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6'-subsituted aminoyl benzimidazole-5-substituted methylindole derivative

A technology of carbamoyl benzimidazole and methyl indole derivatives, which is applied in the field of chemical drugs and their preparation and application, and can solve the problems of not being very significant

Inactive Publication Date: 2019-08-09
DONGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compound Zhang-6f is one of the representative compounds. Its antihypertensive activity is better than that of losartan at the same dose, but it is not very significant. We hope to make further improvements on this basis to enhance its antihypertensive activity

Method used

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  • 6'-subsituted aminoyl benzimidazole-5-substituted methylindole derivative
  • 6'-subsituted aminoyl benzimidazole-5-substituted methylindole derivative
  • 6'-subsituted aminoyl benzimidazole-5-substituted methylindole derivative

Examples

Experimental program
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Effect test

Embodiment 1

[0047] 2-{5-{[2-Ethyl-4-methyl-6-(N-benzylcarbamoyl)-1H-benzimidazol-1-yl]methyl}-1H-indol-1-yl } The preparation of benzoic acid (compound If):

[0048]

[0049] Dissolve N-benzyl-4-methyl-2-ethyl-1H-benzo[d]imidazole-6-carboxamide (compound c, 349 mg, 1.20 mmol) in 20 mL N,N-dimethylformamide Add sodium hydrogen (86.4mg, 3.6mmol) and stir at room temperature for 30min. Slowly add N-methoxycarbonylphenyl-5-bromomethylindole (compound III, 453 mg, 1.32 mmol) in N,N-dimethylformamide solution (10 mL) dropwise. After the dropwise addition was completed, the mixture was stirred and reacted at room temperature for about 2 h, and the reaction was monitored by TLC until the reaction was complete. 2 mL of 2M sodium hydroxide solution was added, and the reaction was stirred at room temperature for about 2 h. After the reaction is complete, adjust the pH value to 5-6 with 2M dilute hydrochloric acid, add 200 mL of dichloromethane and 200 mL of water to the reaction solution, and t...

Embodiment 2

[0052] 2-{5-{[2-Methyl-4-methyl-6-(N-benzylcarbamoyl)-1H-benzimidazol-1-yl]methyl}-1H-indole-1 The preparation of -yl}benzoic acid (compound Ia):

[0053] The preparation method is as described in Example 1.

[0054] 1 HNMR (400MHz, CDCl 3 ,ppm)δ8.05(d,J=7.7Hz,1H),7.66-7.60(m,1H),7.59-7.49(m,2H),7.46(d,J=6.4Hz,2H),7.32(d ,J=11.8Hz,6H),7.10(d,J=8.3Hz,1H),6.97(s,1H),6.91-6.88(m,1H),6.48(s,1H),6.37(d,J= 7.0Hz, 1H), 5.56(s, 2H), 2.88(q, J=7.6Hz, 2H), 2.57(s, 3H), 1.28(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl 3 ,ppm)δ169.35,168.58,158.63,137.91,137.84,137.54,134.80,131.74,131.16,130.17,128.80,128.70,128.70,128.63,128.19,128.13,128.01,127.91,127.91,127.56,127.38,126.37,126.24,122.32 ,120.99,117.13,110.36,108.33,99.78,45.72,16.89,12.54.MS(ESI)m / z:529.19[M+H] + .

Embodiment 3

[0056] 2-{5-{[2-Ethyl-4-methyl-6-(N-benzylcarbamoyl)-1H-benzimidazol-1-yl]methyl}-1H-indole-1 The preparation of -yl}benzoic acid (compound Ib):

[0057] The preparation method is as described in Example 1.

[0058] 1 HNMR (400MHz, CDCl 3 ,ppm)δ8.05(d,J=7.7Hz,1H),7.66-7.60(m,1H),7.59-7.49(m,2H),7.46(d,J=6.4Hz,2H),7.32(d ,J=11.8Hz,6H),7.10(d,J=8.3Hz,1H),6.97(s,1H),6.91-6.88(m,1H),6.48(s,1H),6.37(d,J= 7.0Hz, 1H), 5.56(s, 2H), 2.88(q, J=7.6Hz, 2H), 2.57(s, 3H), 1.28(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl 3 ,ppm)δ169.35,168.58,158.63,137.91,137.84,137.54,134.80,131.74,131.16,130.17,128.80,128.70,128.70,128.63,128.19,128.13,128.01,127.91,127.91,127.56,127.38,126.37,126.24,122.32 ,120.99,117.13,110.36,108.33,99.78,45.72,22.15,16.89,12.54.MS(ESI)m / z:534.24[M+H] + .

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Abstract

The invention relates to a 6'-subsituted aminoyl benzimidazole-5-substituted methylindole derivative and preparation and application thereof. The structure is shown in the general formula I. In preparation, reactants are subjected to substituting reaction; then, alkaline liquor is added for hydrolysis, and the derivative is obtained. The obtained compound is an angiotensin II receptor (AT1 receptor) antagonist and is applied in preparation of medicines for preventing or treating hypertension, coronary heart diseases, heart, brain and kidney vessel diseases, migraine, pulmonary arterial hypertension and other diseases.

Description

technical field [0001] The invention belongs to the field of chemical medicine and its preparation and application, in particular to a 6'-substituted carbamoyl benzimidazole-5-substituted methyl indole derivative and its preparation and application. Background technique [0002] Angiotensin II receptor antagonist (Angiotensin II receptor antagonist, ARB) is a class of drugs that act on the renin-angiotensin system. ARB is mainly used in the treatment of hypertension, especially for patients with heart failure, recovery from myocardial infarction, diabetic nephropathy, proteinuria, left ventricular hypertrophy, atrial fibrillation, metabolic syndrome, and intolerance to ACEI. The drug does not inhibit the breakdown of bradykinin or other kinins, and rarely causes the dry cough and / or angioedema that are common with ACE inhibitor therapy. The antihypertensive effect of ARB is good and the side effects are small. Commonly used are losartan, valsartan, telmisartan, candesartan,...

Claims

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Application Information

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IPC IPC(8): C07D403/06A61P35/00A61P9/10A61P25/06A61P9/12A61P9/00
CPCA61P9/00A61P9/10A61P9/12A61P25/06A61P35/00C07D403/06
Inventor 陈志龙吴卓夏明宝王艳慧阮氏芳英贝若秋陈婷朱智甲王力严懿嘉吴晓锋阮继武
Owner DONGHUA UNIV