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Water-soluble tanshinone II A derivative, preparation and application thereof

A technology for tanshinone and derivatives, which is applied to water-soluble tanshinone IIA derivatives and the fields of preparation and application thereof, can solve the problems of poor water solubility, low blood drug concentration, low bioavailability and the like

Active Publication Date: 2018-01-05
西安秦申嘉合药物研究有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the biggest defect of tanshinone IIA is its extremely low bioavailability, which is attributed to: First, poor absorption due to poor water solubility, which is inseparable from its structural characteristics
As a diterpene quinone compound, Tanshinone IIA is a planar molecule with strong hydrophobicity. The molecule has no polar groups, has very little polarity, is almost insoluble in water, and has little solubility in methanol and ethanol. It has good solubility in polar organic solvents such as chloroform, ethyl acetate, ether, etc., which greatly limits its clinical application
Second, due to the serious hepatic first-pass effect of tanshinone IIA after oral administration, the blood drug concentration after entering the blood circulation is extremely low, and its bioavailability is less than 3.5%.
Therefore, fail to develop an effective pharmaceutical preparation directly made of tanshinone IIA so far for clinical use

Method used

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  • Water-soluble tanshinone II A derivative, preparation and application thereof
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  • Water-soluble tanshinone II A derivative, preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Embodiment one: the preparation of tanshinone IIA disodium phosphate:

[0088] (1) Synthesis of acetylated tanshinone IIA: Take tanshinone IIA (1.47g, 5mmol) and 10% palladium carbon (318mg, 3mmol) in 20mL dry tetrahydrofuran, replace it with hydrogen three times, and place it in a hydrogen atmosphere at room temperature (15-25°C) Stir until the red color fades to a colorless solution, inject acetic anhydride (2.1g, 20mmol) into the syringe, and then slowly inject pyridine (1.6g, 20mmol), dropwise in about 10 minutes, stir at room temperature 15-25°C for 3 hours, filter, 25 Concentrate under reduced pressure with a rotary evaporator with a vacuum of 0.1Mpa to remove the solvent, dilute with 50mL of ethyl acetate, wash with an equal volume of 1M dilute hydrochloric acid and water once each, and decompress the ethyl acetate solution at 25°C with a rotary evaporator with a vacuum of 0.1Mpa Concentrate to obtain a crude product, suspend the crude product in 30mL of methanol...

Embodiment 2

[0105] Example 2: Protective effect of tanshinone IIA disodium phosphate on focal cerebral ischemia-reperfusion injury in rats

[0106] (1) Purpose of the experiment

[0107] The model of focal cerebral ischemia-reperfusion injury in rats was established by means of suture middle cerebral artery occlusion (MCAO), and the prevention and treatment effect of tanshinone IIA disodium phosphate on focal cerebral ischemia-reperfusion injury in rats was observed.

[0108] (2) Experimental materials

[0109] 2.1 Test drugs

[0110] Name: Tanshinone IIA disodium phosphate (prepared in Example 1); traits: reddish-brown powder; solvent: 0.9% sodium chloride injection;

[0111] Test substance concentration: 3mg / ml

[0112] 2.2 Experimental control

[0113] Blank control (sham operation group): 0.9% sodium chloride injection;

[0114] Negative control (model group): 0.9% sodium chloride injection;

[0115] Positive control: Edaravone injection (must store); specification: 5ml: 10mg; ...

Embodiment 3

[0163] Example 3: Experimental Study on the Effect of Tanshinone IIA Disodium Phosphate on Myocardial Ischemia in Rats

[0164] (1) Purpose: To observe the effect of tanshinone IIA disodium phosphate on myocardial ischemia in rats

[0165] (2) Materials and methods

[0166] 2.1 Test drugs

[0167] Name: Tanshinone IIA Disodium Phosphate; Properties: Reddish-brown powder; Solvent: 0.9% Sodium Chloride Injection

[0168] Test substance concentration: 3mg / ml

[0169] 2.2 Experimental control

[0170] Blank control (sham operation group): 0.9% sodium chloride injection;

[0171] Negative control (model group): 0.9% sodium chloride injection;

[0172] 2.3 Animals

[0173] Strain: SD rat; Grade: SPF; Gender: male; Body weight: 220g

[0174] Source: Provided by Shanghai Sipro-Bikay Laboratory Animal Co., Ltd.

[0175] Total number of animals: 70

[0176] Animal production license number: SCXK (Shanghai) 2013-0016

[0177] Feeding conditions: room temperature 20-25°C, humidi...

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Abstract

The invention provides a water-soluble tanshinone II A derivative. The water-soluble tanshinone II A derivative is characterized in that the tanshinone II A derivative is a phosphate derivative or phosphamide derivative of compound 1 shown as the formula in the specification, wherein R is hydrogen, alkyl, hydroxy, hydroxymethyl, aldehyde group, carboxyl, alkoxy, aryl, halogenated alkyl, amino or ammonio; R' is phosphoryl shown as formula W in the specification, phosphoryl pharmaceutical salt or phosphamide derivative. Animal experiments of the tanshinone II A derivative show that the derivative has good pharmaceutical effect on rat focal cerebral ischemia-reperfusion injury model and rat myocardial ischemia model, and can be used for preparation of drugs treating cardiovascular and cerebrovascular diseases. The derivative provided by the invention has good water solubility, is suitable for preparation into injection or freeze dried powder dosage forms, and has great clinical application value. The invention also provides a preparation method of the derivative.

Description

Background technique [0001] Cardiovascular and cerebrovascular diseases are a general term for cardiovascular and cerebrovascular diseases, and their causes are usually due to ischemia or hemorrhage in the heart, brain and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, high blood pressure, etc. disease. Cardiovascular and cerebrovascular disease is a common disease that seriously threatens the health of human beings, especially middle-aged and elderly people over 50 years old. It has the characteristics of high prevalence, high disability rate and high mortality rate. However, there are still more than 50% of cerebrovascular accident survivors who cannot take care of themselves completely. The number of cardiovascular and cerebrovascular diseases in the world is as high as 15 million people every year, ranking first among various causes of death. Therefore, drugs for the treatment of cardiovascular and cerebrovascular diseases have become an urge...

Claims

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Application Information

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IPC IPC(8): C07J73/00A61K31/665A61P9/00A61P9/10
CPCY02P20/55
Inventor 孙青张卫东袁虎
Owner 西安秦申嘉合药物研究有限公司
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