O-substituted hydroxyaryl derivatives

Abstract

A medicament having inhibitory activity against NF-κB activation which comprises as an active ingredient a substance selected from the group consisting of a compound represented by the following general formula (I) and a pharmacologically acceptable salt thereof, and a hydrate thereof and a solvate thereof: wherein X represents a connecting group whose number of atoms in a main chain is 2 to 5 (said connecting group may be substituted), “A” represents an acyl group which may be substituted, (provided that unsubstituted acetyl group and unsubstituted acryloyl group are excluded,) or a C 1 to C 6 alkyl group which may be substituted, or A may bind to connecting group X to form a cyclic structure which may be substituted, “E” represents an aryl group which may be substituted or a heteroaryl group which may be substituted, ring Z represents an 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 above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above, or a heteroarene 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 above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above.

1 . A compound represented by formula (I-1) or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         E 1  represents a di-substituted phenyl group wherein the two substituents of the di-substituted phenyl group are halogenated alkyl groups, 
         ring Z 1  represents a benzene ring wherein said benzene ring has a halogen atom in addition to the group represented by formula —O-A 1  and the group represented by formula —CONH-E 1 , and 
         A l  represents
 an N,N-di(alkyl)carbamoyl group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl group, and 
 a carboxy group; 
 
 an N-alkyl-N-aryl-carbamoyl group; 
 a phosphono group which may be substituted with an aralkyl group, 
 an N,N-di(alkyl)sulfamoyl group; 
 a sulfo group; 
 an acyl-oxy-methylene group wherein said acyl group is selected from
 an alkyl-carbonyl group, 
 a 6-membered monocyclic non-aromatic 
 heterocyclic-carbonyl group, and 
 an N,N-di(alkyl)carbamoyl group, 
 and said acyl-oxy-methylene group may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl group, and 
 a carboxy group; 
 
 
 an alkyl-oxy-carbonyl-oxy-methylene group which may be substituted with an alkyl group;
 a 6-membered monocyclic heteroaryl-carbonyl group; 
 an alkyl-sulfonyl group; 
 an aryl-sulfonyl group which may be substituted with one or more alkyl groups; 
 an N-alkyl-carbamoyl group which may be substituted with one or more substituents independently selected from 
 an alkyl-oxy-carbonyl group, 
 a carboxy group, 
 an alkoxy group, 
 an N-alkyl-carbamoyl group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl-amino group, 
 an alkyl-oxy-carbonyl group, and 
 a carboxy group, and 
 
 an N-aralkyl-carbamoyl group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl group, and 
 a carboxy group; 
 
 
 an N-aralkyl-carbamoyl group which may be substituted with one or more alkyl-oxy-carbonyl groups; 
 an N-aryl-carbamoyl group which may be substituted with one or more alkyl-sulfanyl groups;
 an alkyl-carbonyl group which may be substituted with one or more substituents independently selected from 
 an alkoxy group, 
 an alkyl-carbonyl-oxy group, 
 an aryl-oxy group which may be substituted with one or more halogen atoms, 
 an alkyl-oxy-carbonyl group, 
 an aralkyl-oxy-carbonyl group, 
 a 6-membered non-aromatic heterocyclic ring-carbonyl group, 
 an alkyl-carbonyl-amino group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl group, 
 an alkyl-oxy-carbonyl-amino group, 
 a carboxy group, and 
 an amino group, 
 
 an alkyl-oxy-carbonyl-amino group, 
 an aralkyl-oxy-carbonyl-amino group, 
 an amino group, 
 a carboxy group, and 
 an aralkyl-carbonyl-amino group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl-amino group, and 
 an amino group; 
 
 
 an aralkyl-carbonyl group which may be substituted with one or more substituents independently selected from
 an alkylenedioxy group, 
 an amino group, 
 an alkyl-oxy-carbonyl-amino group, and 
 an alkyl-carbonyl-amino group which may be substituted with one or more substituents independently selected from
 an amino group, and 
 a carboxy group; or 
 
 
 an aryl-carbonyl group which may be substituted with one or more substituents independently selected from
 a hydroxy group, and 
 an alkyl-carbonyl-oxy group. 
 
 
       
     
     
         2 . The compound according to  claim 1  or a salt thereof, wherein E 1  is a 3,5- or 2,5-di-substituted phenyl group wherein the two substituents of the 3,5- or 2,5-di-substituted phenyl group are halogenated alkyl groups. 
     
