NF-kappaB inhibitor comprising phenylmethyl benzoquinone as an active ingredient

Abstract

An NF-κB inhibitor having as an active ingredient a benzoquinone derivative represented by the general formula (1) wherein R 1 , R 2 , and R 3 are each independently H, alkyl having 1 to 5 carbons, or alkoxy having 1 to 5 carbons; R 4 is H, hydroxymethyl, alkyl, or carboxyl which is optionally esterified or amidated; Z is represented by the formula (A); and, n is an integer from 0 to 6, or its hydroquinone form or a pharmaceutically acceptable salt thereof.

1 . An NF-κB inhibitor comprising as an active ingredient a benzoquinone derivative represented by the following general formula (1):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , and R 3  are each independently a hydrogen atom, an alkyl group having 1 to 5 carbons, or an alkoxy group having 1 to 5 carbons;  
 R 4  is a hydrogen atom, a hydroxymethyl group, an alkyl group, or a carboxyl group which is optionally esterified or amidated;  
 Z is  
                     
 and, n is an integer from 0 to 6,  
 or its hydroquinone form, or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The NF-κB inhibitor according to  claim 1  in which R 1  and R 2  are a hydrogen atom, a methyl group, or a methoxy group.  
     
     
         3 . The NF-κB inhibitor according to  claim 1  or  2  in which R 3  is a hydrogen atom or a methyl group.  
     
     
         4 . The NF-κB inhibitor according to  claim 1 ,  2 , or  3  in which Z is  
       
         
           
           
               
               
           
         
       
       and n is an integer 0.  
     
     
         5 . The NF-κB inhibitor according to  claim 1 ,  2 , or  3  in which Z is  
       
         
           
           
               
               
           
         
       
       and n is an integer 1, 2, or 3.  
     
     
         6 . The NF-κB inhibitor according to any one of  claims 1  to  5  in which R 4  is a group —COOR 5  wherein R 5  is a hydrogen atom, an optionally substituted alkyl group having 1 to 8 carbons, an optionally substituted phenyl group, or an optionally substituted aralkyl group having 7 to 11 carbons.  
     
     
         7 . The NF-κB inhibitor according to any one of  claims 1  to  5  in which R 4  is a group —CONR 6 R 7  wherein R 6  and R 7  are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 8 carbons, an optionally substituted bicyclic unsaturated or partially saturated hydrocarbon ring group having 9 to 11 carbons, an optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted aralkyl group having 7 to 11 carbons, or a heteroaryl-C 1 -C 3 -alkyl group, or R 6  and R 7 , together with the nitrogen atom to which they are attached, represent a heterocyclic group which may further contain a nitrogen, oxygen, and/or sulfur atom.  
     
     
         8 . The NF-κB inhibitor according to any one of  claims 1  to  5  in which R 4  is a group —CONR 6 R 7  wherein R 6  and R 7 , together with the nitrogen atom to which they are attached, represent a 5- to 10-membered optionally substituted, nitrogen-containing heterocyclic group which may contain, in addition to the carbon and nitrogen atom, 1 to 3 heteroatoms selected from the group consisting of a nitrogen, oxygen and sulfur atom, the carbon atom on said cyclic group being optionally a ketone form or the sulfur atom on said cyclic group being optionally an oxide form.  
     
     
         9 . The NF-κB inhibitor according to  claim 1 ,  6 ,  7 , or  8  in which R 1  and R 2  are a methyl group or a methoxy group; R 3  is a methyl group: R 4  is a carboxyl group which is optionally esterified or amidated; Z is  
       
         
           
           
               
               
           
         
       
       and n is an integer 1, 2, or 3.  
     
     
         10 . The NF-κB inhibitor according to any one of  claims 1  to  9  which is a suppressing agent for the gene expression of one or more substances selected from the group consisting of IL-1, TNF-α, IL-2, IL-6, IL-8, iNOS, granulocyte colony-stimulating factor, interferon-β, ICAM-1, VCAM-1, ELAM-1, major histocompatibility system class I, major histocompatibility system class II, β2-microglobulin, immunoglobulin light chain, serum amyloid A, angiotensinogen, complement B, complement C4, c-myc, HIV, HTLV-1, SV40, CMV, and adenovirus.  
     
