Imidazole-5-carboxylic acid derivatives, the preparation method therefor and the uses thereof

Abstract

The invention discloses imidazole-5-carboxylic acid derivatives, and their preparation methods. The derivatives of the invention are Angiotensin II receptor antagonists with angiotensin II antagonistic activity and antihypertensive activity, and thereby can be used as a therapeutical agent to treat hypertension.

The invention claimed is: 
     
       1. A compound of formula (I), or its pharmaceutically acceptable salts, 
       
         
           
           
               
               
           
         
         wherein R is 
       
       
         
           
           
               
               
           
         
         wherein R1 and R2 are independently selected from the group consisting of hydrogen, straight or branched C 1 -C 4 alkyl, and C 3 -C 7 cycloalkyl, and wherein the alkyl or the cycloalkyl group is unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, Br, NH 2 , and OH. 
       
     
     
       2. The compound and or its pharmaceutically acceptable salts according to  claim 1 , wherein R is 
       
         
           
           
               
               
           
         
         wherein R2 is selected from the group consisting of straight or branched C 1 -C 4  alkyl, and C 3 -C 7  cycloalkyl. 
       
     
     
       3. The compound and or its pharmaceutically acceptable salts according to  claim 1  wherein R is 
       
         
           
           
               
               
           
         
         wherein R1 is selected from the group consisting of hydrogen, straight or branched C 1 -C 4  alkyl, and C 3 -C 7  cycloalkyl. 
       
     
     
       4. The compound and or its pharmaceutically acceptable salts according to  claim 1  wherein R is 
       
         
           
           
               
               
           
         
         wherein R2 is selected from the group consisting of hydrogen, straight or branched C 1 -C 4  alkyl, and C 3 -C 7  cycloalkyl. 
       
     
     
       5. The compound and or its pharmaceutically acceptable salts according to  claim 4 , wherein R2 is straight or branched C 1 -C 4  alkyl. 
     
     
       6. The compound or its pharmaceutically acceptable salts according to  claim 1 , wherein the compounds are selected from the following group consisting of:
 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, pivaloyloxymethyl ester; 
 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester; 
 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(ethoxycarbonyl)oxy]methyl ester; and 
 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(tert-butoxycarbonyl)oxy]methyl ester. 
 
     
     
       7. A pharmaceutical composition comprising 0.05-50 mg of the compound or its pharmaceutically acceptable salts according to  claim 1 , and pharmaceutically acceptable carriers, excipients or diluents. 
     
     
       8. A method of treating hypertension, by inhibiting I receptors of angiotensin II, comprising the step of administrating a patient in need of such treatment with the compound or its pharmaceutically acceptable salts according to  claim 1  in the amount of 0.05-30 mg/kg weight/day. 
     
     
       9. A process to prepare the compound of formula I according to  claim 1  or a pharmaceutically acceptable salt thereof, comprising the steps of:
 (a) losartan potassium is oxidized to 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid; 
 
       
         
           
           
               
               
           
         
         (b) the oxidative product obtained from step (a) is reacted with triphenylchloromethane to give 2-butyl-4-chloro-1-[2′-(1-triphenylmethyl-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid; 
       
       
         
           
           
               
               
           
         
         (c) the product obtained from the step (b) is reacted with the compounds of formula X—R to give esterified intermediates under alkaline condition; then the trityl is deprotected to give the compound of formula I, wherein X is halogen and R represents the following structures: 
       
       
         
           
           
               
               
           
         
         wherein, R1 and R2 are independently selected from the group consisting of hydrogen, straight or branched C 1 -C 4  alkyl, and C 3 -C 7  cycloalkyl, 
       
       
         
           
           
               
               
           
         
         (d) and optionally converting the product of step (c) to a pharmaceutically acceptable salt thereof. 
       
     
     
       10. A compound selected from:
 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, pivaloyloxymethyl ester;   2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester;   2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(ethoxycarbonyl)oxy]methyl ester; and   2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(tert-butoxycarbonyl)oxy]methyl ester.   
     
     
       11. 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester of the formula: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       12. A pharmaceutically acceptable salt of a compound selected from:
 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, pivaloyloxymethyl ester;   2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester;   2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(ethoxycarbonyl)oxy]methyl ester; and   2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(tert-butoxycarbonyl)oxy]methyl ester.   
     
     
       13. A pharmaceutically acceptable salt of 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester. 
     
     
       14. A pharmaceutical composition comprising 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester, and a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
       15. A pharmaceutical composition comprising a pharmaceutically acceptable salt of 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester, and a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
       16. A method of treating hypertension, by inhibiting the type I receptor of angiotensin II, comprising administrating to a patient in need of said treating an amount effective for treating hypertension of 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester. 
     
     
       17. A method of treating hypertension, by inhibiting the type I receptor of angiotensin II, comprising administrating to a patient in need of said treating an amount effective for treating hypertension of a pharmaceutically acceptable salt of 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester.