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Medicinal application of indazole compounds in preparation of medicines for preventing and/or treating pulmonary arterial hypertension (PAH)

A pulmonary arterial hypertension and compound technology, which is applied in the field of medicine, can solve the problems of no literature reports, etc., and achieve the effects of preventing and treating right ventricular hypertrophy, reducing tissue and organ damage, and low production cost

Inactive Publication Date: 2016-12-07
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the research on DL0805 derivatives is mainly focused on the in vitro level, so far there is no literature report on the role of this type of compound in the treatment of pulmonary arterial hypertension

Method used

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  • Medicinal application of indazole compounds in preparation of medicines for preventing and/or treating pulmonary arterial hypertension (PAH)
  • Medicinal application of indazole compounds in preparation of medicines for preventing and/or treating pulmonary arterial hypertension (PAH)
  • Medicinal application of indazole compounds in preparation of medicines for preventing and/or treating pulmonary arterial hypertension (PAH)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Establishment of a model of pulmonary hypertension in rats.

[0048] Monocrotaline is a kind of pyrrolidine alkaloid extracted from wild lily seeds. It is converted into wild lily pyrrole by mixed function oxidase in the liver in rats, and wild lily pyrrole damages pulmonary vascular endothelial cells, thereby causing pulmonary artery smooth muscle cells Progressive proliferation leads to a progressive increase in pulmonary arterial pressure, resulting in a model of pulmonary hypertension in rats. Dosing was started one week after the model was established, and DL0805 derivatives were given continuously for 18 days. In this embodiment, by observing the rat electrocardiogram, measure the rat aortic pressure and pulmonary artery pressure (right ventricular pressure), measure the index of each organ of the experimental rat, the degree of right ventricular thickening, serum enzymes and pulmonary hypertension markers, tissue inflammatory factors As well as histom...

Embodiment 2

[0057] Example 2: Improvement effect of DL0805 derivatives on electrocardiogram in rats with pulmonary arterial hypertension.

[0058] Rats in each of the above groups were fasted overnight after the last administration, anesthetized with pentobarbital sodium 50mg / kg the next day, needle-shaped electrodes were inserted subcutaneously in the front and rear limbs, and the electrocardiogram of lead II of the rats was recorded, and the S wave deepening of the electrocardiogram was observed. case and the R wave inversion case. The results show( figure 2 ), the electrocardiogram of normal rats was in a normal state, and the injection of monocrotaline caused the right axis deviation of the electrocardiogram in rats, resulting in R wave inversion and S wave deepening, and right ventricular dysfunction. Two positive drugs, bosentan and fasudil, can significantly improve the ECG changes in rats caused by monocrotaline, and the DL0805 derivatives can improve the ECG changes in rats cau...

Embodiment 3

[0059] Example 3: Effects of DL0805 Derivatives on Aortic Pressure and Heart Rate in Rats with Pulmonary Hypertension

[0060] Cut the rat neck skin along the midline, bluntly separate the neck muscles, and carefully separate the left common carotid artery obliquely below the trachea. Ligate the distal end, temporarily stop the bleeding with a hemostat at the proximal end, make a V-shaped incision, insert a PE catheter filled with heparin saline into the carotid artery, and fix it with sutures, then loosen the hemostat to allow smooth blood flow , observe the carotid artery pressure, that is, aortic systolic pressure, diastolic blood pressure and heart rate. The results show (Table 3 and image 3 ), resulting in a compensatory increase in aortic pressure due to cardiac insufficiency due to pulmonary hypertension. Given the positive drug bosentan, this phenomenon was less improved; another positive drug, Fasudil, could significantly reduce the increase in aortic pressure. Ad...

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Abstract

The invention relates to a novel pharmacologic effect of a novel Rho kinase inhibitor (DL0805 derivative) with indazole as a mother nucleus, and an application of the compound in preparation of a product for preventing, alleviating and / or treating PAH and complications thereof. The DL0805 derivative has the pharmacologic effects of relaxing pulmonary artery vessels, reducing pulmonary artery pressure, treating pulmonary vascular injury caused by the PAH, recovering lung tissue functions, relieving hypertrophy and enlargement of right ventricle, treating cardiac failure and liver function damages, significantly reducing death rate of animals suffered from the PAH, and preventing and treating the PAH and complications thereof. The DL0805 derivative can be synthesized through known methods and has mature preparation processes, so that a reliable source of the compound can be provided. The compound is excellent for treating the PAH and complications thereof and can be used for preparing the product for preventing, alleviating and / or treating the PAH and the complications thereof, such as chronic obstructive emphysema, chronic pulmonary heart diseases, right heart failure, liver function damages.

Description

technical field [0001] The invention belongs to the technical field of medicines, and relates to innovative drug DL0805 derivatives with indazole as the core and the use of DL0805 derivatives in the preparation of products for preventing, alleviating and / or treating pulmonary arterial hypertension and its complications. technical background [0002] Primary pulmonary hypertension is a rare but very serious condition. The age of its onset population is on the low side, about 75% of patients are concentrated in the age group of 20-40 years old, and about 15% of patients are under 20 years old. At present, there is still no clear conclusion on the pathogenesis of pulmonary hypertension, and primary hyperplasia of pulmonary arterioles leading to vascular occlusion may be the main cause of its pathogenesis. [0003] When pulmonary hypertension occurs, the patient will show symptoms such as dyspnea, palpitations, chest pain, hemoptysis, and syncope. In the late stage, hypoxia, ri...

Claims

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Application Information

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IPC IPC(8): A61K31/416A61P9/12A61P11/00A61P9/04A61P9/00A61P1/16A23L33/00
CPCA23V2002/00A61K31/416A23V2200/326A23V2200/314A23V2200/32
Inventor 方莲花谢平杜冠华袁天翊焦晓臻陈俞材
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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