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Salt of imidazole-carboxylic acid derivant, production method and pharmaceutical composition thereof

A pharmacy, general formula technology, applied in the direction of drug combination, active ingredients of heterocyclic compounds, and medical preparations containing active ingredients, etc., can solve the problems of poor compound solubility, complicated preparation process and insoluble

Active Publication Date: 2008-06-11
HUIZHOU XINLITAI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, in the process of research on this type of imidazole-5-carboxylic acid derivatives, it was found that it is insoluble in conventional solvents, and it is necessary to use pharmaceutical methods such as solid dispersion technology to enhance the water solubility of this type of compound, resulting in Complicated preparation process
Therefore, there is an urgent need to develop new forms of imidazole-5-carboxylic acid derivatives to solve the problem of poor solubility of such compounds, so as to be suitable for conventional preparation processes and prepare more ideal antihypertensive drugs

Method used

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  • Salt of imidazole-carboxylic acid derivant, production method and pharmaceutical composition thereof
  • Salt of imidazole-carboxylic acid derivant, production method and pharmaceutical composition thereof
  • Salt of imidazole-carboxylic acid derivant, production method and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] 2-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropyl) Oxy)carbonyl]methoxyester (Compound 1)

[0079] 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylic acid (prepared by US5138069 report method) , reacted with triphenylchloromethane to give 2-butyl-4-chloro-1-[2'-(1-trityl-tetrazol-5-yl)1,1'-biphenyl-methyl yl]imidazole-5-carboxylic acid. Add 2-butyl-4-chloro-1-[2'-(1-trityl-tetrazol-5-yl)1,1'-biphenyl-methyl"imidazole to the 100ml single-necked bottle in turn -5-Carboxylic acid, 0.523g, K 2 CO 3 0.124g, 5ml of N,N-dimethylacetamide, stirred at room temperature for 20min, added 0.562g of chloromethyl isopropoxyformate at room temperature, and reacted at 45-50°C for 16h. After the reaction is completed, filter, add 30 ml of water to the filtrate, extract twice with 30 ml of ethyl acetate, dry the organic phase, and concentrate to obtain 1.724 g of an oily substance, which is dire...

Embodiment 2

[0086] 2-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropyl) Oxy)carbonyl]methoxyester, potassium salt (compound 2)

[0087]

[0088] In a 100ml three-necked flask, add 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylic acid , 2.50 g (4.52 mmol) of 1-[(isopropoxy)carbonyl]methoxyester and 25 ml of tetrahydrofuran (THF). After stirring and dissolving, 0.645 g of potassium trimethylsiliconate (4.52 mmol, 90% content, Aldrich) dissolved in 15 ml of THF was added, and the reaction was carried out at room temperature of 28° C. for 17 h.

[0089] After the reaction, there was a small amount of white flocs in the reaction solution, which was filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid crude product. Recrystallization from a mixed solution of isopropyl ether and ethanol (3:1 v / v) gave 1.42 g of 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1 '-Bipheny...

Embodiment 3

[0100] 2-Butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropyl Oxy)carbonyl]methoxy ester, potassium salt (Compound 2)

[0101]

[0102] Take 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl) 1,1′-biphenyl-methyl] imidazole-5-carboxylic acid, 1-[(iso Propoxy) carbonyl] methoxy ester 2.0g (3.62mmol), dissolved in 20ml isopropanol, slowly added 15% potassium 2-ethylhexanoate 4.83g (3.98mmol) at room temperature (25°C) ), heated up to 75°C, and reacted for 17h.

[0103] Heating was stopped, the temperature was naturally lowered to room temperature, and left standing for 48 hours, a small amount of white solid was precipitated. After filtration, 0.51 g of white solid was obtained, with a yield of 24%. After purification, it is 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylic acid, 1 -[(isopropoxy)carbonyl]methoxy ester, potassium salt.

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Abstract

The invention provides a pharmacy acceptable salt type of imidazole-5-carboxyl acid derivative, a relative preparation method and a drug compound. The inventive salt has good solubility in general solvent as water and methanol, good biological availability in animal body and the application for developing general agent to treat high blood pressure.

Description

technical field [0001] The present invention relates to the pharmaceutically acceptable salt form of imidazole-5-carboxylic acid derivative, its preparation method and pharmaceutical composition. Through the research on the salt-forming method of imidazole-5-carboxylic acid derivatives, a new form of this type of compound is obtained, which effectively solves the problem of complex preparation process caused by the poor solubility of this type of compound. Background technique [0002] Angiotensin II is the major vasoconstrictor hormone of the renin-angiotensin-aldosterone system (RAAS), which plays an important role in the pathophysiology of a variety of chronic diseases. It exists in a variety of tissues, and the main way of its production is: angiotensinogen can be converted into decapeptide angiotensin I (AngI) through the action of renin. AngI has only weak vasoconstriction effect, and can be further activated in the blood vessels. Angiotensin II (AngII), which is conv...

Claims

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Application Information

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IPC IPC(8): C07D403/10A61K31/4178A61K31/41A61P9/12
Inventor 安东郭建辉
Owner HUIZHOU XINLITAI PHARMA
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