Colchicine derivative

A technology for colchicine and derivatives, applied in the field of colchicine derivatives, can solve problems such as weak effect, and achieve the effects of high cell selectivity and good anti-tumor activity

Active Publication Date: 2015-02-25
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] (2) The B ring has a certain affinity with tubulin, but the effect is not strong. The modification of the C-7 side chain of the B ring is mainly used to adjust the pharmacokinetic characteristics of colchicine derivatives

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] The synthesis of embodiment 1 compound 1

[0111]

[0112] Compound 1, which converts the C ring of colchicine into aniline, can be synthesized by the classic Fernholz method (see JustusLie bigs Ann. 1950), or it can be synthesized by referring to the method disclosed in the Chinese invention with application number 201210049085.3, and synthesized according to the above chemical reaction equation.

Embodiment 2

[0113] The synthesis of embodiment 2 compound 2

[0114]

[0115] 2.75g of compound 1 was dissolved in 65mL of 0.12M HCl, 13g of sodium sulfate was added, 2.5g of hydroxylamine hydrochloride and 2.1g of chloral were added successively under stirring, and the reaction was carried out at 55°C for 24 hours. 3 × 50mLEtOAc extraction (that is, extraction 3 times, each time with 50mLEtOAc), anhydrous Na2SO4 drying, silica gel column chromatography (EtOAc / EtOH=10:1, that is, the mobile phase composition is a mixture of EtOAc and EtOH with a volume ratio of 10:1 liquid), to obtain 3.3 g (yield 100%) of product 2 as a light yellow solid.

[0116] Compound 2H-NMR (500MHz, d 6 -DMSO): 1.90 (1H, s), 1.94 (1H, m), 2.0~2.2 (2H, m), 2.54 (1H, m), 3.49 (3H, s), 3.79 (3H, s), 3.84 ( 3H,s),4.49(1H,m),6.78(1H,s),7.28(1H,d),7.63(1H,dd),7.67(1H,d),7.72(1H,s),8.42(1H ,d), 10.24(1H,s), 12.19(1H,s). Compound 2 HRMS (high resolution mass spectrometry): C 22 h 25 N 3 o 6 Na + Theoretical va...

Embodiment 3

[0117] The synthesis of embodiment 3 compound 3 and compound 4

[0118]

[0119] 95mL of methanesulfonic acid was preheated to 40°C, 2.5g of compound 2 was added under stirring, the temperature was slowly raised to 85°C, and the reaction was carried out for 1 hour. After cooling, it was poured into 500mL ice water, extracted with 10×50mL EtOAc, washed with saturated brine, saturated aqueous sodium bicarbonate solution, saturated brine, and anhydrous Na 2 SO 4 Drying, silica gel column chromatography (CH 2 Cl 2 / MeOH=10:1), 1.0 g (yield 36%) of red solid product compound 3 and 0.3 g (yield 10%) of compound 4 were obtained.

[0120] Compound 3H-NMR (500MHz, d 6 -DMSO): 1.89 (3H, s), 1.96 (1H, m), 2.1~2.2 (2H, m), 2.56 (1H, m), 3.52, (3H, s), 3.79 (3H, s), 3.84 (3H, s), 4.47 (1H, m), 6.80 (1H, s), 6.89 (1H, s), 7.37 (1H, s), 8.56 (1H, d, J8Hz), 11.09 (1H, s).

[0121] Compound 3 HRMS: C 22 h 22 N 2 o 6 The theoretical value is 410.1478; the measured value is 410.1479...

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Abstract

The present invention discloses a colchicine derivative, which has a structure formula represented by a formula (I), wherein R is hydrogen, an optionally substituted hydrocarbon group and an optionally substituted heterocyclic group, R1 is H, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, a sulfonyl group and a substituted formyl group, R2 and R3 independently are H, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, a substituted formyl group, a carboxyl group and a sulfonyl group, R4 and R5 independently are H, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, a substituted oxyl group and an acyl group, R6 is hydrogen, an optionally substituted C1-C6 aliphatic hydrocarbon group and a substituted oxyl group, R7 is hydrogen, an optionally substituted C1-C6 aliphatic hydrocarbon group, a substituted oxyl group, an acyl group and a substituted formyl group, and R6R7 is a covalent bond. The colchicine derivative has a good anti-tumor activity and high cell selectivity, and can be expected to be a cell-specific drug with a low toxic-side effect.

Description

technical field [0001] The invention relates to the field of drugs with antitumor activity, in particular to a colchicine derivative. Background technique [0002] Colchicine is a natural alkaloid that can also be synthesized artificially. It is commonly used clinically to treat acute gout (ac utegout), familial Mediterranean fever (familial Mediterranean fever), scleroderma (seleroderma), Behcet's disease (Behcet's disease), liver cirrhosis (cirrhosi), etc., and its effective dose is 0.015 mg / kg, the toxic dose is about 0.1 mg / kg, and the lethal dose is 0.8 mg / kg, with large toxic and side effects and low therapeutic index. [0003] Colchicine mainly acts on tubulin, and it can combine with tubulin to destabilize tubulin, showing strong anti-tumor activity in vitro and a broad anti-tumor spectrum, but due to its high toxicity, it cannot be used in the clinical practice of cancer. applied in treatment. In order to obtain colchicine derivatives with high activity and low t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C251/36C07C249/04C07C233/41C07C231/12C07D209/70C07D497/10C07D513/10C07D487/04C07D209/94C07D317/64C07D491/147A61P35/00
Inventor 钟建华沈莉萍王彦广
Owner ZHEJIANG UNIV
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