Novel n-acylurea derivative and composition comprising same for prevention or treatment of cardiovascular disease

Abstract

The present invention relates to a novel N-acylurea derivative and the use thereof for the prevention or treatment of cardiovascular disease, and more particularly to a novel N-acylurea derivative, a pharmaceutical composition for prevention or treatment of cardiovascular disease, which contains the N-acylurea derivative as an active ingredient, and a method of preparing the N-acylurea derivative. The N-acylurea derivative according to the present invention can inhibit platelet aggregation by inhibiting the activity of talin in the intracellular matrix, and thus can be useful for the prevention or treatment of cardiovascular disease.

What is claimed is: 
     
         1 . A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is tetrazolyl, piperazinyl, morpholinyl, phenyl linked by O, or benzodioxolyl linked by O, wherein the tetrazolyl, piperazinyl, morpholinyl, phenyl, or benzodioxolyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  haloalkyl, C 1-6  alkoxy, phenyl, phenoxy, and —O—C 2-20  alkylene-phenyl; 
         R 2  is phenyl, pyridinyl, C 2-20  alkylene-phenyl, C 2-20  alkylene-indolyl, or C 2-20  alkylene-dihydroindolyl, wherein the phenyl, pyridinyl, indolyl, or dihydroindolyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, —C 1-6  alkoxy-C 1-6  alkyl, —O-phenyl, and —O—C 2-20  alkylene-phenyl; and 
         R 3  and R 4  are each independently hydrogen, C 1-6  alkyl or C 1-6  haloalkyl. 
       
     
     
         2 . The compound or the pharmaceutically acceptable salt thereof of  claim 1 , wherein R 1  is tetrazolyl, phenyl linked by O or benzodioxolyl linked by O, wherein the tetrazolyl, phenyl or benzodioxolyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  haloalkyl, C 1-6  alkoxy, phenyl, phenoxy, and —O—C 2-20  alkylene-phenyl. 
     
     
         3 . The compound or the pharmaceutically acceptable salt thereof of  claim 1 , wherein the tetrazolyl, phenyl linked by O or benzodioxolyl linked by O in R 1  is substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  alkoxy, phenyl and phenoxy. 
     
     
         4 . The compound or the pharmaceutically acceptable salt thereof of  claim 1 , wherein R 2  is phenyl, C 2-20  alkylene-indolyl or C 2-20  alkylene-dihydroindolyl, wherein the phenyl, indolyl, or dihydroindolyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, —C 1-6  alkoxy-C 1-6  alkyl, —O-phenyl, and —O—C 2-20  alkylene-phenyl. 
     
     
         5 . The compound or the pharmaceutically acceptable salt thereof of  claim 1 , wherein the phenyl, pyridinyl, indolyl, or dihydroindolyl in R 2  is substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  alkoxy, phenoxy, and —O—C 2-20  alkylene-phenyl. 
     
     
         6 . The compound or the pharmaceutically acceptable salt thereof of  claim 1 , wherein R 3  and R 4  are each independently hydrogen. 
     
     
         7 . A pharmaceutical composition for treating cardiovascular disease, comprising the compound or the pharmaceutically acceptable salt thereof of  claim 1 , as an active ingredient, and a pharmaceutically acceptable carrier. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the cardiovascular disease is selected from the group consisting of hypertension, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, arteriosclerosis, cerebrovascular disease and arrhythmia. 
     
