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Tanshinone IIA piperazine compounds as well as preparation method and application thereof

A compound, tanshinone technology, applied in the field of medicine, can solve problems such as unclear target mechanism

Active Publication Date: 2019-07-16
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 compounds as well as preparation method and application thereof
  • Tanshinone IIA piperazine compounds as well as preparation method and application thereof
  • Tanshinone IIA piperazine compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1 Synthesis of compound XYD-1

[0081] Add paraformaldehyde (15 mg, 0.5 mmol), zinc acetate (2 mg, 0.01 mmol) and 1-benzyl piperazine (50 mg, 0.2 mmol) to the chloroform containing Tanshinone IIA (59 mg, 0.2 mmol) / Acetic acid solution (3 mL) and react overnight under reflux conditions. After the completion of the reaction detected by TLC, it was filtered. The filtrate obtained was evaporated to dryness under reduced pressure and purified directly by silica gel column chromatography (V Petroleum ether :V Ethyl acetate =10:1~1:1) to obtain compound XYD-1 of Example 1 (99 mg, yield 89%). 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] Preparation of Example 2 to Example 13 Refer to the operating route of Example 1, using different substituted piperazines (commercially available...

Embodiment 14

[0087] Example 14 Synthesis of Compound XYD-14

[0088] Add Tanshinone IIA formic acid (34 mg, 0.1 mmol) to the N -Cyclopentylethylpiperazine (20 mg, 0.1 mmol), EDCI (38 mg, 0.2 mmol) and HOBt (13 mg, 0.1 mmol) in 1 mL N , N -In the dimethylformamide solution, the reaction is stirred at room temperature for 24 hours. After the reaction is complete, add 5 mL of water to quench, then add ethyl acetate (2×10 mL) for extraction, wash with saturated brine, the resulting organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure and evaporated to dryness, and subjected to silica gel column chromatography Purification (V Chloroform :V Methanol =80:1-20:1) to obtain 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] Preparation of Example 15 to Example 20 Refer to the operating rout...

Embodiment 21

[0093] Example 21 Synthesis of Compound XYD-21

[0094] Add Tanshinone IIA acrylic acid (36 mg, 0.1 mmol) to the N -Cyclopentylethylpiperazine (20 mg, 0.1 mmol), DCC (41 mg, 0.2 mmol) and DMAP (24 mg, 0.2 mmol) in 1 mL N , N -Dimethylformamide solution, and stir at room temperature for 24 hours. After the reaction was completed, it was quenched by adding 5 mL of water, then added with ethyl acetate (10 mL) for extraction, washed with saturated brine, the resulting organic phase was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and purified by silica gel column chromatography (V Chloroform :V Methanol =80:1-20:1) to obtain 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 invention provides tanshinone piperazine compounds having a structure represented by a formula I shown in the description. Tests show that the compounds not only have a calcium channel block effect, but also have an effect of inhibiting endothelial cell apoptosis and an improved lipid-water distribution coefficient, and can be used for treating diseases caused by calcium ion cell influx and endothelial cell damage. The invention also provides a preparation method of the compounds and an application of the compounds in preparation of medicines for preventing and treating cardiovascular andcerebrovascular 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 protective effect and calcium ion antagonistic activity and pharmaceutically acceptable salts thereof. The present invention also relates to the preparation methods of these compounds, and the use of these compounds in the treatment and / or prevention of cardio-cerebrovascular and neurodegenerative diseases or disorders related to calcium ion channel abnormalities (calcium ion influx) in humans or other mammals Use as a new type of calcium antagonist. Background technique [0002] Tanshinone IIA is a fat-soluble diterpene quinone active ingredient found in the traditional Chinese medicine for promoting blood circulation and removing blood stasis, and it accounts for about 0.35% of the medicinal material. Pharmacological activity studies have found that Tanshinone IIA has a wide range of pharmacological effect...

Claims

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Application Information

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Patent Type & Authority Applications(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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