Lipid-rich plaque regressing agents

Abstract

The present invention provides a lipid-rich plaque regressing agent comprising a compound represented by Formula: in which ring A is a cyclic hydrocarbon or the like; ring B is a heterocyclic ring or the like; each of X and Y is —NR 1 — (in which R 1 is a hydrocarbon or the like); D is a C 1-3 alkylene group or the like; E is —NH— or the like; G is a bond or the like; and Ar is an aryl or the like; D may be taken together with a constituent atom of the ring B to form a ring, and R 4 may be taken together with a constituent atom of the ring B to form a ring.

1 - 11 . (canceled)  
   
   
       12 . A compound represented by Formula [V]:  
     
       
         
         
             
             
         
       
     
     in which each of R 10  and R 11  is a hydrogen atom, halogen atom, optionally substituted linear hydrocarbon group, or hydroxyl group which may be substituted by an optionally substituted linear hydrocarbon group, or the both may be taken together with the adjacent carbon atoms to form an optionally substituted cyclic hydrocarbon or a dihydrofuran ring which may be substituted by an oxo group, ring I is an optionally substituted benzene ring or optionally substituted pyridine ring, ring J is an optionally substituted benzene ring or optionally substituted pyridine ring, provided that when R 10  is a hydrogen atom, then R 11  is an optionally substituted linear hydrocarbon group, or a salt thereof.  
   
   
       13 . The compound according to  claim 12  wherein each of R 10  and R 11  is a hydrogen atom, halogen atom or optionally substituted linear hydrocarbon group, or the both are taken together with the adjacent carbon atoms to form an optionally substituted cyclic hydrocarbon.  
   
   
       14 . The compound according to  claim 12  wherein each of R 10  and R 11  is a halogen atom or optionally substituted C 1-7  alkyl group.  
   
   
       15 . The compound according to  claim 12  wherein the cyclic hydrocarbon is a C 5-7  cyclic hydrocarbon.  
   
   
       16 . The compound according to  claim 12  wherein the ring J is a benzene ring substituted by halogenated alkyl group and/or halogen atom.  
   
   
       17 . The compound according to  claim 12  wherein the ring I is a benzene ring which may be substituted by alkyl group, halogenated alkyl group or halogen atom.  
   
   
       18 . A compound represented by Formula [VI]:  
     
       
         
         
             
             
         
       
     
     in which each of R 12  and R 13  is a hydrogen atom, halogen atom or optionally substituted linear hydrocarbon group, or the both may be taken together with the adjacent carbon atoms to form an optionally substituted cyclic hydrocarbon,  
     
       
         
         
             
             
         
       
     
     is an optionally substituted phenyl group (provided that 2-chlorophenyl and 2-fluorophenyl are excluded), and ring L is an optionally substituted benzene ring or optionally substituted pyridine ring, provided that when  
     
       
         
         
             
             
         
       
     
     is a phenyl group, then R 13  is not a methyl group, and when  
     
       
         
         
             
             
         
       
     
     is a 2-methylphenyl group, then R 13  is not a chlorine atom, or a salt thereof.  
   
   
       19 . The compound according to  claim 18  wherein each of R 12  and R 13  is a halogen atom or C 1-3 alkyl group.  
   
   
       20 . The compound according to  claim 18  wherein the cyclic hydrocarbon is a C 5-7  cyclic hydrocarbon.  
   
   
       21 . The compound according to  claim 18  wherein  
     
       
         
         
             
             
         
       
     
     is a phenyl group which may be substituted by a C 1-3 alkyl group.  
   
   
       22 . The compound according to  claim 18  wherein the ring L is a substituted benzene ring.  
   
   
       23 . 2-[7-Chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide; 
 2-[7-chloro-4-(3-chlorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-4-(3-chloro-4-fluorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-4-(3-chloro-4-fluorophenyl)-6-methyl-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-methyl-4-(3-methylphenyl)-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-methyl-4-(3-methylphenyl)-2-oxo-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-2-oxo-4-phenyl-6-[(4-phenylpiperazin-1-yl)methyl]-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-[[4-(4-chlorophenyl)-3,6-dihydropyridin-1 (2H)-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-[[4-(4-chlorophenyl)-3,6-dihydropyridin-1 (2H)-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-[[4-(3-methylphenyl)piperidin-1-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide;    2-[7-chloro-6-[[4-(3-methylphenyl)piperidin-1-yl]methyl]-2-oxo-4-phenyl-2H-chromen-3-yl]-N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide; or a salt thereof.    
   
