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[0006] (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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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 Justus Liebigs 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 sodiumsulfate was added, 2.5g of hydroxylaminehydrochloride 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 with 50mLEtOAc), anhydrous Na 2 SO 4 Drying, silica gelcolumn 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), yielded 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 resolutionmass spectrometry): C 22 h 25 N 3 o 6 Na + Theoretical value: 450.1636; measured 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 sodiumbicarbonate solution, saturated brine, and anhydrous Na 2 SO 4 Drying, silica gelcolumn 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.
[0121] Compound 3 HRMS: C 22 h 22 N 2 o 6 The theoretical value is 410.1478; the measured value is 410.1479.
[0122] Compou...
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Abstract
The invention discloses a colchicine derivative, the structural formula of which is shown in (I), wherein, for example, R is hydrogen, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; R1 is H, an optionally substituted hydrocarbon group , an optionally substituted heterocyclic group, an acyl group, a sulfonyl group, a substituted formyl group; R2 and R3 are independently H, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, a substituted formyl group, a carboxyl group, Sulfonyl; R4 and R5 are independently H, optionally substituted hydrocarbon group, optionally substituted heterocyclic group, substituted oxy group, acyl group; R6 is hydrogen, optionally substituted C1~C6 aliphatic hydrocarbon group, substituted oxy group; R7 is hydrogen, optionally substituted C1~C6 aliphatic hydrocarbon group, substituted oxygen group, acyl group, substituted formyl group; R6R7 is a covalent bond. The colchicine derivative disclosed by the invention has good anti-tumor activity and high cell selectivity, and is expected to be a cell-specific drug with less toxic and side effects.
Description
[0001] This application is a divisional application with the title of "colchicine derivatives" for an invention and creation. The filing date of the original application is September 3, 2012, and the application number of the original application is 201210318831.4. technical field [0002] The invention relates to the field of drugs with antitumor activity, in particular to a colchicine derivative. Background technique [0003] Colchicine is a natural alkaloid that can also be synthesized artificially. It is commonly used clinically to treat acute gout, familial Mediterranean fever, scleroderma, Behcet's disease, cirrhosi, etc., and its effective dose is 0.015mg / kg, the toxic dose is about 0.1mg / kg, and the lethal dose is 0.8mg / kg, with large toxic and side effects and low therapeutic index. [0004] 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...
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