6-pyridin benzimidazole indole derivatives and preparation method thereof, and application of 6-pyridin benzimidazole indole derivatives in field of medicine

A technology of indole derivatives and benzimidazoles, which is applied in the field of 6-pyridine benzimidazole indole derivatives, can solve problems such as restriction, agonism, and metabolic instability

Active Publication Date: 2017-03-01
SHANGHAI XIANHUI MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in clinical practice, it is limited due to oral ineffectiveness, unstable metabolism, and agonistic effect on part of A II
In 1982, Japanese Takeda Pharmaceutical Co., Ltd. found that S-8307 could inhibit A II-induced arterial constriction a...

Method used

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  • 6-pyridin benzimidazole indole derivatives and preparation method thereof, and application of 6-pyridin benzimidazole indole derivatives in field of medicine
  • 6-pyridin benzimidazole indole derivatives and preparation method thereof, and application of 6-pyridin benzimidazole indole derivatives in field of medicine
  • 6-pyridin benzimidazole indole derivatives and preparation method thereof, and application of 6-pyridin benzimidazole indole derivatives in field of medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 2-(4-((2-n-propyl-4-methyl-6-(pyridin-2-yl)benzimidazolyl)methyl)-1H-indol-1-yl)benzoic acid (Compound Ib ) preparation method specifically comprises the following steps:

[0029] Step 1: Synthesis of N-o-cyanophenyl-1H-indole-4-carbaldehyde (compound V):

[0030]

[0031] Dissolve 1H-indole-4-carbaldehyde (10.00g, 68.97mmol) in N,N-dimethylformamide (150mL), add o-fluorobenzonitrile (8.40mL, 75.86mmol) and potassium carbonate (19.03g , 137.94 mmol). The mixture was stirred and refluxed at 160° C. for about 2 h, and monitored by TLC until the reaction was complete. After the temperature of the reaction solution was lowered to room temperature, it was filtered, and the filter cake was washed three times with dichloromethane (20 mL). 200 mL of dichloromethane and 200 mL of water were added to the filtrate, and the organic phase was separated; the aqueous phase was extracted with dichloromethane (150 mL×3), and the organic phases were combined. The organic phase was...

Embodiment 2

[0045] 2-(4-((2-n-propyl-4-methyl-6-(pyridin-2-yl)benzimidazolyl)methyl)-1H-indol-1-yl)benzoic acid (Compound Ib ) preparation method specifically comprises the following steps:

[0046] Step 1: Synthesis of N-o-carboxyphenyl-4-hydroxymethyl-1H-indole (compound X):

[0047]

[0048] Dissolve N-o-cyanophenyl-4-hydroxymethyl-1H-indole (10g, 40.32mmol) in ethylene glycol (100mL), slowly add 5M sodium hydroxide (80mL) solution dropwise, after the addition is complete Stir at reflux. After the completion of the reaction as monitored by TLC, cool to room temperature, add 5M hydrochloric acid (about 80 mL) solution under ice bath to adjust the pH to 5-7, extract three times with dichloromethane (100 mL×3), and combine the organic phases. The organic phase was washed with saturated brine (100 mL×3), dried over anhydrous magnesium sulfate, filtered, and the organic phase was evaporated under reduced pressure to obtain a pale yellow solid. The solid was recrystallized to obtain ab...

Embodiment 3

[0059] 2-(4-((2-ethyl-4-methyl-6(pyridin-2-yl)benzimidazolyl)methyl)-1H-indol-1-yl)benzoic acid (compound Ia) Preparation:

[0060] The synthesis method is as described in Example 1 and Example 2. 1 H NMR (400MHz, DMSO): δ12.92(s, 1H), 8.59(d, J=4.7Hz, 1H), 8.06(s, 1H), 7.99-7.91(m, 2H), 7.84-7.81(m , 2H), 7.74(t, J=7.6Hz, 1H), 7.61-7.51(m, 3H), 7.32-7.20(m, 1H), 7.06-6.95(m, 2H), 6.72(d, J=3.2 Hz, 1H), 6.41-6.30(m, 1H), 5.87(s, 2H), 2.85(q, J=7.4Hz, 2H), 2.65(s, 3H), 1.29(t, J=7.5Hz, 3H ). 13 C NMR(101MHz,DMSO)δ167.33,157.59,157.29,149.71,143.05,137.75,137.48,137.24,137.22,136.41,133.05,133.03,131.11,130.48,129.22,128.96,128.94,128.49,126.50,122.50,122.26 , 121.13, 120.53, 116.80, 109.68, 106.37, 101.17, 44.85, 20.84, 17.15, 12.13. HRMS (ESI) m / z: 487.2121 [M+H] + .

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Abstract

The invention discloses 6-pyridin benzimidazole indole derivatives and a preparation method thereof. The compounds are novel angiotensin II receptor antagonists and can be used for prevention and treatment of cardiovascular, cerebrovascular and renal-vascular diseases like hypertension, coronary heart disease and pulmonary arterial hypertension.

Description

technical field [0001] The invention relates to a new class of 6-pyridine benzimidazole indole derivatives and a preparation method of the compounds. The compound can effectively prevent and treat cardiovascular and cerebrovascular diseases such as hypertension, coronary heart disease, migraine and pulmonary hypertension. Background technique [0002] In 1970, Marshall et al. synthesized the first angiotensin II (Angiotensin II, A II) receptor antagonist - the peptide compound Sarasin (Saralasin: Sarl-Ala8-Ang II), which is compatible with angiotensin II The structure is very similar, and it has a specific antagonistic effect on isolated tissues. However, in clinical practice, it is limited due to oral ineffectiveness, unstable metabolism and agonistic effect on part of A II. In 1982, Japanese Takeda Pharmaceutical Co., Ltd. found that S-8307 could inhibit A II-induced arterial constriction and pressor effect in rabbits when studying the diuretic and antihypertensive effec...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P9/10A61P9/12A61P13/12A61P25/06
Inventor 陈志龙朱伟波鲍晓璐任何廖平永严懿嘉陈聃烨
Owner SHANGHAI XIANHUI MEDICAL TECH
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