Acylated derivatives of homoharringtonine, its preparation method and application

The technology of homoharringtonine and harringtonine acyl is applied in the fields of natural medicine and medicinal chemistry, and can solve the problems of synthesis and application of new homoharringtonine derivatives that have not yet been seen

Active Publication Date: 2016-03-09
BENSEN PHARMA SHANGHAI CORP LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Acylated derivatives of homoharringtonine, its preparation method and application
  • Acylated derivatives of homoharringtonine, its preparation method and application
  • Acylated derivatives of homoharringtonine, its preparation method and application

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Experimental program
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Effect test

Embodiment 1

[0134] Embodiment 1: the synthesis of compound BS-HH-001

[0135]

[0136] In the formula, HHT: homoharringtonine; Ac 2 O: acetic anhydride; DIPEA: N,N-diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DCM: dichloromethane; BS-HH-001: 2,6-diacetylhomoharringtonate base; BS-HH-002: 6-acetylhomoharringtonine.

[0137] Homoharringtonine HHT (125 mg, 0.23 mmol), diisopropylethylamine (444 mg, 3.44 mmol) and 4-dimethylaminopyridine (28 mg, 0.023 mmol) were dissolved in dichloromethane (2 mL), and Add acetic anhydride (351mg, 3.44mmol) to the mixed solution, react at 35°C for 24 hours, wash the reaction solution with water, and then wash with saturated sodium bicarbonate, dry, concentrate, and the obtained crude product is purified by preparative liquid chromatography , to obtain white solid compound BS-HH-001 (43.3 mg, 30%).

[0138] LC-MS: retention time: 1.11min (98.7%), m / z: 630.5[M+H] + . 1 HNMR (300MHz, CDCl 3 ): δ6.60(d, 2H), 5.80-5.93(m, 3H), 5.02(s, 1H), 3.76(d...

Embodiment 2

[0139] Embodiment 2: the synthesis of compound BS-HH-002

[0140]

[0141] In the formula, HHT: homoharringtonine; Ac 2 O: acetic anhydride;

[0142] to Ac 2 Homoharringtonine HHT (1g, 1.84mmol) was added to O (20mL), the reaction was heated to 80°C, and the reaction was stirred for 13 hours. After the reaction was completed, the reaction solution was concentrated to obtain a viscous crude product, which was solidified after adding diethyl ether. Ethyl acetate was added to the solidified crude product to dissolve it, washed with saturated potassium carbonate solution, concentrated, and the obtained crude product was purified by a silica gel column (EA:PE=1:2) to obtain a yellow oil, which was recrystallized with ether A white solid compound BS-HH-002 (654 mg, 61%) was obtained, while homoharringtonine HHT starting material (354 mg) was recovered. BS-HH-002: LC-MS: retention time: 1.00min (96.74%), m / z: 588.2[M+H] + . 1 HNMR (400MHz, CDCl 3 ): δ6.62(s, 1H), 6.55(s, 1H)...

Embodiment 3

[0144] Embodiment 3: the synthesis of compound BS-HH-077

[0145]

[0146] In the formula, HHT: homoharringtonine; Yi: cyclopentylcarboxylic acid; 4-ppy: 4-(1′-tetrahydropyrrole) pyridine; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane.

[0147] Dissolve homoharringtonine (110 mg, 0.2 mmol), cyclopentylcarboxylic acid (46 mg, 0.4 mmol), 4-(1'-tetrahydropyrrole) pyridine (60 mg, 0.4 mmol) in dichloromethane (2 mL) , dicyclohexylcarbodiimide (83mg, 0.4mmol) was added to the solution, heated to reflux for three hours, and then filtered. The filtrate was concentrated, and the obtained crude product was purified by high performance liquid chromatography to obtain BS-HH-077 (35.9 mg, 28%) as a light yellow powdery solid.

[0148] LC-MS: retention time: 1.52min (95.63%), m / z: 642.6[M+H] + . 1 HNMR (300MHz, CDCl 3 ): δ6.63(s, 1H), 6.59(s, 1H), 5.99(d, J=9.0Hz, 1H), 5.90(m, 2H), 5.09(s, 1H), 3.80(m, 1H) , 3.73(s, 3H), 3.57(s, 3H), 3.49-3.54(m, 1H), 2.73-3.02(m, 2H), 2.42-2...

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Abstract

The present invention relates to the fields of natural medicine and medicinal chemistry, and relates to, as represented by formula (I) and formula (II), a novel acylated derivative of homoharringtonine or a pharmaceutically acceptable salt thereof, a method for preparing the compounds, a pharmaceutical composition comprising the compound, and an application thereof in preparing an antitumor medicament.

Description

technical field [0001] The present invention belongs to the field of natural medicine and medicinal chemistry and relates to novel homoharringtonine derivatives, especially acylated derivatives of homoharringtonine, methods for preparing these compounds, compositions containing the compounds and their preparation methods. Use in antineoplastic drugs. Background technique [0002] Homoharringtonine (Homoharringtonine, HHT) is also known as oxygen-3-[(2R)-2,6-dihydroxy-2-(2′-methoxy-2′-oxoethyl)-6- Methylheptanoyl] cephalotaxine (O-3-[(2R)-2,6-dihydroxy-2-(2'-methoxy-2'-oxoethyl)-6-methylheptanoyl]cephalotaxine) is a Chinese herbal medicine Sanjian The alkaloids obtained by extracting and separating from Cephatotaxus fortuneif or plants of the same genus. There are 9 species in the genus of the genus Triaxaceae, 8 of which are produced in China. This genus contains a variety of alkaloids, among which harringtonine, homoharringtonine, isoharringtonine and deoxyharringtonine ...

Claims

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Application Information

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IPC IPC(8): C07D491/20A61K31/55A61P35/00
CPCC07D491/20
Inventor 徐荣臻荣风光谢福文赖洪喜
Owner BENSEN PHARMA SHANGHAI CORP LTD
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