     
         11 . The NF-κB inhibitor according to any one of  claims 1  to  9  which is a preventive or therapeutic agent for inflammatory diseases.  
     
     
         12 . The NF-κB inhibitor according to any one of  claims 1  to  9  which is a preventive or therapeutic agent for autoimmune diseases.  
     
     
         13 . The NF-κB inhibitor according to any one of  claims 1  to  9  which is a preventive or therapeutic agent for viral diseases.  
     
     
         14 . A preventive or therapeutic agent for diseases caused by the activation of NF-κB comprising as an active ingredient a benzoquinone derivative represented by the following general formula (1):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , and R 3  are each independently a hydrogen atom, an alkyl group having 1 to 5 carbons, or an alkoxy group having 1 to 5 carbons;  
 R 4  is a hydrogen atom, a hydroxymethyl group, an alkyl group, or a carboxyl group which is optionally esterified or amidated;  
 Z is  
                     
 and, n is an integer from 0 to 6,  
 or its hydroquinone form, or a pharmaceutically acceptable salt thereof.  
 
     
     
         15 . A novel compound selected from: 
 N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]morpholine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]thiomorpholine S-oxide,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]thiomorpholine S-dioxide,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]piperidine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]dimethylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]isopropylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]ethanolamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]benzylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]phenethylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]morpholine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]thiomorpholine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]piperidine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]dimethylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]isopropylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]ethanolamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]benzylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]phenethylamine,    N-[3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]piperidine,    N-[3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]thiomorpholine,    N-[3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]morpholine,    N-[3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]isopropylamine,    3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid,    N-[3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]piperidine,    N-[3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]morpholine,    N-[3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]isopropylamine,    N-[3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]thiomorpholine,    N-[3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]isopropylamine,    N-[3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]piperidine,    N-[3-[4-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]morpholine,    N-[3-[3-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]isopropylamine,    N-[3-[3-(3,5,6-trimethyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]piperidine,    3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid,    N-[3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acryloyl]thiomorpholine,    3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid,    N-[3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]piperidine,    N-[3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]morpholine,    N-[3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]thiomorpholine,    N-[3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]isopropylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-(s)-2-(methoxymethyl)pyrrolidine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]isonipecotamide,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-4-methylpiperidine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-2-methylpiperidine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-3-methylpiperidine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-4-methoxyaniline,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-2-hydroxyaniline,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-3,4-dimethoxyaniline,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-D,L-alaninol,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-D,L-pipecolic acid ethylester,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-L-prolinamide,    4-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]aminophenylacetonitrile,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-4-pentylaniline,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-(s)-(−)-1-phenylethylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-(R)-(+)-1-phenylethylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-1,3-dimethylbutylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]cycloheptylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-3,5-dimethylpiperidine,    1-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-4-ethoxycarbonylpiperazine,    1-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-4-phenylpiperazine,    1-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-4-hydroxy-4-phenylpiperidine,    1-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-4-(4-chlorophenyl)-4-hydroxypiperidine,    1-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-4-(2-methoxyphenyl)piperazine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline,    4-acetyl-4-phenyl-1-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]piperidine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-1,2,3,4-tetrahydroisoquinoline,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]isoamylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]cyclohexylamine,    N-[3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionyl]-4-hydroxyaniline,    4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid,    N-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoyl]morpholine,    N-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoyl]isopropylamine,    N-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoyl]piperidine,    N-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoyl]thiomorpholine,    3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid,    N-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoyl]isopropylamine,    N-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)piperidine,    N-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)morpholine,    N-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)thiomorpholine,    4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid,    N-[4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]butanoyl]morpholine,    N-[4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]butanoyl]thiomorpholine,    N-[4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]butanoyl]piperidine,    N-[4-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]butanoyl]isopropylamine,    4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid,    N-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetyl]morpholine,    N-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetyl]piperidine,    N-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetyl]thiomorpholine,    N-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetyl]isopropylamine,    3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid,    N-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetyl]piperidine,    N-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetyl]thiomorpholine,    N-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetyl]morpholine,    N-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetyl]morpholine,    4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]-n-butyric acid,    N-[4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]butanoyl]piperidine,    N-[4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]butanoyl]thiomorpholine,    N-[4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]butanoyl]morpholine, and    N-[4-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]butanoyl]isopropylamine.    
     