     
         3 . The compound according to  claim 1  or a salt thereof, wherein E 1  is a di-substituted phenyl group wherein one of the substituents of the di-substituted phenyl group is trifluoromethyl group, and the other substituent is a halogenated alkyl group. 
     
     
         4 . The compound according to  claim 1  or a salt thereof, wherein E 1  is a 3,5- or 2,5-bis(trifluoromethyl)phenyl group. 
     
     
         5 . The compound according to  claim 1  or a salt thereof, wherein the following partial formula (Iz 1 -1) in the formula (I-1) containing ring Z 1    
       
         
           
           
               
               
           
         
         is represented by the following formula (Iz 1 -2), 
       
       
         
           
           
               
               
           
         
         wherein R z1  represents a halogen atom. 
       
     
     
         6 . The compound according to  claim 1  or a salt thereof, wherein A 1  is
 an N,N-di(alkyl)carbamoyl group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl group, and 
 a carboxy group; 
   an N-alkyl-N-phenyl-carbamoyl group;   a phosphono group which may be substituted with a benzyl group,   an N,N-di(alkyl)sulfamoyl group;   a sulfo group;   an acyl-oxy-methylene group wherein said acyl group is selected from
 an alkyl-carbonyl group, 
 a 6-membered monocyclic non-aromatic heterocyclic-carbonyl group wherein said 6-membered monocyclic non-aromatic heterocyclic group is a piperidino group or a morpholino group, and 
 an N,N-di(alkyl)carbamoyl group, 
 and said acyl-oxy-methylene group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl group, and 
 a carboxy group; 
 
   an alkyl-oxy-carbonyl-oxy-methylene group which may be substituted with an alkyl group;   a 6-membered monocyclic heteroaryl-carbonyl group wherein said 6-membered monocyclic heteroaryl group is selected from 2-pyridyl group, 3-pyridyl group and 4-pyridyl group;   an alkyl-sulfonyl group;   a phenyl-sulfonyl group which may be substituted with one or more alkyl groups;   an N-alkyl-carbamoyl group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl group, 
 a carboxy group, 
 an alkoxy group, 
 an N-alkyl-carbamoyl group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl-amino group, 
 an alkyl-oxy-carbonyl group, and 
 a carboxy group, and 
 
 an N-benzyl-carbamoyl group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl group, and 
 a carboxy group; 
 
   an N-benzyl-carbamoyl group which may be substituted with one or more alkyl-oxy-carbonyl groups;   an N-phenyl-carbamoyl group which may be substituted with one or more alkyl-sulfanyl groups;   an alkyl-carbonyl group which may be substituted with one or more substituents independently selected from
 an alkoxy group, 
 an alkyl-carbonyl-oxy group, 
 a phenyl-oxy group which may be substituted with one or more halogen atoms, 
 an alkyl-oxy-carbonyl group, 
 a benzyl-oxy-carbonyl group, 
 a piperidino-carbonyl group, 
 an alkyl-carbonyl-amino group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl group, 
 an alkyl-oxy-carbonyl-amino group, 
 a carboxy group, and 
 an amino group, 
 
 an alkyl-oxy-carbonyl-amino group, 
 a benzyl-oxy-carbonyl-amino group, 
 an amino group, 
 a carboxy group, and 
 a phenyl-alkyl-carbonyl-amino group which may be substituted with one or more substituents independently selected from
 an alkyl-oxy-carbonyl-amino group, and 
 an amino group; 
 
   a phenyl-alkyl-carbonyl group which may be substituted with one or more substituents independently selected from
 an alkylenedioxy group, 
 an amino group, 
 an alkyl-oxy-carbonyl-amino group, and 
 an alkyl-carbonyl-amino group which may be substituted with one or more substituents independently selected from
 an amino group, and 
 a carboxy group; or 
 
   a phenyl-carbonyl group which may be substituted with one or more substituents independently selected from
 a hydroxy group, and 
 an alkyl-carbonyl-oxy group. 
   
