Dihydroorotic acid dehydrogenase inhibitor

Abstract

The present invention provides a novel dihydroorotic acid dehydrogenase inhibitor which is applicable to various diseases. When used as an active ingredient, a compound represented by formula (I): (wherein X represents a halogen atom, R 1 represents a hydrogen atom, R 2 represents an alkyl group containing 1 to 7 carbon atoms, R 3 represents —CHO, and R 4 represents —CH 2 —CH═C(CH 3 )—R 0 (wherein R 0 represents an alkyl group containing 1 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon, etc.)), an optical isomer thereof or a pharmaceutically acceptable salt thereof has a high inhibitory effect on dihydroorotic acid dehydrogenase and can be used as an immunosuppressive agent, a therapeutic agent for rheumatism, an anticancer agent, a therapeutic agent for graft rejection, an antiviral agent, an anti- H. pylori agent, a therapeutic agent for diabetes or the like.

1 . A dihydroorotic acid dehydrogenase inhibitor comprising, as an active ingredient(s), one or two or more of compounds represented by formula (I): 
       
         
           
           
               
               
           
         
         (wherein
 X represents a halogen atom, 
 R 1  represents a hydrogen atom, 
 R 2  represents an alkyl group containing 1 to 7 carbon atoms, 
 R 3  represents —CHO, and 
 R 4  represents —CH 2 —CH═C(CH 3 )—R 0  (wherein R 0  represents an alkyl group containing 1 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon, an alkenyl group containing 2 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon, or an alkynyl group containing 2 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon)), optical isomers thereof and pharmaceutically acceptable salts thereof, as well as a pharmaceutically acceptable carrier. 
 
       
     
     
         2 . The dihydroorotic acid dehydrogenase inhibitor according to  claim 1 , wherein
 X represents a chlorine atom,   R 2  represents a methyl group, and   R 4  represents —CH 2 —CH═C(CH 3 )—R 0  (wherein R 0  represents an alkyl group containing 1 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon, or an alkenyl group containing 2 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon), provided that when Ro has a substituent, the substituent is selected from the group consisting of —O—CO—C(CH 3 ) 3 , —O—CO—CH(CH 3 ) 2 , —C(CH 3 ) 2 —O—CH 3 , —O-(2-furyl), —OH, —CH(OCH 3 )—CH 2 —CO—C(CH 3 ) 3 , —CHO, —CO—O—CH 3 , —CO—CH 3 , —O—CO—CH 3  and —CO—C(CH 3 ) 3 .   
     
     
         3 . The dihydroorotic acid dehydrogenase inhibitor according to  claim 1 , wherein the compounds represented by formula (I) are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The dihydroorotic acid dehydrogenase inhibitor according to  claim 1 , which comprises glycerol. 
     
     
         5 . The dihydroorotic acid dehydrogenase inhibitor according to  claim 1 , which is used as an immunosuppressive agent. 
     
     
         6 . The dihydroorotic acid dehydrogenase inhibitor according to  claim 1 , which is used as a therapeutic agent for rheumatism. 
     
     
         7 . The dihydroorotic acid dehydrogenase inhibitor according to  claim 1 , which is used as an anticancer agent. 
     
     
         8 . The dihydroorotic acid dehydrogenase inhibitor according to  claim 1 , which is used as a therapeutic agent for graft rejection in organ transplantation. 
     
     
         9 . The dihydroorotic acid dehydrogenase inhibitor according  claim 1 , which is used as a therapeutic agent for diabetes. 
     
     
         10 . The dihydroorotic acid dehydrogenase inhibitor according to  claim 1 , which is used as an antiviral agent. 
     
     
         11 . The dihydroorotic acid dehydrogenase inhibitor according to  claim 1 , which is used as an anti- H. pylori  agent. 
     
     
         12 . A kit comprising a dihydroorotic acid dehydrogenase inhibitor comprising, as an active ingredient(s), one or two or more of compounds represented by formula (I): 
       
         
           
           
               
               
           
         
         (wherein
 X represents a halogen atom, 
 R 1  represents a hydrogen atom, 
 R 2  represents an alkyl group containing 1 to 7 carbon atoms, 
 R 3  represents —CHO, and 
 R 4  represents —CH 2 —CH═C(CH 3 )—R 0  (wherein R 0  represents an alkyl group containing 1 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon, an alkenyl group containing 2 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon, or an alkynyl group containing 2 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon)), optical isomers thereof and pharmaceutically acceptable salts thereof, as well as instructions for use thereof. 
 
       
     
     
         13 . The kit according to  claim 12 , wherein
 X represents a chlorine atom,   R 2  represents a methyl group, and   R 4  represents —CH 2 —CH═C(CH 3 )—R 0  (wherein R 0  represents an alkyl group containing 1 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon, or an alkenyl group containing 2 to 12 carbon atoms which may have a substituent on the terminal carbon and/or on a non-terminal carbon), provided that when Ro has a substituent, the substituent is selected from the group consisting of —O—CO—C(CH 3 ) 3 , —O—CO—CH(CH 3 ) 2 , —C(CH 3 ) 2 —O—CH 3 , —O-(2-furyl), —OH, —CH(OCH 3 )—CH 2 —CO—C(CH 3 ) 3 , —CHO, —CO—O—CH 3 , —CO—CH 3 , —O—CO—CH 3  and —CO—C(CH 3 ) 3 .   
     
     
         14 . The kit according to  claim 12 , wherein the compounds represented by formula (I) are selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The kit according to  claim 12 , which comprises glycerol. 
     
     
         16 . The kit according to  claim 12 , which is used as an immunosuppressive agent. 
     
     
         17 . The kit according to  claim 12 , which is used as a therapeutic agent for rheumatism. 
     
     
         18 . The kit according to  claim 12 , which is used as an anticancer agent. 
     
     
         19 . The kit according to  claim 12 , which is used as a therapeutic agent for graft rejection in organ transplantation. 
     
     
         20 . The kit according to  claim 12 , which is used as a therapeutic agent for diabetes. 
     
     
         21 . The kit according to  claim 12 , which is used as an antiviral agent. 
     
     
         22 . The kit according to  claim 12 , which is used as an anti- H. pylori  agent.