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Drugs for prevention and treatment of pulmonary arterial hypertension and their synthesis and application

A technology for drugs and condensation reactions, which can be used in drug combinations, active ingredients of heterocyclic compounds, cardiovascular system diseases, etc. Improve the effect of easy oxidation and promote long-term effect

Inactive Publication Date: 2016-04-13
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in the above-mentioned new drugs, there are many disadvantages in clinical application, such as patients need to implant central venous catheters, and use portable infusion pumps, etc.
In addition, high price, serious adverse reactions and complex administration methods all greatly limit their application

Method used

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  • Drugs for prevention and treatment of pulmonary arterial hypertension and their synthesis and application
  • Drugs for prevention and treatment of pulmonary arterial hypertension and their synthesis and application
  • Drugs for prevention and treatment of pulmonary arterial hypertension and their synthesis and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Preparation of Intermediate 3

[0033]

[0034] Take 8.00g of 3,4-dimethoxyphenylacetic acid (1), 6.00g of p-methoxybenzaldehyde (2), 15mL of acetic anhydride and 6mL of anhydrous triethylamine, stir and heat to 130°C, and reflux for 6h. After standing at room temperature, add 22.00g of potassium carbonate and 90mL of distilled water, stir evenly, and then heat to 130°C for reflux for 0.5h. After standing at room temperature, the pH was adjusted to 4.0 with concentrated hydrochloric acid, the solid was filtered off, and the solid was recrystallized with methanol, with a yield of 46.65%.

[0035] Synthesis of Target Compounds by Acid Chloride Method

[0036]

[0037] Take 6.28g of intermediate 3 in a clean 100mL single-necked bottle, cool to 0°C, add 6mL of SOCl under nitrogen atmosphere 2 , stirred for 15 minutes, removed the nitrogen gas, and heated to reflux at 79°C for 2~3 hours to obtain the acid chloride solution of intermediate 3. After airing at room tem...

Embodiment 2

[0045] Take 8.00g of 3,4-dimethoxyphenylacetic acid (1), 6.00g of p-methoxyphenylacetaldehyde (2), 15mL of acetic anhydride and 6mL of anhydrous pyridine, stir and heat to 130°C, and reflux for 6h. After standing at room temperature, add 22.00g of potassium carbonate and 90mL of distilled water, stir evenly, and then heat to 130°C for reflux for 0.5h. After standing at room temperature, the pH was adjusted to 4.0 with concentrated hydrochloric acid, the solid was filtered out, and the solid was recrystallized with methanol to obtain the following compound with a yield of 46.65%.

[0046]

[0047] Above-mentioned compound further adopts the condensation method similar to embodiment 1 to be able to prepare following compound,

[0048] .

Embodiment 3

[0049] Example 3: Pharmacological experiments and results of the target compound prepared in Example 1

[0050] 1. Measurement of nitric oxide release in vitro: Nitrate compounds can release NO in the presence of acidic environment and excess mercapto compounds. Nitrite ion NO produced by oxidation of NO 2 - , its concentration is determined by Griess method, which indirectly reflects the nitric oxide release ability of the compound. This method is simple, rapid and reproducible. In this experiment, this method was used to measure the NO release amount of the target compound BZ-1 in vitro to investigate its NO release effect. The control drugs were isosorbide mononitrate and sodium nitroprusside. Using nitrite ion NO 2 - It can undergo diazotization and coupling reactions with Griess reagent to generate a purple-red product. Measure its absorbance value at a wavelength of 540nm to indirectly measure the release of NO. The release environment of NO is the environment of rat...

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Abstract

The invention discloses a drug for preventing and treating pulmonary artery hypertension, synthesis and applications thereof. The drug has a structural formula (I) which is represented in the description, wherein the R1 and R2 are independently selected from -CH3 and -CH2CH3. The compound is prepared by the following steps: making phenylacetic acid derivatives and benzoic acid derivatives carry out a Perkin reaction in the presence of acetic anhydride and an alkaline catalyst so as to obtain an intermediate, and then making the intermediate carry out condensation reactions with isosorbide mononitrate so as to obtain the compound represented by the structural formula (I). The structure of a primer namely iso-resveratrol is modified so as to strengthen the stability, thus the biological utilization degree of the iso-resveratrol is increased and the drug has a long-acting effect; furthermore, the shortages of easy oxidation and difficult storage of resveratrol with hydroxyl structure are overcome.

Description

technical field [0001] The invention relates to an alkylated isoresveratrol benzyl nitrate nitric oxide donor compound, which can be used as a drug for preventing or treating diseases related to pulmonary arterial hypertension, such as chronic obstructive pulmonary disease (chronic obstructive pulmonary disease, COPD), High altitude pulmonary edema (high altitude pulmonary edema, HAPE), etc., belong to the field of medicinal chemistry. Background technique [0002] Pulmonary arterial hypertension (PAH) is an important pathophysiological link in the occurrence and development of many clinical cardiopulmonary vascular diseases. It is characterized by a progressive increase in pulmonary artery pressure and pulmonary vascular resistance. Medial hyperplasia and adventitial hypertrophy eventually lead to obstruction of the lumen of the pulmonary arterioles. The clinical manifestations are right ventricular dysfunction, progressive dyspnea, chest pain, syncope, fatigue, and periph...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04A61K31/34A61P9/12A61P11/00
CPCC07D493/04
Inventor 王剑波王平安冯力王雷琛张迪
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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