     
         16 . An inhibitor of TNF-α production comprising as an active ingredient a benzoquinone derivative represented by the following general formula (1):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , and R 3  are each independently a hydrogen atom, an alkyl group having 1 to 5 carbons, or an alkoxy group having 1 to 5 carbons;  
 R 4  is a hydrogen atom, a hydroxymethyl group, an alkyl group, or a carboxyl group which is optionally esterified or amidated;  
 Z is  
                     
 and, n is an integer from 0 to 6,  
 or its hydroquinone form, or a pharmaceutically acceptable salt thereof.  
 
     
     
         17 . The inhibitor of TNF-α production according to  claim 16  in which R 1  and R 2  are a hydrogen atom, a methyl group, or a methoxy group.  
     
     
         18 . The inhibitor of TNF-α production according to  claim 16  or  17  in which R 3  is a hydrogen atom or a methyl group.  
     
     
         19 . The inhibitor of TNF-α production according to  claim 16 ,  17 , or  18  in which z is  
       
         
           
           
               
               
           
         
       
       and n is an integer 0.  
     
     
         20 . The inhibitor of TNF-α production according to  claim 16 ,  17 , or  18  in which Z is  
       
         
           
           
               
               
           
         
       
       and n is an integer 1, 2, or 3.  
     
     
         21 . The inhibitor of TNF-α production according to any one of  claims 16  to  20  in which R 4  is a group —COOR 5  wherein R 5  is a hydrogen atom, an optionally substituted alkyl group having 1 to 8 carbons, an optionally substituted phenyl group, or an optionally substituted aralkyl group having 7 to 11 carbons.  
     
     
         22 . The inhibitor of TNF-α production according to any one of  claims 16  to  20  in which R 4  is a group —CONR 6 R 7  wherein R 6  and R 7  are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 8 carbons, an optionally substituted bicyclic unsaturated or partially saturated hydrocarbon ring group having 9 to 11 carbons, an optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted aralkyl group having 7 to 11 carbons, or a heteroaryl-C 1 -C 3 -alkyl group, or R 6  and R 7 , together with the nitrogen atom to which they are attached, represent a heterocyclic group which may further contain a nitrogen, oxygen, and/or sulfur atom.  
     
     
         23 . The inhibitor of TNF-α production according to any one of  claims 16  to  20  in which R 4  is a group —CONR 6 R 7  wherein R 6  and R 7 , together with the nitrogen atom to which they are attached, represent a 5- to 10-membered optionally substituted, nitrogen-containing heterocyclic group which may contain, in addition to the carbon and nitrogen atom, 1 to 3 heteroatoms selected from the group consisting of a nitrogen, oxygen and sulfur atom, the carbon atom on said cyclic group being optionally a ketone form or the sulfur atom on said cyclic group being optionally an oxide form.  
     
     
         24 . The inhibitor of TNF-α production according to  claim 16 ,  21 ,  22 , or  23  in which R 1 and R 2  are a methyl group or a methoxy group; R 3  is a methyl group: R 4  is a carboxyl group which is optionally esterified or amidated; Z is  
       
         
           
           
               
               
           
         
       
       and n is an integer 1, 2, or 3.  
     
     
         25 . The inhibitor of TNF-α production according to any one of  claims 16  to  24  which is a suppressing agent for the gene expression of one or more substances selected from the group consisting of IL-1, TNF-α, IL-2, IL-6, IL-8, iNOS, granulocyte colony-stimulating factor, interferon-β, ICAM-1, VCAM-1, ELAM-1, plasminogen activator-inhibiting factor I, major histocompatibility system class I, major histocompatibility system class II, β2-microglobulin, immunoglobulin light chain, serum amyloid A, angiotensinogen, complement B, complement C4, c-myc, HIV, HTLV-1, SV40, CMV, and adenovirus.  
     
     
         26 . The inhibitor of TNF-α production according to any one of  claims 16  to  24  which is a preventive or therapeutic agent for inflammatory diseases.  
     
     
         27 . The inhibitor of TNF-α production according to any one of  claims 16  to  24  which is a preventive or therapeutic agent for autoimmune diseases.  
     