   
       24 . A prodrug of a compound according to  claim 12 .  
   
   
       25 . A pharmaceutical composition comprising a compound according to  claim 12  or a prodrug thereof, and a pharmaceutically acceptable carrier.  
   
   
       26 . A method for inhibiting progression of an arteriosclerotic focus comprising administering an effective amount of a compound having a lipid-rich plaque regressing effect or a salt thereof to a mammal in need thereof.  
   
   
       27 . The method according to  claim 26  wherein said compound is administered in combination with an HMG-CoA reductase inhibitor.  
   
   
       28 . A method for producing the compound according to  claim 12  or a salt thereof, which comprises reacting a compound represented by Formula [VII]:  
     
       
         
         
             
             
         
       
     
     [in which each symbol is as defined in  claim 12 ] or a salt thereof or a reactive derivative thereof with a compound represented by Formula [VIII]:  
     
       
         
         
             
             
         
       
     
     [in which each symbol is as defined in  claim 12 ] or a salt thereof.  
   
   
       29 . A method for producing the compound according to  claim 18  or a salt thereof, which comprises reacting a compound represented by Formula [IX]:  
     
       
         
         
             
             
         
       
     
     [in which each symbol is as defined in  claim 18 ] or a salt thereof or a reactive derivative thereof with a compound represented by Formula [X]:  
     
       
         
         
             
             
         
       
     
     [in which each symbol is as defined in  claim 18 ] or a salt thereof.  
   
   
       30 . A method for producing the compound according to  claim 18  or a salt thereof, which comprises reacting a compound represented by Formula [XI]:  
     
       
         
         
             
             
         
       
     
     [in which each symbol is as defined in  claim 18 ] or a salt thereof with a compound represented by Formula [XII]:  
     
       
         
         
             
             
         
       
     
     [in which each symbol is as defined in  claim 18 ] or a salt thereof.  
   
   
       31 . A method for regressing a lipid-rich plaque in a mammal, which comprises administering an effective amount of the compound according to  claim 23  or a salt thereof to a mammal.  
   
   
       32 . A method for preventing and treating acute coronary artery syndrome in a mammal, which comprises administering an effective amount of the compound according to  claim 12  or a salt thereof to a mammal.  
   
   
       33 . A method for preventing and treating acute myocardial infarction in a mammal, which comprises administering an effective amount of the compound according to  claim 12  or a salt thereof to a mammal.  
   
   
       34 . A method for preventing and treating unstable angina in a mammal, which comprises administering an effective amount of the compound according to  claim 12  or a salt thereof to a mammal.  
   
   
       35 . A method for preventing and treating peripheral artery occlusion in a mammal, which comprises administering an effective amount of the compound according to  claim 12  or a salt thereof to a mammal.  
   
   
       36 . A method for regressing a lipid-rich plaque in a mammal, which comprises administering an effective amount of the compound according to  claim 12 , a salt thereof or a prodrug thereof to a mammal.  
   
   
       37 . A method for regressing a lipid-rich plaque in a mammal, which comprises administering an effective amount of the compound according to  claim 18 , a salt thereof or a prodrug thereof to a mammal.  
   
   
       38 - 44 . (canceled)  
   
   
       45 . A prodrug of a compound according to  claim 18 .  
   
   
       46 . A prodrug of a compound according to  claim 23 .  
   
   
       47 . A pharmaceutical composition comprising a compound according to  claim 18  or a prodrug thereof, and a pharmaceutically acceptable carrier.  
   
   
       48 . A pharmaceutical composition comprising a compound according to  claim 23  or a prodrug thereof, and a pharmaceutically acceptable carrier.  
   
   
       49 . A method for inhibiting acyl coenzyme A cholesterol acyl transferase in a mammal comprising administering an effective amount of a compound of  claim 12 , a salt thereof or a prodrug thereof to a mammal in need thereof.  
   
   
       50 . A method for inhibiting acyl coenzyme A cholesterol acyl transferase in a mammal comprising administering an effective amount of a compound of  claim 18 , a salt thereof or a prodrug thereof to a mammal in need thereof.  
   
   
       51 . A method for inhibiting acyl coenzyme A cholesterol acyl transferase in a mammal comprising administering an effective amount of a compound of  claim 23 , a salt thereof or a prodrug thereof to a mammal in need thereof.