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.

1 . A method of inhibiting activation of NF-κB, of 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 thereof, a hydrate thereof, 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 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-pyrrolizino)-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,   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-pyrrolizino)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl group,   ring Z is a benzene ring which may further have one or more substituents selected from the following substituent group γ-1z 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; wherein substituent group γ-1z is 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 heterocyclic group which may be substituted, an acyl group which may be substituted, an ureido group which may be substituted, an thioureido group which may be substituted, a diazenyl group which may be substituted.   
     
     
         3 . The method according to  claim 2 , wherein
 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-pyrrolizino)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl 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. 
 
     
     
         4 . The method according to  claim 3 , wherein
 A is a hydrogen atom,   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-pyrrolizino)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl group,   R z  is a halogen atom.   
     
     
         5 . The method according to  claim 4 , wherein
 A is a hydrogen atom,   E is a 2,5-bis(trifluoromethyl)phenyl group,   R z  is a halogen atom.   
     
     
         6 . The method according to  claim 5 , wherein
 A is a hydrogen atom,   E is a 2,5-bis(trifluoromethyl)phenyl group,   R z  is a bromine atom.   
     
     
         7 . The method according to  claim 1 , wherein
 E is a 2,5-bis(trifluoromethyl)phenyl group.   
     
     
         8 . The method according to  claim 1 , which comprises inhibiting expression of a gene for one or more substances selected from the following substance group δ, wherein substance group 6 is 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, nitricoxide synthetase, major histocompatibility antigen family class I, major histocompatibility antigen family class II, β2-microglobulin, 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 an adenovirus gene. 
     
     
         9 . 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. 
     
     
         10 . The method according to  claim 9 , wherein the mammal is a human. 
     
     
         11 . 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. 
     
     
         12 . The method according to  claim 11 , wherein the mammal is a human. 
     
     
         13 . 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. 
     
     
         14 . The method according to  claim 13 , wherein the mammal is a human. 
     
     
         15 . 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 2,5-bis(trifluoromethyl)phenyl group. 
 
     
     
         16 . The compound according to  claim 15  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 2,5-bis(trifluoromethyl)phenyl group. 
 
     
     
         17 . The compound according to  claim 16  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 2,5-bis(trifluoromethyl)phenyl group.   
     
     
         18 . The compound according to  claim 17  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein
 A 1  is a hydrogen atom,   R 1z  is a halogen atom,   E 1  is a 2,5-bis(trifluoromethyl)phenyl group.   
     
     
         19 . The compound according to  claim 18  or a salt thereof, or a hydrate thereof or a solvate thereof, wherein
 A 1  is a hydrogen atom,   R 1z  is a bromine atom,   E 1  is a 2,5-bis(trifluoromethyl)phenyl group.   
     
     
         20 . 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 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-pyrrolizino)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl group. 
 
     
     
         21 . The compound according to  claim 20  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-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-pyrrolizino)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl group. 
 
     
     
         22 . The compound according to  claim 21  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-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-pyrrolizino)-5-(trifluoromethyl)phenyl group or a 2-morpholino-5-(trifluoromethyl)phenyl group.