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Preparation of compound with tanshinone IIA and cyclovirobuxine D composite structure and application of compound in prevention of cardiovascular diseases

A technology of cyclovirboxicin and composite structure, which is applied to the preparation of a class of compounds with a composite structure of tanshinone IIA and cyclovirboxicin D and its application in the prevention of cardiovascular diseases, and can solve the problem of poor water solubility and cyclovirboxicin Star D has problems such as narrow use range, to achieve the effect of maintaining activity, eliminating potential risks, and improving water solubility

Active Publication Date: 2016-11-23
北京桦冠医药科技有限公司
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AI Technical Summary

Problems solved by technology

[0009] Pharmacological experiments and clinical application studies have shown that the scope of use of cyclovir buxicine D is relatively narrow, and its water solubility is poor

Method used

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  • Preparation of compound with tanshinone IIA and cyclovirobuxine D composite structure and application of compound in prevention of cardiovascular diseases
  • Preparation of compound with tanshinone IIA and cyclovirobuxine D composite structure and application of compound in prevention of cardiovascular diseases
  • Preparation of compound with tanshinone IIA and cyclovirobuxine D composite structure and application of compound in prevention of cardiovascular diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Preparation of 9β,19-cyclo-16α-hydroxy-4,4,13,14-tetramethyl-3-methylamino-17-[1-(tanshinone IIA)amino]ethylpregnane (A)

[0043]

[0044] Step 1: Synthesis of Bromotanshinone IIA Compound A-1

[0045] Add compound tanshinone IIA (1.00g, 3.4mmol) and 80 ml of acetic acid in the flask, add Br dropwise therein 2(0.54g, 3.4mmol) in 20ml of acetic acid solution, stirred at room temperature for 4 hours. Dilute with water, extract with DCM, combine the extracts, wash with water, sodium sulfite aqueous solution, saturated sodium chloride, and dry over anhydrous magnesium sulfate. Column chromatography (petroleum ether / ethyl acetate=30 / 1) gave red solid A-1 (1.012 g, yield 80%)

[0046] 1 H NMR (300MHz, CDCl 3 )δ7.63(d, 1H), 7.52(d, 1H), 3.16(t, 2H), 2.2(s, 3H), 1.78(m, 2H), 1.65(m, 2H), 1.3(s, 6H )

[0047] EIMS (m / z): 374, 372

[0048] Step 2: 9β,19-cyclo-16α-hydroxy-4,4,13,14-tetramethyl-3-methylamino-17-[1-(tanshinone IIA group)amino]ethylpregnane (A ) preparatio...

Embodiment 2

[0054] 9β,19-Cyclo-16α-Hydroxy-4,4,13,14-Tetramethyl-3-methylamino-17-[1-(tanshinone IIA methylene)amino]ethylpregnane (B ) preparation

[0055]

[0056] Mix 1.56 g of tanshinone IIA, 0.5 ml of 37% formaldehyde solution, 7.4 g of cyclovirbuxine D, and 50 ml of acetic acid, heat and reflux in an oil bath for 10 hours, remove the solvent from the mixture under reduced pressure to obtain a red solid, which is dissolved in 30 ml of DCM, Add 10 ml of saturated sodium carbonate for washing, separate the layers, dry the filtrate, concentrate, and separate by column chromatography on silica gel (eluent: DCM / methanol = 10:1) to obtain 1.12 g (yield 36%) of compound B.

[0057] 1 H-NMR (CDCl 3 )δ7.34(d, 1H), 7.25(d, 1H), 3.48(s, 2H), 3.22-3.26(m, 5H), 2.9(t, 2H), 2.8(m, 1H), 2.6(m , 1H), 2.3(s, 3H), 1.95(s, 3H), 1.2-1.8(m, 19H), 1.04(s, 6H), 0.98(s, 6H), 0.89(s, 6H)

[0058] LCMS m / z, 709.5(M+1) +

[0059] Purity: HPLC-UV (280nm): 99.1%.

Embodiment 3

[0061] 9β,19-cyclo-16α-hydroxy-4,4,13,14-tetramethyl-3-methylamino-17-[1-(tanshinone IIA acyl)amino]ethylpregnane (C) preparation

[0062]

[0063] Step 1: Preparation of intermediate C-1 aldehyde tanshinone IIA

[0064] Add 1 mL of dry DMF to a dry flask, and add 0.2 mL of POCl dropwise under stirring 3 , stirred for 15 minutes, and a solution of tanshinone IIA (287 mg, 1.3 mmol) in 3 mL of DMF was added. React overnight at 80-85 degrees. Cool to room temperature, pour into ice water, adjust pH to 7, extract with ethyl acetate, combine organic phases, wash with water, wash with saturated sodium chloride, dry over anhydrous magnesium sulfate, simple column chromatography (petroleum ether / ethyl acetate=20 / 1) The oily liquid C-1 was obtained, which was directly used in the next reaction.

[0065] Step 2: Preparation of Intermediate C-2 Tanshinone IIA Formic Acid

[0066] Add the above obtained liquid into 10 ml of 0.3N potassium permanganate solution and stir overnight ...

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Abstract

The invention relates to preparation of a compound with a tanshinone IIA and cyclovirobuxine D composite structure and an application of the compound in prevention of cardiovascular diseases. The compound is shown in a formula (I), wherein definition of X is shown in the specification. The compound shown in the formula (I) combines the main active ingredient tanshinone IIA of a traditional Chinese medicine danshen root and the main active ingredient cyclovirobuxine D of a traditional Chinese medicine Huangyangning, and according to modern molecular drug design, and effects of the tanshinone IIA and the cyclovirobuxine D for preventing and treating the cardiovascular diseases are retained while the defects of low solubility of the tanshinone IIA and insufficient purity of the cyclovirobuxine D as the main active ingredient in the traditional Chinese medicine Huangyangning are overcome. The compound shown in the formula (I) can be taken as a potential drug for preventing and treating the cardiovascular diseases.

Description

technical field [0001] The invention relates to the preparation of a composite structure compound of tanshinone IIA and cyclovirboxicin D and its application in preventing and treating cardiovascular diseases. This type of compound is a combination of the main active ingredient tanshinone IIA of the traditional Chinese medicine Salvia miltiorrhiza and the main active ingredient cyclovirboxaxin D of the traditional Chinese medicine Buyangning. Through modern drug molecular design, both tanshinone IIA and cyclovirboxuxin D are retained in the prevention and treatment of heart disease. The efficacy of vascular diseases, and to avoid the low solubility of tanshinone IIA and the shortcomings of insufficient purity of the active ingredient cyclovirbuxicin D in the traditional Chinese medicine Buyangning. Background technique [0002] Salvia miltiorrhiza is the dry root and rhizome of Salvia miltiorrhizaBge., a plant of the Labiatae family, which is included in "Shen Nong's Materia...

Claims

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Application Information

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IPC IPC(8): C07J73/00A61K31/58A61P9/00
Inventor 蔡苹
Owner 北京桦冠医药科技有限公司
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