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6'-substituted benzimidazole-5-substituted methylindole derivative and preparation and application thereof

A technology of methyl indole derivatives and benzimidazoles, which is applied in the field of antagonists and their preparation and application, and can solve problems such as metabolic instability, agonism, and restriction

Inactive Publication Date: 2017-05-31
DONGHUA UNIV +1
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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 the contraction and pressor effect of rabbit arteries induced by A Ⅱ when studying the diuretic and antihypertensive effects of imidazole acetic acid compounds. Although the activity is weak, it belongs to the A Ⅱ receptor exclusive Monosexual antagonist without the agonistic effect of saraxin

Method used

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  • 6'-substituted benzimidazole-5-substituted methylindole derivative and preparation and application thereof
  • 6'-substituted benzimidazole-5-substituted methylindole derivative and preparation and application thereof
  • 6'-substituted benzimidazole-5-substituted methylindole derivative and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] 2-{5-{[2-Propyl-4-methyl-6-(benzo[d]oxazol-2-yl)-1H-benzo[d]imidazol-1-yl]methyl}- The preparation method of 1H-indol-1-yl}benzoic acid (compound Ib):

[0057] Step 1: Synthesis of 4-methyl-2-propyl-6-(4-benzoxazol-2-yl)benzimidazole IVb:

[0058]

[0059] Compound IIc (534 mg, 2.45 mmol) was slowly added to polyphosphoric acid (15 mL) heated to 80°C, stirred and heated to 150°C. Compound IIIb (320mg, 2.94mmol) was slowly added to the former polyphosphoric acid solution several times. After the addition was complete, the reaction was stirred at 150°C for 12h. After the reaction is complete, pour the reaction solution into 100 mL of ice water, and adjust the pH to 8-10 with concentrated ammonia water, a large amount of precipitate will appear, filter, and wash the filter cake three times with 5% ethanol solution. After the filter cake was dried, the resulting filter cake was purified by column chromatography to obtain about 357 mg of light yellow solid Compound IVb ...

Embodiment 2

[0064] 2-{5-{[2-Ethyl-4-methyl-6-(benzo[d]oxazol-2-yl)-1H-benzo[d]imidazol-1-yl]methyl}- The preparation method of 1H-indol-1-yl}benzoic acid (compound Ia):

[0065] The experimental procedure was as described in Example 1, and the yield was 57.6%. 1 H NMR (400MHz, DMSO) δ12.84(s, 1H), 8.20(s, 1H), 7.91(d, J=5.6Hz, 2H), 7.78-7.73(m, 2H), 7.70(d, J= 7.6Hz, 1H), 7.58(d, J=7.6Hz, 1H), 7.49(d, J=7.9Hz, 1H), 7.43(d, J=3.2Hz, 1H), 7.42-7.35(m, 2H) ,7.30(s,1H),7.08(d,J=8.3Hz,1H),6.99(d,J=8.6Hz,1H),6.59(d,J=3.0Hz,1H),5.70(s,2H) ,2.97(q,J=7.4Hz,2H),2.66(s,3H),1.35(t,J=7.4Hz,3H). 13C NMR(101MHz,DMSO)δ167.11,163.47,158.49,150.20,144.56,141.79,137.32,136.05,135.34,132.61,130.66,130.46,128.98,128.57,128.37,128.27,127.93,124.98,124.71,121.02,121.00,120.58 ,119.64,119.38,118.06,110.69,110.28,107.54,102.78,46.46,20.43,16.45,11.66.MS(ESI)m / z:527.2[M+H] + .

Embodiment 3

[0067] 2-{5-{[2-Butyl-4-methyl-6-(benzo[d]oxazol-2-yl)-1H-benzo[d]imidazol-1-yl]methyl}- The preparation method of 1H-indol-1-yl}benzoic acid (compound Ic):

[0068] The experimental procedure was as described in Example 1, and the yield was 58.7%. 1 H NMR(400MHz,DMSO)δ12.97(s,1H),8.18(s,1H),7.90(s,1H),7.86(d,J=7.6Hz,1H),7.80-7.71(m,2H) ,7.66(m,1H),7.53(m,1H),7.44(m,2H),7.42-7.33(m,2H),7.28(s,1H),7.10(d,J=8.5Hz,1H), 6.97(d, J=8.6Hz, 1H), 6.56(d, J=3.2Hz, 1H), 5.70(s, 2H), 2.94(t, 2H), 2.65(s, 3H), 1.82-1.68(m ,2H),1.44-1.37(m,2H),0.89(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO)δ167.81,163.92,158.05,150.65,145.08,142.24,137.51,136.45,135.66,132.51,130.97,130.94,129.38,129.02,128.69,128.59,128.23,125.43,125.16,121.48,121.43,120.92 ,120.04,119.83,118.43,111.15,110.81,108.03,103.08,46.98,29.69,27.10,22.44,16.90,14.19.MS(ESI)m / z:555.2[M+H] + .

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Abstract

The invention relates to a 6'-substituted benzimidazole-5-substituted methylindole derivative and preparation and application thereof. A structural formula of the 6'-substituted benzimidazole-5-substituted methylindole derivative is shown as the accompanying drawing. Benzoxazole and oxazolo pyridine groups are introduced in a site 6 of benzimidazole; then, 5-substituted indole is used for replacing phenyl groups in an iosartan medicine biphenyl structure; the design and the synthesis are performed by finding the optimum bond length through increasing or decreasing the length of a carbon chain on a site 2 of the benzimidazole.

Description

technical field [0001] The invention belongs to the field of antagonists and their preparation and application, in particular to a 6'-substituted benzimidazole-5-substituted methylindole derivative and its preparation and application. Background technique [0002] In 1970, Marshall et al synthesized the first angiotensin II (Angiotensin Ⅱ, A Ⅱ) receptor antagonist - peptide compound Sarasin (Saralasin: Sarl-Ala8-Ang Ⅱ), which is related to 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 some A II. In 1982, Japanese Takeda Pharmaceutical Co., Ltd. found that S-8307 could inhibit the contraction and pressor effect of rabbit arteries induced by A Ⅱ when studying the diuretic and antihypertensive effects of imidazole acetic acid compounds. Although the activity is weak, it belongs to the A Ⅱ receptor e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/00C07D498/04A61K31/437A61K31/423A61P9/12A61P9/10A61P25/06
CPCC07D498/00C07D498/04
Inventor 陈志龙鲍晓璐朱伟波吴卓严懿嘉唐鹤生王力虞鑫海朱智甲徐永芬
Owner DONGHUA UNIV