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N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like

A technology of phenylindolemethyl and methyl benzimidazole, which is applied to N-phenylindolylmethyl substituted bisbenzimidazole derivatives and their application fields such as depressurization, can solve limitations and metabolic instability , agitation, etc.

Active Publication Date: 2013-09-25
陈志龙
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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, when Japanese Takeda Pharmaceutical Company studied the diuretic and antihypertensive effects of imidazole acetic acid compounds, it was found that S-8307 could inhibit the rabbit arterial contraction and pressor effect induced by A II. Although the activity was weak, it was AII receptor-specific Sexual antagonist without the agonistic effect of saraxin

Method used

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  • N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like
  • N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like
  • N-phenylindole methyl substituted bis-benzimidazole derivative and application thereof in reducing blood pressure and the like

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] 2-(4-((2-n-propyl-4-methyl-6(1-methylbenzimidazol-2-yl)benzimidazolyl)methyl)-1H-indol-1-yl) The preparation method of benzoic acid (compound Ic) specifically comprises the following steps:

[0032] Step 1: (4-((2-n-Propyl-4-methyl-6(1-methylbenzimidazol-2-yl)benzimidazolyl)methyl)-1H-indol-1-yl ) (phenyl) ketone (compound IIIc) synthesis

[0033] 2-n-propyl-4-methyl-6(-1-methylbenzimidazol-2-yl)benzimidazole (IIc) (455mg, 1.49mmol) and 60% sodium hydride (NaH) (39.42 mg, 1.64mmol) was dissolved in 20mL tetrahydrofuran (THF). Nitrogen (N 2 ) under protection, stirred at 50°C for 20min. After cooling to room temperature, slowly add 50 mL of THF solution dissolved with 10-20 mmol (4-(bromomethyl)-1H-indol-1-yl)phenyl ketone dropwise, and continue heating and stirring for 3 h. The reaction solution was poured into 15 mL of ice water. Extracted three times with ethyl acetate (30 mL×3), combined the organic phases and washed once with saturated brine (50 mL). The orga...

Embodiment 2

[0041] 2-(4-((2,4-Dimethyl-6(1-methylbenzimidazol-2-yl)benzimidazolyl)methyl)-1H-indol-1-yl)benzoic acid ( The preparation method of compound Ia):

[0042] The experimental procedure is as described in Example 1, and the yield is 32.7%. 1 H NMR (400MHz, DMSO) δ: 11.98(brs, 1H, COO-H), 7.92(d, 1H, J=7.68Hz, Ph-H), 7.81(m, 4H, Ph-H), 7.55(t ,1H,J 1 =7.64Hz,J 2 =7.64Hz, Ph-H), 7.49(s, 1H, Ph-H), 7.43(s, 1H, Ph-H), 7.34(m, 4H, Ph-H), 7.28(d, 1H, J= 8.24Hz, Ph-H), 7.02(t, 1H, J 1 =7.64,J 2 =7.92Hz, N-C 2 -H), 6.50(d, 2H, J=7.92Hz, N-C 3 -H), 5.73(s, 1H, N-CH 2 -Ph), 3.74(s, 3H, N-CH 3 ), 2.78 (s, 3H, Ph-CH 3 ), 2.04(s, 3H, C-C H 3 ). MS (ESI) m / z: 526.3 [M+H] + .

Embodiment 3

[0044]2-(4-((2-Ethyl-4-methyl-6(1-methylbenzimidazol-2-yl)benzimidazolyl)methyl)-1H-indol-1-yl)benzene The preparation method of formic acid (compound 1b):

[0045] The experimental procedure is as described in Example 1, and the yield is 29.1%. 1 H NMR (400MHz, DMSO) δ: 11.88 (brs, 1H, COO-H), 7.84 (d, 1H, J=7.68Hz, Ph-H), 7.80 (s, 1H, Ph-H), 7.76 (m , 3H, Ph-H), 7.51(m, 3H, Ph-H), 7.34(d, 2H, J=3.8Hz, Ph-H), 7.28(m, 3H, Ph-H), 7.02(t, 1H,J 1 =7.64,J 2 =7.92Hz, N-C 2 -H), 6.50(d, 2H, J=7.92Hz, N-C 3 -H), 5.73(s, 1H, N-CH 2 -Ph), 3.74(s, 3H, N-CH 3 ), 2.46(m, 2H, C H 2 CH 3 ), 2.30 (s, 3H, Ph-CH 3 ), 1.27(t, 3H, J=15.04Hz, CH 2 C H 3 ). MS (ESI) m / z: 540.2 [M+H] + .

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Abstract

The invention discloses an N-phenylindole methyl substituted bis-benzimidazole derivative which is prepared by organically connecting periphery substituted benzpyrole and bis-benzimidazole as well as benzoic acid. The derivative is an angiotensin II receptor antagonist, and can be used for preventing or treating diseases of hypertension, cardiovascular disease, renal vascular diseases, pulmonary hypertension and the like.

Description

technical field [0001] The invention relates to a new class of bisbenzimidazole derivatives substituted by N-phenylindole methyl group and a preparation method of the compounds. The compound can effectively prevent and treat hypertension, other cardiovascular and cerebrovascular diseases, pulmonary arterial hypertension and other diseases. 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, when Japanese Takeda Pharmaceutical Company studied the diuretic and antihypertensive effects of imidazole acetic acid compounds, it was found that S-8307 could inhibit the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/14A61K31/4184A61P9/12A61P9/00A61P13/12
Inventor 陈志龙吴丹梁丽莎达雅静
Owner 陈志龙