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Tanshinone IIA piperazine compound and its preparation method and application

A compound, tanshinone technology, applied in the field of medicine, can solve the problem of unclear target mechanism, etc., and achieve the effect of strong calcium ion antagonism, good water solubility and lipid-water distribution coefficient, and good endothelial cell protection effect.

Active Publication Date: 2021-09-24
SHANGHAI XINGYE PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although these analogs have improved to a certain extent compared with Tanshinone IIA in terms of water solubility and / or stability and / or biological activity, they still have not changed the key issue of unclear target mechanism based on therapeutic dose-effect

Method used

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  • Tanshinone IIA piperazine compound and its preparation method and application
  • Tanshinone IIA piperazine compound and its preparation method and application
  • Tanshinone IIA piperazine compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Synthesis of Example 1 Compound XYD-1

[0081] Paraformaldehyde (15 mg, 0.5 mmol), zinc acetate (2 mg, 0.01 mmol), and 1-benzhydrylpiperazine (50 mg, 0.2 mmol) were added to a solution containing tanshinone IIA (59 mg, 0.2 mmol) in chloroform / Acetic acid solution (3 mL), and react overnight under reflux conditions. After the TLC detection reaction was complete, filter, and the gained filtrate was evaporated to dryness under reduced pressure and directly purified by silica gel column chromatography (V 石油醚 :V 乙酸乙酯 =10:1~1:1), the compound XYD-1 of Example 1 (99 mg, yield 89%) was obtained. MS-ESI [M+H] + 559.3; 1 H NMR (400 MHz, CDCl 3 ) δ 7.62-7.57 (m, 2H), 7.30-7.23 (m, 10H), 4.21(s, 1H), 3.60 (s, 2H), 3.18 (t, J = 6.3 Hz, 2H), 2.72-2.38 (m, 8H), 2.24 (s,3H), 1.88-1.74 (m, 2H), 1.67-1.62 (m, 2H), 1.31 (s, 6H).

[0082] The preparation of Example 2 to Example 13 refers to the operation route of Example 1, using different substituted piperazines (commercially a...

Embodiment 14

[0087] The synthesis of embodiment 14 compound XYD-14

[0088] Tanshinone IIA formic acid (34 mg, 0.1 mmol) was added to the N - 1 mL of cyclopentylaminoethylpiperazine (20 mg, 0.1 mmol), EDCI (38 mg, 0.2 mmol) and HOBt (13 mg, 0.1 mmol) N , N - in dimethylformamide solution, and stirred at room temperature for 24 hours. After the reaction was completed, 5 mL of water was added to quench, then ethyl acetate (2×10 mL) was added to extract, washed with saturated brine, the obtained organic phase was dried over anhydrous sodium sulfate, concentrated and evaporated to dryness under reduced pressure, and subjected to silica gel column chromatography Purification (V 氯仿 :V 甲醇 =80:1~20:1), to obtain the compound XYD-14 of Example 14 (39 mg, yield 75%). MS-ESI [M+H] + 518.3; 1 H NMR (400 MHz, CDCl 3 ) δ 7.72-7.57 (m, 2H), 3.86-3.70 (m, 3H), 3.52-3.20 (m, 5H), 2.82-2.46 (m, 11H), 2.02-1.54 (m, 8H), 1.32-1.26 (m ,6H).

[0089] The preparation of Example 15 to Example 20 refe...

Embodiment 21

[0093] Example 21 Synthesis of Compound XYD-21

[0094] Tanshinone IIA acrylic acid (36 mg, 0.1 mmol) was added to the N - 1 mL of cyclopentylaminoethylpiperazine (20 mg, 0.1 mmol), DCC (41 mg, 0.2 mmol) and DMAP (24 mg, 0.2 mmol) N , N - dimethylformamide solution and stirred at room temperature for 24 hours. After the reaction was completed, 5 mL of water was added to quench, then ethyl acetate (10 mL) was added to extract, washed with saturated brine, the obtained organic phase was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and purified by silica gel column chromatography (V 氯仿 :V 甲醇 =80:1~20:1), to obtain the compound XYD-21 of Example 21 (43 mg, yield 80%). MS-ESI [M+H] + 544.3; 1 H NMR (400 MHz, CDCl 3 ) δ 7.65-7.50 (m, 3H), 6.46 (d, J = 15.2 Hz, 1H),3.83-3.68 (m, 4H), 3.48-3.37 (m, 4H), 3.21-3.17 (m, 4H), 2.69-2.62 (m, 2H),2.40 (s, 3H), 2.01-1.74 (m, 6H), 1.65-1.61 (m, 2H), 1.31 (s, 6H).

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Abstract

The present invention provides a class of tanshinone piperazine compounds with the structure shown in formula I. Tests show that these compounds not only have calcium ion channel blocking effect, but also have the effect of inhibiting endothelial cell apoptosis and improved lipid-water distribution coefficient, which can be used It is used to treat diseases caused by calcium ion influx into cells and endothelial cell damage. The invention also provides a preparation method of the compound and its application in the preparation of drugs for the prevention and treatment of cardiovascular and cerebrovascular diseases and neurodegenerative diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a class of tanshinone IIA piperazine compounds with vascular endothelial cell protection and calcium ion antagonistic activity and pharmaceutically acceptable salts thereof. The present invention also relates to the preparation method of these compounds, and the use of these compounds in the treatment and / or prevention of cardiovascular and cerebrovascular and neurodegenerative diseases or diseases related to abnormal calcium ion channels (calcium ion influx) in humans or other mammals Use as a novel calcium ion antagonist. Background technique [0002] Tanshinone IIA is a fat-soluble diterpene quinone active ingredient found in traditional Chinese medicine Danshen for promoting blood circulation and removing blood stasis, accounting for about 0.35% of the medicinal material. Pharmacological activity studies have found that Tanshinone IIA has a wide range of pharmacological effec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J73/00A61K31/58A61P9/00A61P9/06A61P9/12A61P11/00A61P9/04
CPCC07J73/003
Inventor 宋维彬柳艳辉于汶君穆静殷保兵左传涛魏珩张瑞
Owner SHANGHAI XINGYE PHARM TECH CO LTD
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