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Imidazole carboxylic acid derivative

A carboxyl group, compound technology, applied in the field of medicine, can solve the problems of drug selectivity, unsatisfactory safety, etc.

Inactive Publication Date: 2014-08-06
TONGHUA SIHUAN PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the selectivity and safety of the above drugs are not satisfactory.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] Example 1: 1-((2-(2-(1H-tetrazol-5-yl)phenyl)quinolin-6-yl)methyl)-4-(2-hydroxypropan-2-yl) - Preparation of 2-propyl-1H-imidazole-5-carboxylic acid (compound 1)

[0152] 1) Preparation of 2-bromo-6-bromomethylquinoline

[0153]

[0154] 2-Bromo-6-methylquinoline (0.13 g, 0.585 mmol), peroxybenzoic acid (0.114 g, 0.643 mmol) and N-bromosuccinimide (0.2 g, 1.12 mmol) were dissolved in 50 mL In carbon chloride, heated to 70°C and stirred for 5 hours, cooled, and the mixture obtained by distillation under reduced pressure was directly used in the next reaction.

[0155] 2) Preparation of ethyl 1-((2-bromoquinolin-6-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate

[0156]

[0157] 4-(2-Hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (0.287g, 1.2mmol) and 0.165g potassium carbonate were dissolved in 20mL DMF and added while stirring The 2-bromo-6-bromomethylquinoline mixture obtained in the previous step was stirred fo...

Embodiment 2

[0165] Example 2: 1-((5-(2-(1H-tetrazol-5-yl)phenyl)pyridin-2-yl)methyl)-4-(2-hydroxypropan-2-yl)- Preparation of 2-propyl-1H-imidazole-5-carboxylic acid (compound 2)

[0166] 1) Preparation of ethyl 1-((5-bromopyridin-2-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate

[0167]

[0168] 4-(2-Hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (4g, 16.7mmol), 2-bromomethyl-5-bromopyridine (4.48g, 18mmol ) and potassium carbonate (9, 49mmol) were dissolved in 25mL DMA, stirred at room temperature for 18 hours, diluted with water, extracted with ethyl acetate, combined organic phases, washed with saturated sodium chloride solution, silica gel column (petroleum ether / acetic acid=ethyl ether) Ester 4:1) to give ethyl 1-((5-bromopyridin-2-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate Esters 4.2g.

[0169] 2) 1-((5-(2-(1H-tetrazol-5-yl)phenyl)pyridin-2-yl)methyl)-4-(2-hydroxypropan-2-yl)-2- Preparation of eth...

Embodiment 3

[0176] Example 3: 1-((1-(2-(1H-tetrazol-5-yl)phenyl)-1H-indol-4-yl)methyl)-4-(2-hydroxypropan-2 Preparation of -yl)-2-propyl-1H-imidazole-5-carboxylic acid (compound 3)

[0177] 1) Preparation of 2-(4-(hydroxymethyl)-1H-indol-1-yl)benzocyanide

[0178]

[0179] 2-iodobenzonitrile (5g, 4.4mmol), 4-hydroxymethylindole (0.6g, 4mmol), cuprous iodide (76mg, 0.4mmol) and potassium carbonate (0.83g) were placed in 20mL DMSO , heated to 90°C, kept for 12 hours, cooled after completion, poured into water, extracted with ethyl acetate, the combined organic phase was washed with water, saturated sodium chloride, dried, concentrated, silica gel column chromatography (petroleum ether / acetic acid Ethyl ester=10:1), separated to obtain 0.78g of 2-(4-(hydroxymethyl)-1H-indol-1-yl)benzocyanide.

[0180] 2) Preparation of 2-(4-(bromomethyl)-1H-indol-1-yl)benzocyanide

[0181]

[0182] Dissolve 2-(4-(hydroxymethyl)-1H-indol-1-yl)benzocyanide (1g, 4mmol) in 10mL of dichloromethane, cool ...

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Abstract

The present invention belongs to the technical field of medicine, and particularly relates to an imidazole carboxylic acid derivative represented by a general formula (I), a pharmaceutically acceptable salt, a stereoisomer, or a deuterated substance thereof, wherein R1, R2, R3, X, L , C<1> and C<2> are defined in the description. The present invention further relates to a preparation method for the compounds, pharmaceutical preparations containing the compounds, and uses of the compounds in preparation of drugs for treatment and / or prevention of cardiovascular diseases. The general formula (I) is shown in the description.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and specifically relates to imidazole carboxylic acid derivatives, pharmaceutically acceptable salts thereof, stereoisomers or deuterated products thereof, and also relates to preparation methods of these compounds, pharmaceutical preparations containing these compounds, And the use of these compounds in the preparation of medicines for treating and / or preventing cardiovascular diseases. Background technique [0002] Angiotensin receptor blockers (ARBs) are an important class of antihypertensive drugs, and have established their status as effective antihypertensive drugs among many drugs for the treatment of hypertension. ARB drugs have good antihypertensive efficacy and good safety, and have good organ protection effect on patients with type II diabetes and diabetic nephropathy while reducing blood pressure. For hypertensive patients with heart failure and normal blood pressure Patient...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D403/14C07D409/14C07D417/14C07D413/12C07D403/10A61K31/4178A61K31/422A61K31/4439A61K31/427A61K31/4709A61P9/12A61P9/04A61P9/10A61P9/00A61P29/00A61P9/06
CPCC07D401/14C07D403/10C07D403/14C07D409/14C07D413/12C07D417/14
Inventor 吴永谦周岩
Owner TONGHUA SIHUAN PHARM
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