Spiro heterocyclic ketone N-phenyl indole compound, its preparation method and application in controlling cardiovascular diseases and other medicine fields

A technology of phenylindole compound and heterospirone, applied in the field of medicinal chemistry, can solve problems such as metabolic instability

Active Publication Date: 2012-11-28
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 partial AngII agonism
In 1982, when Japan's Takeda Pharmaceutical Company was studying the diuretic and antihypertensive effects of imidazole acetic acid compounds, it first discovered that S-8307 could inhibit the Ang II-induced rabbit arterial contraction and boosting effect. Although the activity is weak, it belongs to the Ang II receptor Specific antagonist without the agonistic effect of Saralasin

Method used

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  • Spiro heterocyclic ketone N-phenyl indole compound, its preparation method and application in controlling cardiovascular diseases and other medicine fields
  • Spiro heterocyclic ketone N-phenyl indole compound, its preparation method and application in controlling cardiovascular diseases and other medicine fields
  • Spiro heterocyclic ketone N-phenyl indole compound, its preparation method and application in controlling cardiovascular diseases and other medicine fields

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] The compound: 2-butyl-3-[[1-[2-(1H-tetrazol-5-yl)phenyl]-1H-indol-4-yl]methyl]-1,3-di The preparation method of azaspiro[4,4]non-1-en-4-one (compound Ib) specifically comprises the following steps:

[0025]

[0026] Step 1: Synthesis of 2-butyl-3-[(1-benzoyl-1H-indol-4-yl)methyl]-1,3-diazaspiro[4,4]non-1-ene -4-ketone (compound Ib 3 )

[0027] Butyl heterospirone (compound Ib 1 ) was prepared by referring to literature (J Med Chem, 1993, 36: 4230-4238). (4-(bromomethyl)-1H-indol-1-yl)(phenyl)methyl ketone (compound Ib 2 ) was prepared with reference to literature (J Med Chem, 1993, 36, 3371-3380). Butylheterospirone (800 mg, 3.48 mmol) and 60% NaH (293 mg, 7.33 mmol) were dissolved in 15 mL of anhydrous THF. Under nitrogen protection, stir at 50 °C for 30 min. After cooling to room temperature, 10 mL of anhydrous THF solution containing (4-(bromomethyl)-1H-indol-1-yl)(phenyl)methyl ketone (1000 mg, 3.18 mmol) was slowly added dropwise. Then heated and stirred...

Embodiment 2

[0035] 2-Propyl-3-[[1-[2-(1H-tetrazol-5-yl)phenyl]-1H-indol-4-yl]methyl]-1,3-diazaspiro The preparation method of cyclo[4,4] non-1-en-4-one (I a):

[0036] The experimental procedure is as described in Example 1, and the yield is 46.7%. 1 HNMR (400MHz, CDCl 3 )δ: 8.20 (1H, m, N-CH), 7.59-6.70 (7H, m, Ph-H), 6.54 (1H, m, CH=C), 4.91 (2H, s, N-CH 2 ), 2.25-2.22 (2H, t, J=7.2Hz, C H 2 CH 2 CH 3 ), 1.86 (8H, m, CH 2 CH 2 CH 2 CH 2 ), 1.49 (2H, m, C H 2 CH 3 ), 0.85-0.81 (3H, t, J=7.2HZ, -CH3); MS (ESI) m / z 454.5 [M+1] +

Embodiment 3

[0038] 2-Propyl-3-[[1-[2-(1H-tetrazol-5-yl)phenyl]-1H-indol-5-yl]methyl]-1,3-diazaspiro The preparation method of cyclo[4,4]non-1-en-4-one (IIa):

[0039] The experimental procedure is as described in Example 1, and the yield is 45.9%. 1 HNMR (400MHz, CDCl 3 )δ: 8.05 (1H, m, N-CH), 7.59-6.70 (7H, m, ph-H), 6.54 (1H, m, CH=C), 4.91 (2H, s, N-CH 2), 2.25-2.22 (2H, t, J=7.2Hz, C H 2 CH 2 CH 3 ), 1.96 (8H, m, CH 2 CH 2 CH 2 CH 2 ), 1.59 (2H, m, C H 2 CH 3 ), 0.85-0.81 (3H, t, J=7.2Hz, -CH3); MS (ESI) m / z: 454.5 [M+1] + .

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Abstract

The invention discloses a spiro heterocyclic ketone N-phenyl indole compound, its preparation method and application in controlling cardiovascular diseases and other medicine fields. The compound is formed by organically connecting spiro heterocycle, indole, phenyl ring and tetrazole, is an AT1 type acceptor retarding agent of angiotensin II, and can be used for preventing or treating hypertension, coronary heart disease, disease in blood vessels of heart, brain and kidney, hemicrania, pulmonary hypertension and other diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of medicines for the prevention and treatment of hypertension, other cardiovascular and cerebrovascular diseases, migraine, pulmonary hypertension and other diseases. Background technique [0002] The renin-angiotensin system (RAS) is an important factor in the regulation of blood pressure and electrolyte balance. Angiotensinogen secreted by the liver is converted into angiotensin I (Ang I) under the action of renin. Ang I generates angiotensin II (AngII) under the action of angiotensin-converting enzyme (ACE). AngII receptors mainly include AngII type 1 receptors (AT 1 receptor), Ang II type 2 receptor (AT 2 receptor) two receptor subtypes. At present, it is believed that the physiological function of AngII is mainly caused by AT 1 receptor mediated. When AngII and AT 1 When the receptor acts, it leads to the strengthening of cardiovascular contraction, the hype...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14A61K31/4184A61P9/12A61P9/10A61P9/00A61P25/06
Inventor 陈志龙袁伟东达雅静乜永艳郄骊李福民叶颖
Owner 陈志龙
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