifluoromethyl)phenyl]benzamide,  
 5-chloro-N-[2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide,  
 5-chloro-2-hydroxy-N-[2-(1-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide, and  
 5-chloro-2-hydroxy-N-[2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl]benzamide.  
 
     
     
         27 . The compound according to  claim 26  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z 2  is a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position, E 2  is a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, or a 3-methoxy-5-(trifluoromethyl)phenyl group.  
     
     
         28 . The compound according to  claim 27  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z 2  is a group represented by the following formula:  
       
         
           
           
               
               
           
         
       
       wherein A 2  represents a hydrogen atom or an acetyl group, R 2z  represents a halogen atom, a C 1  to C 6  alkyl group or a C 1  to C 6  halogenated alkyl group, E 2  is a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, or a 3-methoxy-5-(trifluoromethyl)phenyl group.  
     
     
         29 . The compound according to  claim 28  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A 2  is a hydrogen atom, R 2z  is a halogen atom, E 2  is a 3-fluoro-5-(trifluoromethyl)phenyl group, a 3-bromo-5-(trifluoromethyl)phenyl group, or a 3-methoxy-5-(trifluoromethyl)phenyl group.  
     
     
         30 . The compound according to  claim 26  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z 2  is a 2-hydroxyphenyl group which may be substituted in the 5-position or a 2-acetoxyphenyl group which may be substituted in the 5-position, E 2  is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.  
     
     
         31 . The compound according to  claim 30  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z 2  is a group represented by the following formula:  
       
         
           
           
               
               
           
         
       
       wherein A 2  represents a hydrogen atom or an acetyl group, R 2z  represents a halogen atom, a C 1  to C 6  alkyl group or a C 1  to C 6  halogenated alkyl group, E 2  is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.  
     
     
         32 . The compound according to  claim 31  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A 2  is a hydrogen atom, R 2z  is a halogen atom, E 2  is a 2-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-2-(trifluoromethyl)phenyl group, a 4-fluoro-3-(trifluoromethyl)phenyl group, a 4-chloro-3-(trifluoromethyl)phenyl group, a 4-nitro-3-(trifluoromethyl)phenyl group, a 4-cyano-3-(trifluoromethyl)phenyl group, a 2-methyl-3-(trifluoromethyl)phenyl group, a 4-methyl-3-(trifluoromethyl)phenyl group, or a 4-methoxy-3-(trifluoromethyl)phenyl group.  
     
     
         33 . A compound represented by the following general formula (I-3) or a salt thereof, or a hydrate thereof or a solvate thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 Z 3  represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position, E 3  is a group represented by the following formula:  
                     
 wherein  
 R 3e2  and R 3e3  may be the same or different and each represents a hydrogen atom, a hydrocarbon group which may be substituted, or a hydroxyl group which may be substituted, provided that both of R 3e2  and R 3e3  are not simultaneously hydrogen atoms, R 3e5  represents a C 2  to C 6  hydrocarbon group which may be substituted.  
 
     
     
         34 . A compound represented by the following general formula (I-4) or a salt thereof, or a hydrate thereof or a solvate thereof:  
       
         
           
           
               
               
           
         
       
       wherein 
 Z 4  represents 2-hydroxyphenyl group which may be substituted in the 5-position or 2-acetoxyphenyl group which may be substituted in the 5-position, E 4  is a group represented by the following formula:  
                     
 wherein  
 R 4e4  represents a hydrocarbon group which may be substituted, R 4e5  represents a halogen atom, cyano group, an acyl group which may be substituted, or a heterocyclic group which may be substituted.  
 
     
     
         35 . The compound according to  claim 34  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein 
 Z 4  is a group represented by the following formula:  
                     
 wherein A 4  represents hydrogen atom or acetyl group,  
 R 4z  represents a halogen atom, a C 6  to C 10 C aryl group which may be substituted, or a 5-membered heteroaryl group, R 4e4  is a C 1  to C 6  alkyl group which may be substituted, a C 1  to C 6  halogenated alkyl group which may be substituted, or a C 6  to C 10  aryl group which may be substituted, R 4e5  is a halogen atom, a cyano group, a C 1  to C 6  alkyl-carbonyl group which may be substituted, a C 6  to C 10  aryl-carbonyl group which may be substituted, a C 1  to C 6  alkoxy-carbonyl group which may be substituted, or a 6-membered nonaromatic heteroring group which may be substituted.  
 
     
     
         36 . The compound according to  claim 35  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A 4  is a hydrogen atom, R 4z  is a halogen atom, E is a 5-bromo-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 5-bromo-4-(trifluoromethyl)thiazol-2-yl group, a 5-cyano-4-[(1,1-dimethyl)ethyl]thiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group, a 5-acetyl-4-phenylthiazol-2-yl group, a 5-benzoyl-4-phenylthiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(ethoxycarbonyl)thiazol-2-yl group, a 5-ethoxycarbonyl-4-(trifluoromethyl)thiazol-2-yl group, a 5-ethoxycarbonyl-4-phenylthiazol-2-yl group, a 5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-piperidinothiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-morpholinothiazol-2-yl group, a 4-(1,1-dimethyl)ethyl-5-(4-methylpiperidin-1-yl)thiazol-2-yl group, or a 4-(1,1-dimethyl)ethyl-5-(4-phenylpiperidin-1-yl)thiazol-2-yl group.  
     
     
         37 . The compound according to  claim 36  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein A 4  is a hydrogen atom, R 4z  is a halogen atom, E 4  is a 4-(1,1-dimethyl)ethyl-5-[(2,2-dimethyl)propionyl]thiazol-2-yl group.