     
         9 . A method of preparing a compound of Formula 1, comprising:
 (a) obtaining acetamide by mixing and reacting 2-chloroacetamide, N,N-dimethylformamide, potassium carbonate and a nucleophilic reagent in a reactor, terminating a reaction by addition of water, followed by concentrating;   (b) obtaining acetyl isocyanate by adding oxalyl chloride to the obtained acetamide, adding dichloroethane and heating and stirring, followed by concentrating; and   (c) obtaining a compound by adding methylene chloride to the obtained acetyl isocyanate, adding and reacting a nucleophilic reagent, followed by concentrating,   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is tetrazolyl, piperazinyl, morpholinyl, phenyl linked by O, or benzodioxolyl linked by O, wherein the tetrazolyl, piperazinyl, morpholinyl, phenyl, or benzodioxolyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  haloalkyl, C 1-6  alkoxy, phenyl, phenoxy, and —O—C 2-20  alkylene-phenyl; 
         R 2  is phenyl, pyridinyl, C 2-20  alkylene-phenyl, C 2-20  alkylene-indolyl, or C 2-20  alkylene-dihydroindolyl, wherein the phenyl, pyridinyl, indolyl, or dihydroindolyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, —C 1-6  alkoxy-C 1-6  alkyl, —O-phenyl, and —O—C 2-20  alkylene-phenyl; and 
         R 3  and R 4  are each independently hydrogen, C 1-6  alkyl or C 1-6  haloalkyl. 
       
     
     
         10 . A method of preparing a compound of Formula 1, comprising:
 (a) obtaining 2-chloroacetyl isocyanate by mixing 2-chloroacetamide and oxalyl chloride in a reactor, adding dichloroethane and heating and stirring, followed by concentrating;   (b) obtaining carbamoyl 2-chloroacetamide by adding methylene chloride to the obtained 2-chloroacetyl isocyanate, and then adding a nucleophilic reagent and reacting, followed by concentrating; and   (c) obtaining N-acylurea derivative by adding methanol to the obtained carbamoyl 2-chloroacetamide, adding and reacting a nucleophilic reagent while stirring, extracting an N-acylurea derivative using an organic solvent,   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is tetrazolyl, piperazinyl, morpholinyl, phenyl linked by O, or benzodioxolyl linked by O, wherein the tetrazolyl, piperazinyl, morpholinyl, phenyl, or benzodioxolyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  haloalkyl, C 1-6  alkoxy, phenyl, phenoxy, and —O—C 2-20  alkylene-phenyl; 
         R 2  is phenyl, pyridinyl, C 2-20  alkylene-phenyl, C 2-20  alkylene-indolyl, or C 2-20  alkylene-dihydroindolyl, wherein the phenyl, pyridinyl, indolyl, or dihydroindolyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, —C 1-6  alkoxy-C 1-6  alkyl, —O-phenyl, and —O—C 2-20  alkylene-phenyl; and 
         R 3  and R 4  are each independently hydrogen, C 1-6  alkyl or C 1-6  haloalkyl. 
       
     
     
         11 . The method of  claim 9 , wherein the nucleophilic reagent is selected from the group consisting of 4-bromo-3-methoxyanilin, 4-methoxybenzylamine, tryptamine, 2,4-dimethoxyaniline, 4-(benzyloxy)aniline, 2-fluoroaniline, Sesamol, 3-fluoropyridin-2-amine, 4-methoxyphenyl)methanamine, 4-(benzyloxy)aniline HCl, 2-methoxyphenol, 4-phenoxyaniline, 3,5-bis(trifluoromethyl)phenol, 3-bromophenol, 4-bromo-3-methoxyaniline, 2,3-dimethylphenol and 4-(benzyloxy)phenol. 
     
     
         12 . The method of  claim 10 , wherein the nucleophilic reagent is selected from the group consisting of 4-bromo-3-methoxyanilin, 4-methoxybenzylamine, tryptamine, 2,4-dimethoxyaniline, 4-(benzyloxy)aniline, 2-fluoroaniline, Sesamol, 3-fluoropyridin-2-amine, 4-methoxyphenyl)methanamine, 4-(benzyloxy)aniline HCl, 2-methoxyphenol, 4-phenoxyaniline, 3,5-bis(trifluoromethyl)phenol, 3-bromophenol, 4-bromo-3-methoxyaniline, 2,3-dimethylphenol and 4-(benzyloxy)phenol.