     
         28 . The inhibitor of TNF-α production according to any one of  claims 16  to  24  which is a preventive or therapeutic agent for viral diseases.  
     
     
         29 . A preventive or therapeutic agent for diseases caused by the excessive production of TNF-α comprising as an active ingredient a benzoquinone derivative represented by the following general formula (1):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , and R 3  are each independently a hydrogen atom, an alkyl group having 1 to 5 carbons, or an alkoxy group having 1 to 5 carbons;  
 R 4  is a hydrogen atom, a hydroxymethyl group, an alkyl group, or a carboxyl group which is optionally esterified or amidated;  
 Z is  
                     
 and, n is an integer from 0 to 6,  
 or its hydroquinone form, or a pharmaceutically acceptable salt thereof.  
 
     
     
         30 . A benzoquinone derivative represented by the following general formula (1):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1 , R 2 , and R 3  are each independently a hydrogen atom, an alkyl group having 1 to 5 carbons, or an alkoxy group having 1 to 5 carbons;  
 R 4  is a hydrogen atom, a hydroxymethyl group, an alkyl group, or a carboxyl group which is optionally esterified or amidated;  
 Z is  
                     
 and, n is an integer from 0 to 6,  
 provided that when Z is  
                     
 n is not 0, and when Z is  
                     
 n is neither 0 nor 2,  
 or its hydroquinone form, or a pharmaceutically acceptable salt thereof.  
 
     
     
         31 . The benzoquinone derivative according to  claim 30  in which R 1  and R 2  are a hydrogen atom, a methyl group, or a methoxy group, or its hydroquinone form or a pharmaceutically acceptable salt thereof.  
     
     
         32 . The benzoquinone derivative according to  claim 30  or  31  in which R 3  is a hydrogen atom or a methyl group, or its hydroquinone form or a pharmaceutically acceptable salt thereof.  
     
     
         33 . The benzoquinone derivative according to  claim 30 ,  31 , or  32  in which Z is  
       
         
           
           
               
               
           
         
       
       and n is an integer 1 or 3, or its hydroquinone form or a pharmaceutically acceptable salt thereof.  
     
     
         34 . The benzoquinone derivative according to any one of  claims 30  to  33  in which R 4  is a group —COOR 5  wherein R 5  is a hydrogen atom, an optionally substituted alkyl group having 1 to 8 carbons, an optionally substituted phenyl group, or an optionally substituted aralkyl group having 7 to 11 carbons, or its hydroquinone form or a pharmaceutically acceptable salt thereof.  
     
     
         35 . The benzoquinone derivative according to any one of  claims 30  to  33  in which R 4  is a group —CONR 6 R 7  wherein R 6  and R 7  are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 8 carbons, an optionally substituted bicyclic unsaturated or partially saturated hydrocarbon ring group having 9 to 11 carbons, an optionally substituted heterocyclic group, an optionally substituted phenyl group, an optionally substituted aralkyl group having 7 to 11 carbons, or a heteroaryl-C 1 -C 3 -alkyl group, or R 6  and R 7 , together with the nitrogen atom to which they are attached, represent a heterocyclic group which may further contain a nitrogen, oxygen and/or sulfur atom, or its hydroquinone form or a pharmaceutically acceptable salt thereof.  
     
     
         36 . The benzoquinone derivative according to any one of  claims 30  to  33  in which R 4  is a group —CONR 6 R 7  wherein R 6  and R 7 , together with the nitrogen atom to which they are attached, represent a 5- to 10-membered optionally substituted, nitrogen-containing heterocyclic group which may contain, in addition to the carbon and nitrogen atom, 1 to 3 heteroatoms selected from the group consisting of a nitrogen, oxygen and sulfur atom, the carbon atom on said cyclic group being optionally a ketone form or the sulfur atom on said cyclic group being optionally an oxide form, or its hydroquinone form or a pharmaceutically acceptable salt thereof.  
     
     
         37 . The benzoquinone derivative according to  claim 30 ,  34 ,  35 , or  36  in which R 1  and R 2  are a methyl group or a methoxy group; R 3  is a methyl group: R 4  is a carboxyl group which is optionally esterified or amidated; Z is  
       
         
           
           
               
               
           
         
       
       and n is an integer 1 or 3, or its hydroquinone form or a pharmaceutically acceptable salt thereof.