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Oxo-oxadiazole indole derivative as well as preparation method and application thereof

A technology of oxadiazole indole derivatives and oxadiazole, which is applied in the field of new oxooxadiazole indole derivatives and their preparation, and can solve problems such as metabolic instability and AII agonism

Inactive Publication Date: 2017-06-13
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 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 AII-induced rabbit arterial contraction and boosting effects. 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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  • Oxo-oxadiazole indole derivative as well as preparation method and application thereof
  • Oxo-oxadiazole indole derivative as well as preparation method and application thereof
  • Oxo-oxadiazole indole derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] 2-Butyl-4-chloro-1-{{1-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-1H The preparation method of -indol-4-yl} methyl}-1H-imidazole-5-formic acid methyl ester (compound 1b) specifically comprises the following steps:

[0068] Step 1: 2-{4-[(2-Butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]-1H-indol 1-yl}benzonitrile (Compound VIIa- 1) Synthesis of:

[0069]

[0070] Dissolve 2-butyl 4-chloro-5-formylimidazole (10.00 g, 53.75 mmol) in N, N-dimethylformamide (100 mL), add 2-(4-chloromethylindole) benzene Nitrile (15.73 g, 59.12 mmol) and potassium carbonate (14.80 g, 107.50 mmol). The mixture was reacted at room temperature for about 2-4 h, 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 sepa...

Embodiment 2

[0087] 2-Butyl-4-chloro-1-{{1-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-1H -Indol-5-yl}methyl}-1H-imidazole-5-formic acid methyl ester (compound IIa) preparation method:

[0088] The synthesis method is as described in Example 1. 1 H NMR (400MHz, DMSO-d 6 )δ12.61(s, 1H), 7.92-7.78(m, 2H), 7.75-7.60(m, 2H), 7.40(d, J=3.3Hz, 1H), 7.23(d, J=1.7Hz, 1H ), 7.07(d, J=8.5Hz, 1H), 6.96-6.87(m, 1H), 6.66(d, J=3.3Hz, 1H), 5.65(s, 2H), 3.76(s, 3H), 2.67 (t, J=7.6Hz, 2H), 1.62-1.46(m, 2H), 1.33-1.23(m, 2H), 0.81(t, J=7.3Hz, 3H). 13 C NMR(101MHz,DMSO)δ159.84,159.74,156.60,152.86,137.71,135.99,135.61,133.69,131.27,130.67,129.16,129.08,129.00,128.86,121.31,121.21,118.58,117.09,110.69,104.19,52.10 , 48.70, 29.15, 26.41, 22.10, 14.04. MS (ESI) m / z: 506.2 [M+H] + .

Embodiment 3

[0090] 2-Butyl-4-chloro-1-{{1-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]-1H -Indol-4-yl}methyl}-1H-imidazole-5-formic acid (compound IIb) preparation method:

[0091] The synthesis method is as described in Example 1. 1 H NMR (400MHz, DMSO-d 6 )δ7.84(d, J=7.5Hz, 1H), 7.71-7.65(m, 1H), 7.62-7.56(m, 1H), 7.50(d, J=7.8Hz, 1H), 7.34(d, J =3.1Hz, 1H), 7.18(s, 1H), 7.05(d, J=8.4Hz, 1H), 6.87(d, J=8.5Hz, 1H), 6.64-6.51(m, 1H), 5.70(s , 2H), 2.61(t, J=7.3Hz, 2H), 1.60-1.47(m, 2H), 1.32-1.24(m, 2H), 0.81(t, J=7.3Hz, 3H). 13 C NMR(101MHz,DMSO)δ166.54,162.03,159.62,151.47,137.36,136.06,131.97,131.90,131.31,131.26,130.83,129.34,129.28,128.93,128.66,128.40,120.89,118.34,110.76,103.30,48.29 , 29.21, 26.41, 22.14, 14.08. MS (ESI) m / z: 492.1 [M+H] + .

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Abstract

The invention discloses an oxo-oxadiazole indole derivative as well as a preparation method and application thereof. The compound is a novel angiotensin II receptor antagonist and can be used for preventing and treating diseases such as hypertension, coronary heart diseases, heart brain and kidney vascular diseases, migraine and pulmonary artery high pressure diseases.

Description

technical field [0001] The present invention relates to a new class of oxooxadiazole indole derivatives and a preparation method thereof. The compound can effectively prevent and treat diseases such as hypertension, coronary heart disease, cardiovascular and cerebrovascular diseases, migraine, pulmonary hypertension and the like. Background technique [0002] In 1970, Marshall et al. synthesized the first angiotensin II (Angiotensin II, AII) receptor antagonist - the peptide compound Sarasin (Saralasin: Sarl-Ala8-Ang II), which has the same structure as angiotensin II Quite similarly, it has specific antagonistic effects 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 AII-induced rabbit arterial con...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61P9/12A61P9/10A61P13/12A61P25/06A61P11/00
CPCC07D413/14
Inventor 陈志龙朱伟波鲍晓璐任何吴卓严懿嘉陈聃烨
Owner 陈志龙