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Indole ring substituted pyrazole carboxylic acid endothelin receptor antagonist as well as preparation method and application thereof

A technology of indole and pyrazole, which can be used in medical preparations containing active ingredients, pharmaceutical formulations, cardiovascular system diseases, etc., and can solve the problems of lack of treatment drugs and untimely treatment of pulmonary arterial hypertension.

Inactive Publication Date: 2011-06-15
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Pulmonary hypertension is a disease that still plagues the medical field. If it is not treated in time, the survival time is only two to three years. There is still no effective treatment for pulmonary hypertension.

Method used

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  • Indole ring substituted pyrazole carboxylic acid endothelin receptor antagonist as well as preparation method and application thereof
  • Indole ring substituted pyrazole carboxylic acid endothelin receptor antagonist as well as preparation method and application thereof
  • Indole ring substituted pyrazole carboxylic acid endothelin receptor antagonist as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0224] Example 1 Synthesis of Compound V

[0225]

[0226] Compound IV, indole (9.36 g, 80 mmol) was dissolved in anhydrous dichloromethane (160 ml), stirred under an ice-salt bath, and AlCl was added at -5-0 °C 3 (21.12 g, 160 mmol), pay attention to temperature control, slowly add acetic anhydride (7.5 ml, 80 mmol) dropwise at room temperature, add a small amount of nitromethane (30 ml), and react at room temperature for 5 hours. Ice water was added to the reaction solution, a large amount of solid was precipitated, filtered, dried, purified by column (chloroform / methanol, 20:1), and recrystallized from ethanol to obtain a pale yellow solid, namely compound V (3-acetylindole) 3.94g , the yield is 31%. mp 190-191℃, IR (KBr, cm -1 )3180, 1630, 1450, 1250, 1190, 945, 760; 1 H NMR (acetone-d 6 ,) δ8.7-7.0 (m, 5H), 2.4 (s, 3H).

Embodiment 2-8

[0228] Referring to the synthesis operation of Example 1, a different indole derivative was used to replace Compound IV in Example 1 to obtain a different 3-acetylindole derivative, Compound V.

[0229] Table 1 Compound V obtained in Example 2-Example 8

[0230]

Embodiment 9

[0231] Example 9 Synthesis of Compound IV

[0232]

[0233] Compound V, 3-acetyl indole (2.1 g, 13.2 mmol) and diethyl oxalate (2.51 g, 17.2 mmol) were mixed, stirred, added with anhydrous sodium ethoxide (1.8 g, 26.4 mmol), nitrogen protection, room temperature reaction 5 hours. Dilute acetic acid was added to the reaction solution to produce a large amount of solid, suction filtration, the filter cake was washed three times with diluted acetic acid, and the filter cake was dried to obtain a yellow solid, compound IV, 3.4g, yield 100%, melting point: 180.8-182.7°C.

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Abstract

The invention provides a compound shown in the general formula I or pharmaceutically acceptable salts thereof. In the general formula I, R1 is shown in the specification; R2 and R5 are respectively H, alkyl, cycloalkyl, carboxyl, aryl, substituted aryl, benzyl or substituted benzyl independently; R3, R4 and R6 are respectively H, halogen, nitryl, hydroxy, alkyl, cycloalkyl, alkoxy, aryl, substituted aryl or OR' independently; R' is alkyl, cycloalkyl, aryl, substituted aryl, benzyl or substituted benzyl; and R7 is H or alkyl. The invention also provides a method for preparing the compound and an application of the compound. The compound shown in the general formula I or salts thereof have the function of resisting endothelin, can serve as active ingredients for preparing the drugs for treating hypertension or pulmonary arterial hypertension and are effective in a quite wide dosage range.

Description

technical field [0001] The present invention belongs to the field of medicine for blood pressure diseases. Specifically, the present invention relates to an indole ring-substituted pyrazole carboxylic acid derivative selective endothelin receptor antagonist with hypotensive effect, a preparation method and a pharmaceutical composition thereof, and their use in medicine, In particular, the application of drugs for the prevention and / or treatment of hypertension and pulmonary arterial hypertension. Background technique [0002] Hypertension, pulmonary arterial hypertension and other blood pressure diseases are serious diseases. Hypertension is a common disease with high morbidity and usually requires long-term medication. Therefore, finding safe and effective therapeutic drugs has always been an urgent desire of people. Pulmonary arterial hypertension is a disease that still plagues the medical profession. If the disease is not treated in time, the survival time is only two...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14C07D403/04C07D209/32C07D209/30C07D209/18C07D209/12A61K31/404A61K31/4155A61P9/12
Inventor 张大同徐为人谭初兵汤立达邹美香裴媛王玉丽张士俊刘巍
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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