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6'-substituted benzimidazole-4-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, AII agonism, and restriction

Inactive Publication Date: 2017-05-31
DONGHUA UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in clinical practice, it is limited due to oral ineffectiveness, unstable metabolism and agonistic effect on some AII.
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 AⅡ. Although the activity was weak, it belonged to AⅡ receptor specificity Antagonist without the agonistic effect of salad new

Method used

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  • 6'-substituted benzimidazole-4-substituted methylindole derivative and preparation and application thereof
  • 6'-substituted benzimidazole-4-substituted methylindole derivative and preparation and application thereof
  • 6'-substituted benzimidazole-4-substituted methylindole derivative and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] 2-{4-{[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):

[0056] Step 1: Synthesis of 4-methyl-2-propyl-6-(4-benzoxazol-2-yl)benzimidazole IVb:

[0057]

[0058] 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

[0063] 2-{4-{[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):

[0064] The experimental procedure was as described in Example 1, and the yield was 56.3%. 1 H NMR (400MHz, DMSO) δ12.93(s,1H),8.17(s,1H),7.93(m,2H),7.80-7.69(m,3H),7.64-7.48(m,3H),7.39- 7.37(m,2H),7.04-7.00(m,2H),6.73(d,J=3.2Hz,1H),6.33(d,J=5.8Hz,1H),5.95(s,2H),2.91(q ,J=7.5Hz,2H),2.69(s,3H),1.31(t,J=7.5Hz,3H). 13 C NMR(101MHz,DMSO)δ167.66,163.89,159.24,150.64,144.97,142.21,137.66,137.20,136.04,132.94,131.09,130.55,130.55,129.54,128.89,128.89,128.48,126.45,125.44,125.16,122.52,121.51 ,120.12,119.82,116.61,111.14,109.79,107.92,101.14,45.18,20.87,16.93,12.04. MS (ESI) m / z: 527.2 [M+H] + .

Embodiment 3

[0066]2-{4-{[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):

[0067] The experimental procedure was as described in Example 1, and the yield was 48.6%. 1 H NMR(400MHz,DMSO)δ12.90(s,1H),8.15(s,1H),7.98-7.88(m,2H),7.79-7.68(m,3H),7.62-7.52(m,3H), 7.43-7.33(m,2H),7.09-6.95(m,2H),6.74(d,J=3.3Hz,1H),6.34(dd,J=5.6,2.3Hz,1H),5.95(s,2H) ,2.89(t,2H),2.67(s,3H),1.76-1.68(m,2H),1.41-1.31(m,2H),0.85(t,J=7.3Hz,3H). 13 C NMR(101MHz,DMSO)δ167.56,163.88,158.34,150.63,145.02,142.20,137.77,137.20,135.91,133.17,131.18,130.53,130.34,129.48,128.96,128.96,128.52,126.48,125.44,125.16,122.54,121.52 ,120.07,119.82,116.67,111.14,109.75,107.95,101.22,45.23,29.57,27.09,22.38,16.92,14.15.MS(ESI)m / z:555.2[M+H] + .

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Abstract

The invention relates to a 6'-substituted benzimidazole-4-substituted methylindole derivative and preparation and application thereof. A structural formula of the 6'-substituted benzimidazole-4-substituted methylindole derivative is shown as the accompanying drawing. Benzoxazole and oxazolo pyridine groups are introduced in a site 6 of benzimidazole; then, 4-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. The invention also provides application of the 6'-substituted benzimidazole-4-substituted methylindole derivative to the preparation of medicine for preventing and treating hypertension, coronary heart diseases, heart brain and kidney blood vessel diseases, migraine and pulmonary arterial hypertension diseases.

Description

technical field [0001] The invention belongs to the field of antagonists and their preparation and application, in particular to a 6'-substituted benzimidazole-4-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 - the peptide compound Sarasin (Saralasin: Sarl-Ala8-Ang II), which is very similar in structure to angiotensin II , which 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 AII. 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 boosting effect induced by AⅡ. Although the activity was weak, it belonged to AⅡ receptor specifi...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D498/04A61K31/437A61K31/423A61P9/10A61P9/12A61P25/06
CPCC07D413/14C07D498/04
Inventor 陈志龙鲍晓璐朱伟波吴卓张瑞景任何张金燕朱兴博周花园唐鹤生虞鑫海严懿嘉
Owner DONGHUA UNIV
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