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Compound for treating pulmonary arterial hypertension and application thereof

A technology for pulmonary arterial hypertension and compounds, which can be used in medical preparations containing active ingredients, drug combinations, organic chemistry, etc., and can solve problems such as unapproved

Pending Publication Date: 2021-10-19
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, none of these drugs have been approved for the indication of PAH

Method used

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  • Compound for treating pulmonary arterial hypertension and application thereof
  • Compound for treating pulmonary arterial hypertension and application thereof
  • Compound for treating pulmonary arterial hypertension and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Example 1. Synthesis of Benzimidazole Proton Pump Inhibitor Derivatives

[0130] 1. Synthesis of compound 119

[0131]

[0132] (1) Piperonyl chloride

[0133]

[0134] Put piperonol (0.5g, 3.3mmol) and anhydrous DCM in a 50mL reaction flask, under argon protection, add thionyl chloride (0.782mg, 6.6mmol) dropwise under ice bath, and stir for 10 minutes under ice bath Afterwards, stir at room temperature for 1.5 hours, the reaction is complete, the solvent and the remaining thionyl chloride are spin-dried, and petroleum ether is passed through the column to obtain 430 mg of a yellow oily liquid with a yield of 76.9%. GC-MS: m / z: 170.0.

[0135] (2) 2-((Benzo[1,3]dioxolane-5-methyl)-mercapto)-1-hydrogen-benzimidazole

[0136]

[0137] First dissolve NaOH (174mg, 4.4mmol) in ethanol, stir at 60°C for 30 minutes, add the product from the previous step (370mg, 2.2mmol) and 2-mercaptobenzimidazole (325mg, 2.2mmol), heat up and reflux, and the reaction gradually p...

Embodiment 2

[0171] Embodiment 2. The therapeutic effect of proton pump inhibitor dexlansoprazole on pulmonary hypertension animals

[0172] 1. Purpose of the experiment

[0173] The animal model of pulmonary hypertension was established by subcutaneous injection of monocrotaline, and the proton pump inhibitor dexlansoprazole was given for treatment at the same time, and the pulmonary artery hemodynamics and right heart hypertrophy index RVHI of rats were detected to judge the drug effect of dexlansoprazole .

[0174] 2. Experimental animals and experimental methods

[0175] Male SD rats with a body weight of 200-230 g (purchased from Shanghai Xipuer-Bikay Experimental Animal Co., Ltd.), feeding conditions: constant temperature 22±2°C, constant humidity 55±5%, light and dark 12h / day, 24h free feeding drinking water. During the experiment, SD rats were randomly divided into 6 groups: blank control group, pulmonary hypertension model group, selexipag treatment group, low-dose and middle-d...

Embodiment 3

[0184] Embodiment 3. The therapeutic effect of proton pump inhibitor esomeprazole magnesium on pulmonary arterial hypertension animal

[0185] 1. Purpose of the experiment

[0186] Animal models of pulmonary hypertension were established by subcutaneous injection of monocrotaline, and the proton pump inhibitor esomeprazole magnesium was given for treatment at the same time. effect.

[0187] 2. Experimental animals and experimental methods

[0188] Male SD rats with a body weight of 200-230 g were fed under constant temperature of 22±2°C, constant humidity of 55±5%, light and dark for 12 hours / day, and free access to food and water for 24 hours. During the experiment, SD rats were randomly divided into 4 groups: blank control group, pulmonary hypertension model group, selexipag positive drug (1mg / kg, bid) treatment group, esomeprazole magnesium (10mg / kg, qd) treatment group , 6 in each group. On the first day of the experiment, normal saline was subcutaneously injected into...

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Abstract

The new application of the proton pump inhibitor and the derivative thereof in treating pulmonary arterial hypertension is found for the first time. According to the present invention, a monocrotaline is adopted to induce a rat pulmonary arterial hypertension model, a platelet derivative growth factor-BB (Platelet-Derived Growth Factor, PDGF-BB) is adopted to induce abnormal proliferation of pulmonary arterial smooth muscle cells (PASMC), and it is found that the proton pump inhibitors such as dexlansoprazole and the like and the derivatives thereof can reduce the pulmonary arterial pressure, alleviate the thickening of small arteries in the lung, inhibit the abnormal proliferation of the PASMC, so pulmonary arterial hypertension is treated.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to proton pump inhibitor compounds and their derivatives with pulmonary hypertension treatment activity and their application in the treatment of pulmonary hypertension. Background technique [0002] Pulmonary arterial hypertension (PAH) refers to the most common type of pulmonary vascular disease in which the mean pulmonary arterial pressure (mPAP) measured by right heart catheterization is ≥25mmHg at rest and 30mmHg during exercise. The pathological features are progressive increase in pulmonary artery pressure and pulmonary vascular remodeling, and the clinical manifestations are dyspnea, decreased exercise tolerance, fatigue, angina pectoris, and syncope. According to pathological manifestations, hemodynamic characteristics, and clinical diagnosis and treatment strategies, it can be divided into five categories: ①arterial pulmonary hyperte...

Claims

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Application Information

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IPC IPC(8): A61K31/4439A61K31/444A61K31/4184A61K31/435A61K31/5377A61K31/506A61K31/437A61P11/00A61P29/00A61P1/00A61P9/00A61P13/12A61P3/10A61P27/06A61P3/04A61P19/10A61P13/00A61P25/00C07D405/12C07D403/12C07D235/28
CPCA61K31/4439A61K31/444A61K31/4184A61K31/435A61K31/5377A61K31/506A61K31/437A61P11/00A61P29/00A61P1/00A61P9/00A61P13/12A61P3/10A61P27/06A61P3/04A61P19/10A61P13/00A61P25/00C07D405/12C07D403/12C07D235/28
Inventor 李洪林王蕊焦茜赵振江朱丽丽李诗良
Owner EAST CHINA UNIV OF SCI & TECH
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