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1-tanshinone ester derivatives with cardioprotective effect and their application

A technology for tanshinone ester and myocardial protection, which is applied in the field of 1-tanshinone ester derivatives, can solve the problems of poor polarity, low bioavailability and weak efficacy of tanshinone, and achieves the effect of good myocardial protection.

Inactive Publication Date: 2019-09-13
南阳博瑞康科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In order to solve the technical problems of poor polarity, weak efficacy and low bioavailability of tanshinone, the present invention conducts derivative modification research on tanshinone compounds, and discloses 1-tanshinone ester derivatives with cardioprotective effect and their application

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] In a round bottom flask I, add 276 mg of 1-hydroxy-tanshinone and anhydrous CCl 4 (solvent), add 24.2 mg of benzoyl peroxide, add 142.4 mg of N-bromosuccinimide (NBS) in batches, control the temperature at about 60 ° C, stop the reaction after reflux for 1.0 h, and purify on silica gel to obtain 1-Br - Tanshinone IIA;

[0057] In the round bottom flask II, add 180.15 mg of ferulic acid, dimethylformamide (DMF) as solvent, use K 2 CO 3 Adjust the pH to 7.5, stir well, add 298.6 mg of 1-Br-tanshinone IIA, keep the temperature at 50°C, react for 1 hour to end the reaction, remove DMF after cooling, purify by silica gel column or crystallization method, and obtain the target derivative as shown below.

[0058] The target derivative is a brown-red needle-like solid, and its NMR data is:

[0059] 1 H-NMR (400MHz, CDCl 3 , TMS) δ 7.75 (2H, s, H-6, 7), 7.63(1H, d, J=1.6Hz, H-24), 7.59-7.63 (1H, dd, J=1.6, 8.2 Hz, H- 28), 7.52-7.54 (1H, d, J=8.2Hz,H-27), 7.24 (1H, s, H-15)...

Embodiment 2

[0071] In a round bottom flask I, add 276 mg of 1-hydroxy-tanshinone and anhydrous CCl 4 (solvent), add 24.2 mg benzoyl peroxide, add 355.96 mg N-bromosuccinimide (NBS) in batches, control the temperature at about 80 ° C, stop the reaction after reflux for 4.0 h, and purify on silica gel to obtain 1- Br-tanshinone Ⅱ A;

[0072] In the round bottom flask II, add 397.4 mg Danshensu, dimethylformamide (DMF) as solvent, use K 2 CO 3 Adjust the pH to 9.0, stir well, add 373.23mg 1-Br-tanshinone IIA, keep the temperature at 70°C, react for 4h to end the reaction, remove DMF after cooling, use silica gel column or crystallization method to purify, the target derivative obtained is as follows .

[0073] The target derivative is a red solid, and its NMR data are:

[0074] 1 H-NMR (400MHz, CDCl 3, TMS) δ 7.70 (1H, s, H-6), 7.68 (1H, s, H-7),7.62-7.66 (2H, m, H-24, 28),7.48-7.50(1H, d, J =8.38 Hz, H-27),7.26-7.28(1H,m, H-1), 7.18(1H, s, H-15),4.22-4.25(1H, t, H-21), 2.83-2.86 ( 2...

Embodiment 3

[0081] In round bottom flask Ⅰ, add 278mg 1-hydroxy-cryptanshinone and anhydrous CCl 4 (solvent), add 12.1 mg of benzoyl peroxide, add 249.2 mg of N-bromosuccinimide (NBS) in batches, control the temperature at about 70 ° C, stop the reaction after reflux for 2.5 h, and purify on silica gel to obtain 1 - Br-cryptanshinone;

[0082] In the round bottom flask II, add 198.7mg of ferulic acid, dimethylformamide (DMF) as solvent, use K 2 CO 3 Adjust the pH to 8.5, stir well, add 298.6mg 1-Br-cryptanshinone, keep the temperature at 60°C, react for 3h to end the reaction, remove DMF after cooling, purify by silica gel column or crystallization method, and obtain the target derivative as follows.

[0083] The target derivative is a red solid, and its NMR data are:

[0084] 1 H-NMR (400MHz, CDCl 3 , TMS) δ 7.75 (2H, s, H-6, 7), 7.63(1H, d, J=1.6Hz, H-24), 7.59-7.63 (1H, dd, J=1.6, 8.2 Hz, H- 28), 7.52-7.54 (1H, d, J=8.2Hz, H-27), 6.98-6.99 (1H, m, H-1), 6.85 (1H, d, J=16 Hz, H-22...

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Abstract

The invention belongs to the pharmacy field and relates to 1-tanshinone acid ester derivatives with a cardioprotective effect and application of the 1-tanshinone acid ester derivatives. The 1-tanshinone acid ester derivatives are prepared by the following steps: adding tanshinone and anhydrous CCCl4 into a reaction container I, adding benzoyl peroxide and NBS, controlling temperature, stopping reaction after reflux, and carrying out silica gel purification, so as to obtain 1-bromo-tanshinone; adding benzoic acid compounds and a solvent DMF into a reaction container II, regulating the pH by virtue of K2CO3, uniformly stirring, adding 1-bromo-tanshinone, cooling at the end of reaction to remove DMF, and purifying by virtue of a silica gel column or a crystallization method, so as to obtain the 1-tanshinone acid ester derivative. Pharmacological experiments prove that the 1-tanshinone acid ester derivatives have the relatively good cardioprotective effect; and a preparation method of slow-release solid dispersions of the 1-tanshinone acid ester derivatives is researched, the 1-tanshinone acid ester derivatives are microencapsulated by virtue of a low-temperature spray drying technique and is further prepared into various dose forms such as pills, tablets, capsules and powder injections, and new possibilities are provided for the development of novel cardiovascular drugs and the utilization of salvia miltiorrhiza.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to 1-tanshinone ester derivatives with cardioprotective effect and application thereof. Background technique [0002] Danshen is often used to treat coronary heart disease, myocardial infarction, angina pectoris and other diseases because of its medicinal effect of promoting blood circulation and removing blood stasis. Tanshinone IIA is the main active ingredient in tanshinone. Studies have shown that it has the effect of relaxing blood vessels, but the fat solubility of tanshinone IIA is relatively low. Strong, poor water solubility, not conducive to its absorption in the body, so the curative effect is poor. Considering that traditional Chinese medicine uses salvia miltiorrhiza as a whole, tanshinone IIA may work synergistically with other components during the process of salvia miltiorrhiza, and the main components in salvia miltiorrhiza are not only fat-soluble tanshinones, but also water-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J73/00A61K31/58A61P9/10A61P9/00A61P9/06
Inventor 毕跃峰王洋洋吴震杨小敏
Owner 南阳博瑞康科技有限公司