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Acid addition salt of deuteration dehydrogenation phenyl plinabulin compound and application thereof to anti-tumor medicine preparation

A technology of phenylahistine and acid addition salt, which is applied in the field of medicinal chemistry, can solve the problems of unreported preparation methods, etc., and achieve the effects of improving bioavailability, broadening dosage form selection, and improving solubility

Active Publication Date: 2017-10-24
SHENZHEN HUAHONG MARINE BIOMEDICINE CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Meanwhile, regarding (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-diketo acid The preparation method and application of addition salt have not been reported yet

Method used

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  • Acid addition salt of deuteration dehydrogenation phenyl plinabulin compound and application thereof to anti-tumor medicine preparation
  • Acid addition salt of deuteration dehydrogenation phenyl plinabulin compound and application thereof to anti-tumor medicine preparation
  • Acid addition salt of deuteration dehydrogenation phenyl plinabulin compound and application thereof to anti-tumor medicine preparation

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation method of the deuterated dehydrophenylahistine compound having the structure shown in the general formula (I) of the present invention comprises the following steps:

[0032] (1) Synthesis of deuterium aldehyde compound b: starting from the 5-tert-butyl-1H-imidazole-4-carbaldehyde, via NaBD 4 Reduction and manganese dioxide oxidation afford 5-tert-butyl-1H-imidazole-4-deuterocarbaldehyde,

[0033]

[0034] (2) The first step of condensation reaction: first condensing diacetylpiperazine diketone (DKP) with the aldehyde intermediate a or the deuterium aldehyde compound b to form a heterocyclic compound c or a deuterium-containing heterocyclic compound d;

[0035]

[0036] (3) The second condensation reaction: the heterocyclic compound c or the deuterium-containing heterocyclic compound d is condensed with the second condensation reaction aldehyde to form the deuterated dehydrophenylahistin compound; The second condensation reaction aldehyde is benza...

Embodiment 2

[0039] ((3Z,6Z)-3-Benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dione hydrochloride preparation of

[0040]Its specific preparation process includes the following steps: take ((3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine- 2,5-diketone (100mg, 0.30mmol) was dissolved in 3ml of acetone, and hydrochloric acid (16mg, 0.44mmol) diluted with acetone was added dropwise. The reaction was stirred at room temperature for 1.5h, suction filtered, and the filter cake was washed with acetone to obtain a white solid, which was mixed with Hydrochloric acid was salified at a molar ratio of 1:1, and the yield was 72%. m.p.290-291°C; 1H NMR (500MHz, DMSO-d6) δ13.07(brs,1H),11.61(brs,1H),10.19(s ,1H),8.36(brs,1H),7.51(d,J=7.7Hz,2H),7.41(t,J=7.6Hz,2H),7.31(t,J=7.3Hz,1H),6.77(s ,1H),1.35(s,9H), tested by X-ray powder diffraction, the specific characteristic absorption peaks are shown in figure 1 .

Embodiment 3

[0042] ((3Z,6Z)-3-Benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dionemethanesulfonic acid salt preparation

[0043] Its specific preparation process includes the following steps: take ((3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl) deuterated methylene) piperazine- 2,5-Diketone (200mg, 0.59mmol) was dissolved in 4ml of acetone at room temperature, and methanesulfonic acid (86mg, 0.89mmol) diluted with acetone was added dropwise. The reaction was stirred at room temperature for 1.5h, suction filtered, and the filter cake was washed with acetone. 229 mg of white solid was obtained, the yield was 89%, and it was formed into a salt with methanesulfonic acid at a molar ratio of 1:1. m.p. ,1H),10.20(s,1H),8.31(brs,1H),7.53(d,J=7.6Hz,2H),7.43(t,J=7.7Hz,2H),7.33(t,J=7.3Hz , 1H), 6.78(s, 1H), 2.33(s, 3H), 1.37(s, 9H), by X-ray powder diffraction test, the specific characteristic absorption peaks are shown in figure 2 .

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Abstract

The invention discloses and provides an acid addition salt of a deuteration dehydrogenation phenyl plinabulin compound and application thereof to anti-tumor medicine preparation. The invention discloses and provides a preparation process of (3Z,6Z)-3-benzylidene-6-((5-tert-butyl-1H-imidazole-4-yl)deuteration methylene) piperazidine-2,5-diketone compound acid addition salt. The salifying compound aims at obviously improving the solubility and the bioavailability of the active ingredients of the compound; further, the sufficient embodiment and application are achieved in aspects of curative effect and dosage form selection of the anti-tumor medicine.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to an acid addition salt of a deuterated dehydrophenylahistin compound and its application in preparing antitumor drugs. Background technique [0002] ((3Z,6Z)-3-Benzylidene-6-((5-tert-butyl-1H-imidazol-4-yl)deuteromethylene)piperazine-2,5-dione is derived from marine Aspergillus cyclic dipeptide Phenylahistin derivative dehydrophenylahistin (Plinabulin, in the third phase of clinical trials) as the lead compound, a new type of tubulin binding agent obtained through structural modification, has good anti-tumor activity , and can overcome the drug resistance of paclitaxel, it selectively acts near the colchicine binding site of endothelial tubulin, inhibits tubulin polymerization, blocks microtubule formation, stops cells in early mitosis, and induces cell Death. At the same time, it inhibits the formation of new blood vessels and blocks the support of cancer cells, thereb...

Claims

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Application Information

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IPC IPC(8): C07D403/06A61P35/00A61P35/02
CPCC07D403/06
Inventor 李文保丁忠鹏王世潇赵建春管华诗
Owner SHENZHEN HUAHONG MARINE BIOMEDICINE CO LTD
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