Imidazo-5-carboxylic-acid derivatives, its preparing method and use

A kind of imidazole and compound technology, applied in imidazole-5-carboxylic acid derivatives, preparation and application fields

Inactive Publication Date: 2007-08-29
SHANGHAI ALLIST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, only 14% of losartan potassium is metabolized into its active metabolite EXP3174 in the body. Although losartan potassium itself also has strong antihypertensive properties, it is only 3% of the antihypertensive properties of EXP3174

Method used

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  • Imidazo-5-carboxylic-acid derivatives, its preparing method and use
  • Imidazo-5-carboxylic-acid derivatives, its preparing method and use
  • Imidazo-5-carboxylic-acid derivatives, its preparing method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] 2-Butyl-4-chloro-1-[2`-(1H-tetrazol-5-yl)1,1`-biphenyl-methyl]imidazole-5-carboxylic acid

[0085]

[0086] Add 10ml water to 2-butyl-4-chloro-1-[2`-(1H-tetrazol-5-yl)1,1`-biphenyl-methyl]-5-hydroxymethylimidazole 4.57g Dissolve, cool to -5-0°C, add 1.58g KMnO dropwise 4 130ml of aqueous solution, after dropping, react at 50°C for 16h. Stop the reaction, filter, add 1mol / L NaS to the filtrate 2 o 3 50ml, then adjust the pH of the solution to 2-3 with dilute hydrochloric acid, the solution becomes cloudy, extract with ethyl acetate, dry, concentrate, pass through a flash column, and use petroleum ether: ethyl acetate = 1:6 as the mobile phase to obtain a white solid 3.85g, yield 89.1%.

[0087] 1HNMR (CDC13):

[0088] δH 0.801(3H, t, J=3.6), 25(2H, m, J=3.5), 1.49(2H, m, J=5), 2.56(2H, t, J=3.5), 5.58(2H, s ), 6.94-7.08 (4H, m, J=5), 7.65-7.50 (2H, m, J=8.5)

[0089] ESI(-): 435.1

[0090] MP: 125.2-128.5°C

Embodiment 2

[0092] 2-Butyl-4-chloro-1-[2`-(1-trityl-tetrazol-5-yl)1,1`-biphenyl-methyl]imidazole-5-carboxylic acid

[0093]

[0094] In a 100ml one-port bottle, add 2-butyl-4-chloro-1-[2`-(1H-tetrazol-5-yl)1,1`-biphenyl-methyl]imidazole-5-carboxyl Acid 4.36g, 15ml N,N-dimethylformamide, 1.66g potassium carbonate and 2.78g triphenylchloromethane, react overnight at room temperature, stop the reaction, add 100ml water, extract with 100ml ethyl acetate, and wash with saturated brine Once, the organic phase was dried and concentrated to give yellow oil 2-butyl-4-chloro-1-[2`-(1-trityl-tetrazol-5-yl)1,1`-biphenyl -Methyl]imidazole-5-carboxylic acid 7.5 g.

[0095] The crude product obtained in this example was used as the raw material mentioned in the following examples without purification.

Embodiment 3

[0097] 2-Butyl-4-chloro-1-[2`-(1H-tetrazol-5-yl)1,1`-biphenyl-methyl]imidazole-5-carboxylic acid ethyl ester

[0098]

[0099] Add 15ml of absolute ethanol and 312mg of p-toluenesulfonic acid (TsOH) to 678.5mg of raw materials, and reflux for 6h. After the reaction, add 30ml of water, extract with 30ml of ether, dry the organic phase, and concentrate to obtain the colorless oily product 2-butyl-4 -Ethyl chloro-1-[2'-(1H-tetrazol-5-yl)1,1'-biphenyl-methyl]imidazole-5-carboxylate 274 mg, yield 59%.

[0100] 1 H-NMR (CDCl 3 )

[0101] δH(ppm): 0.80-0.85(m, 6H, J=13.6), 1.26(m, 2H, J=20.2), 1.38(H, t, J=14.8), 1.58(m, 2H, J=7.5) , 2.69(q, 2H, J=24.5), 5.44(s, 2H), 6.94-7.50(8H), 8.10(d, 1H, J=6.14)

[0102] ESI (+) m / z: 465.1

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Abstract

The invention discloses an imidazole-5-carboxylic acids derivative and the manufacturing method. It is the angiotensin II acceptor antagon. It has strong angiotensin II antagonize activity and high blood pressure proofing activity. And it could be used as therapeutic agent to cure high blood pressure.

Description

technical field [0001] The present invention relates to imidazole-5-carboxylic acid derivatives and their preparation methods, as well as the application of these derivatives as antihypertensive drugs. Background of the invention [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 (Ang I) through the action of renin. Angiotensin II (Ang II), which is further converted into octapeptide under the action of angiotensin-converting enzyme, is the final physiologically active substance of the renin-angiotensin-aldosterone system (RAS), which can bind to specific vascular Tensin II (AT II) receptor binding to produce vasoconstriction, blood pressure and other physiological effects. [0003] EP025331...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07D403/14A61K31/41A61P9/12
CPCC07D405/14C07D403/10A61P9/12A61P43/00A61K31/41C07D233/90C07D405/10
Inventor 安东郭建辉
Owner SHANGHAI ALLIST PHARM CO LTD
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