Novel anilide compounds and drugs containing the same

Abstract

The invention relates to novel anilide compounds represented by the following formula IV: as that formula is further defined herein. The inventive compounds are useful in the form of a pharmaceutical composition, specifically as an acyl coenzyme A cholesterol acyltransferase (ACAT) inhibitor.

1 . A compound represented by the general formula I, a salt thereof or a solvated compound thereof:  
       
         
           
           
               
               
           
         
         represents a divalent residue of benzene with a substituent(s), heterocycle-condensed benzene which may or may not have a substituent, pyridine which may or may not have a substituent, cyclohexane or naphthalene or  
         
           
             
             
                 
                 
             
           
         
         Ar represents an aryl group which may or may not have a substituent;  
         X represents —NH—, oxygen atom or sulfur atom;  
         Y represents —NR 4 —, oxygen atom, sulfur atom, sulfoxide or sulfone;  
         Z represents single bond or —NR 5 —;  
         R 4  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent;  
         R 5  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent; and  
         n represents an integer of 0 to 15.  
       
     
     
         2 . A compound represented by the following formula II, a salt thereof or a solvated product thereof:  
       
         
           
           
               
               
           
         
         represents a divalent residue of benzene with a substituent(s), heterocycle-condensed benzene which may or may not have a substituent, pyridine which may or may not have a substituent, cyclohexane or naphthalene or  
         
           
             
             
                 
                 
             
           
         
         X represents —NH—, oxygen atom or sulfur atom;  
         Y represents —NR 4 —, oxygen atom, sulfur atom, sulfoxide or sulfone;  
         Z represents single bond or —NR 5 —;  
         R 1 , R 2  and R 3  may be the same or different and represent hydrogen atom, a lower alkyl group, a lower alkoxyl group, halogen atom, hydroxyl group, phosphate group, sulfonamide group, or amino group which may or may not have a substituent; otherwise, any combination of two of R 1 , R 2  and R 3  represents an alkylene dioxy group;  
         R 4  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent;  
         R 5  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent; and  
         n represents an integer of 0 to 15.  
       
     
     
         3 . A compound represented by the following formula III, a salt thereof or a solvated product thereof:  
       
         
           
           
               
               
           
         
         wherein  
         X represents —NH—, oxygen atom or sulfur atom;  
         Y represents —NR 4 —, oxygen atom, sulfur atom, sulfoxide or sulfone;  
         Z represents single bond or —NR 5 —; R 1 , R 2  and R 3  may be the same or different and represent hydrogen atom, a lower alkyl group, a lower alkoxyl group, halogen atom, hydroxyl group, phosphate group, sulfonamide group, or amino group which may or may not have a substituent; otherwise, any combination of two of R 1 , R 2  and R 3  represents alkylene dioxy group;  
         R 4  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent;  
         R 5  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent;  
         R 6 , R 7  and R 8  may be the same or different and represent hydrogen atom, a lower alkyl group which may or may not have a substituent, a lower alkoxyl group which may or may not have a substituent, halogen atom, hydroxyl group, carboxyl group, an alkoxycarbonyl group which may or may not have a substituent, an alkylcarbonyloxy group which may or may not have a substituent, an alkylcarbonyl group which may or may not have a substituent, carbamoyl group which may or may not have a substituent, a hydroxyalkyl group, phosphate group, cyano group, nitro group, sulfonamide group, amino group which may or may not have a substituent, an aminoalkyl group which may or may not have a substituent, or a heterocyclic residue; otherwise, any combination of two of R 6 , R 7  and R 8  represents an alkylene dioxy group, provided that R 6 , R 7  and R 8  never simultaneously represent hydrogen atom; and  
         n represents an integer of 0 to 15.  
       
     
     
         4 . A compound represented by the following general formula IV, a salt thereof or a solvated product thereof:  
       
         
           
           
               
               
           
         
         X represents —NH—, oxygen atom or sulfur atom;  
         Y represents —NR 4 —, oxygen atom, sulfur atom, sulfoxide or sulfone;  
         Z represents single bond or —NR 5 —;  
         R 1 , R 2  and R 3  may be the same or different and represent hydrogen atom, a lower alkyl group, a lower alkoxyl group, halogen atom, hydroxyl group, phosphate group, sulfonamide group, or amino group which may or may not have a substituent; otherwise, any combination of two of R 1 , R 2  and R 3  represents an alkylene dioxy group;  
         R 4  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent;  
         R 5  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent;  
         R 9 , R 10 , R 9 ′, R 10 ′, R 9 ″, R 10 ″, R 9 ′″, and R 10 ′″ may be the same or different and represent hydrogen atom, a lower alkyl group which may or may not have a substituent, a lower alkoxyl group which may or may not have a substituent, halogen atom, hydroxyl group, carboxyl group, an alkoxycarbonyl group which may or may not have a substituent, an alkylcarbonyloxy group which may or may not have a substituent, an alkylcarbonyl group which may or may not have a substituent, carbamoyl group which may or may not have a substituent, a hydroxyalkyl group, phosphate group, sulfonamide group, amino group which may or may not have a substituent, an aminoalkyl group which may or may not have a substituent, or a heterocyclic residue; otherwise, any combination of two thereof represents an alkylene dioxy group; and  
         n represents an integer of 0 to 15.  
       
     
     
         5 . A pharmaceutical composition comprising a compound, a salt thereof or a solvated compound thereof according to any one of  claims 1  to  4 , and a pharmaceutically acceptable carrier.  
     
     
         6 . A pharmaceutical composition according to  claim 5 , which is an ACAT inhibitor, an intra-cellular cholesterol transfer inhibitory agent, a blood cholesterol-reducing agent or a macrophage foaming-suppressing agent.  
     
     
         7 . A pharmaceutical composition according to  claim 5 , which is a prophylactic and therapeutic agent of hyperlipidemia, arteriosclerosis, cerebrovascular diseases, ischemic cardiac diseases, ischemic intestinal diseases or aortic aneurysm.  
     
     
         8 . A method for therapeutically treating diseases with the etiology of ACAT, intra-cellular cholesterol transfer, blood cholesterol or macrophage foaming, comprising administering a therapeutically effective dose of a compound, a salt thereof or a solvated compound thereof according to any one of  claims 1  to  4 .  
     
     
         9 . A method for therapeutically treating hyperlipidemia, arteriosclerosis, cerebrovascular diseases, ischemic cardiac diseases, ischemic intestinal diseases or aortic aneurysm, comprising administering a therapeutically effective dose of a compound, a salt thereof or a solvated compound thereof according to any one of  claims 1  to  4 .  
     
     
         10 . The use of a compound, a salt thereof or a solvated compound thereof according to any one of  claims 1  to  4 , for producing an ACAT inhibitor, an intra-cellular cholesterol transfer inhibitory agent, a blood cholesterol-reducing agent or a macrophage foaming-suppressing agent.  
     
     
         11 . The use of a compound, a salt thereof or a solvated compound thereof according to any one of  claims 1  to  4 , for therapeutically treating hyperlipidemia, arteriosclerosis, cerebrovascular diseases, ischemic cardiac diseases, ischemic intestinal diseases or aortic aneurysm.