     
     
         7 . The compound according to  claim 1  or a salt thereof, wherein A 1  is an N-isopropylcarbamoyl group, an N-benzylcarbamoyl group, an N-(ethoxycarbonylmethyl)carbamoyl group, an N-(carbonylmethyl)carbamoyl group, an N-(1-methoxycarbonylethyl)carbamoyl group, an N-(1-methoxycarbonyl-2-phenylethyl)carbamoyl group, an N[1-methoxycarbonyl-2-(tert-butoxycarbonyl)ethyl]carbamoyl group, an N-({N-[1-(tert-butoxycarbonyl)-2-phenylethyl]carbamoyl}methyl)carbamoyl group, an N-{[N-(1-carboxy-2-phenylethyl)carbamoyl]methyl}carbamoyl group, an N-({N-[1,2-di(tert-butoxycarbonyl)ethyl]carbamoyl}methyl)carbamoyl group, an N-{[N-(1,2-dicarboxyethyl)carbamoyl]methyl}carbamoyl group, an N-({N-[1,5-di(tert-butoxycarbonyl)pentyl]carbamoyl}methyl)carbamoyl group, an N-[(4-methylsulfanyl)phenyl]carbamoyl group, an N,N-dimethylcarbamoyl group, an N,N-diethylcarbamoyl group, an N-methyl-N-phenylcarbamoyl group, an N,N-bis[(ethoxycarbonyl)methyl]carbamoyl group, an N,N-bis(carboxymethyl)carbamoyl group, a pivaloyl group, a valeryl group, a decanoyl group, a benzoyl group, a 2-acetoxybenzoyl group, a phenylacetyl group, a (3,4-methylenedioxyphenyl)acetyl group, a methoxyacetyl group, an acetoxyacetyl group, a phenoxyacetyl group, a (4-chlorophenoxy)acetyl group, a (2,3-dichlorophenoxy)acetyl group, a 2-phenoxypropionyl group, a 2-(4-chlorophenoxy)isobutyryl group, a (tert-butoxycarbonyl)acetyl group, a 3-(benzyloxycarbonyl)propionyl group, a 3-(piperidinocarbonyl)propionyl group, an (acetylamino)acetyl group, a [(benzyloxycarbonyl)amino]acetyl group, a [(tert-butoxycarbonyl)amino]acetyl group, an aminoacetyl group, a 2-[(tert-butoxycarbonyl)amino]isovaleryl group, a 2-amino isovaleryl group, a 2-[(tert-butoxycarbonyl)amino]-4-methylvaleryl group, a 2-amino-4-methylvaleryl group, a 2-[(tert-butoxycarbonyl)amino]-3-phenylpropionyl group, a 2-amino-3-phenylpropionyl group, a 2-[(tert-butoxycarbonyl)amino]-3-(tert-butoxycarbonyl)propionyl group, a 2-[(tert-butoxycarbonyl)amino]-4-(tert-butoxycarbonyl)butyryl group, a 2-amino-4-carboxybutyryl group, a 2,6-bis[(tert-butoxycarbonyl)amino]hexanoyl group, a 2,6-diaminohexanoyl group, a 2-{2-[(tert-butoxycarbonyl)amino]-3-phenylpropionyl}amino-4-methylvaleryl group, a 2-(2-amino-3-phenylpropionyl)amino-4-methylvaleryl group, a 2-{2,3-bis[(tert-butoxycarbonyl)amino]propionyl}amino-4-methylvaleryl group, a 2-(2-amino-3-carboxypropionyl)amino-4-methylvaleryl group, a 2-{2,6-bis[(tert-butoxycarbonyl)amino]hexanoyl}amino-4-methylvaleryl group, a 2-(2,6-diaminohexanoyl)amino-4-methylvaleryl group, a 2-(2-amino-4-methylvaleryl)amino-3-phenylpropionyl group, a 2-(2-amino-3-carboxypropionyl)amino-3-phenylpropionyl group, an ethyl group, an isopropyl group, a methoxymethyl group, an acetoxymethyl group, a (pivaloyloxy)methyl group, a 1-(ethoxycarbonyloxy)ethyl group, a [(piperidinocarbonyl)oxy]methyl group, a [(morpholinocarbonyl)oxy]methyl group, a ({[4-(ethoxycarbonyl)piperidin-1-yl]carbonyl}oxy)methyl group, a {[(4-carboxypiperidin-1-yl)carbonyl]oxy}methyl group, an (}N,N-bis[(ethoxycarbonyl)methyl]carbamoyl}oxy)methyl group, an {[N,N-bis(carboxymethyl)carbamoyl]oxy}methyl group, a 2-hydroxyethyl group, an (ethoxycarbonyl)methyl group, a carboxymethyl group, a (benzyloxycarbonyl)methyl group, a 3,4,5,6-tertaacetoxy-tetrahydropyran-2-yl group, or an N-phthalylmethyl group.