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Diaryl thioether compound, preparation method and application of thereof in tumor resistance

A compound and phenyl technology, applied in the direction of sulfide preparation, antineoplastic drugs, active ingredients of heterocyclic compounds, etc., can solve problems such as poor water solubility

Inactive Publication Date: 2012-03-28
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, CA4 also has its weakness - poor water solubility, so Pettit et al. used it as a lead compound to synthesize its phosphate prodrug CA4P (US5561122), which greatly improved its water solubility, and is currently conducting phase III clinical trials

Method used

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  • Diaryl thioether compound, preparation method and application of thereof in tumor resistance
  • Diaryl thioether compound, preparation method and application of thereof in tumor resistance
  • Diaryl thioether compound, preparation method and application of thereof in tumor resistance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Preparation of O-ethyl-S-(3,4,5-trimethoxyphenyl)dithiocarbonate (ZLM-1)

[0075]

[0076] Dissolve 3,4,5-trimethoxyaniline (22.3g) in 30.5mL of concentrated hydrochloric acid and 250mL of water, cool to about 0°C in an ice bath, slowly add NaNO dropwise under stirring 2 Aqueous solution (9.2g), temperature controlled not to exceed 5°C, continued reaction for 15min after dropping, then added AcONa (20.0g). This diazonium salt solution was slowly added dropwise to KS2COEt aqueous solution (48.7g dissolved in 120mL water) at about 80°C, and reacted at 70-80°C for 1h. After the reaction was completed, cool to room temperature, extract 100 mL×3 with EA, and combine the organic phases. Then dry with anhydrous sodium sulfate. After suction filtration, the filtrate was obtained, and the solvent was spun off to obtain 30.4 g of a reddish-brown oil, which was separated on a silica gel column to obtain 11.8 g of light yellow-white viscous solid, with a yield of 34%. 1 H NMR...

Embodiment 2

[0078] Preparation of 3,4,5-trimethoxy-1-[(3-amino-4-nitrophenyl)thio]benzene (ZLM-2)

[0079]

[0080] Dissolve O-ethyl-S-(3,4,5-trimethoxyphenyl)dithiocarbonate ZLM-1 (4.0g) in THF (66mL), slowly add LiAlH in portions 4 (2.11g), refluxed for 1h, cooled to room temperature, adjusted to pH=5 with 10% HCl, then extracted 100mL×3 with EA, combined the organic phases, dried with anhydrous sodium sulfate for 1h, and then filtered with suction to obtain the filtrate, which was spun The solvent is removed to obtain 3,4,5-trimethoxythiophenol. Under nitrogen protection, K 2 CO 3(5.8g) and 5-chloro-2-nitroaniline (1.2g) were added to a 50mL two-necked flask, and then the 3,4,5-trimethoxythiophenol obtained in the previous step was dissolved in DMF (23.7mL) Add it into the reaction flask, reflux at 120°C, and monitor by TLC (developing solvent: PE:EA=4:1). The raw materials disappeared, the reaction was stopped, cooled to room temperature, diluted with 200 mL of water, extracted...

Embodiment 3

[0082] Preparation of 3,4,5-trimethoxy-1-[(3-acetamido-4-nitrophenyl)thio]benzene (ZLM-3)

[0083]

[0084] 3,4,5-Trimethoxy-1-[(3-amino-4-nitrophenyl)thio]benzene ZLM-2 (50 mg) was added to a mixture of acetic anhydride (17 μL) and acetic acid (9 μL) In the solvent, reflux at 85-90°C for 2h. Low boiling point substances were distilled off under reduced pressure to obtain 61mg of yellow solid with a yield of 93%, mp 168.1-170.2°C. 1 H NMR (400MHz, CDCl 3 ): δ2.26(s, 3H), 3.87(s, 6H), 3.92(s, 3H), 6.73(dd, J=7.2, 1.8Hz, 1H), 6.81(s, 2H), 8.07(d, J=8.8Hz, 1H), 8.61(d, J=6.0Hz, 1H), 10.48(s, 1H). 13 C NMR (400MHz, CDCl3): δ25.7, 56.3, 61.0, 112.2, 117.6, 119.8, 123.7, 126.2, 132.9, 135.2, 139.6, 151.4, 154.0, 168.9. MS (EI) m / z: 378 (M + ).

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Abstract

The invention relates to the field of the development of new medicines, and relates to the field of the development of new medicines of anti-tumor medicines, in particular to a compound. A structure of the compound is shown as a general formula I, wherein A is selected from 4- nitro-substituted phenyl shown as a structural formula II, 4-alkoxy substituted phenyl shown as a structural formula III and a substituted heterocyclic ring shown as a structural formula IV or a structural formula V, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 and R18 are selected from hydrogen, halogen, hydroxyl, amido, substituted amio, cyan, alkyl, alkoxy, nitryl, acylamino, halogenated alkyl, acyl, formyl, carboxy, carbalkoxy or substituted alkyl having 1 to 3 carbon atoms independently, and R5, R6, R7 and R8 are not the hydrogen simultaneously; R9 is selected from alkyl having 1 to 3 carbon atoms or substituted alkyl having 1 to 3 carbon atoms; and X and Y are selected from nitrogen, oxygen or sulphur independently. The compound has the effects of resisting abnormal neovascularization and inhibiting the polymerization of microtubulin and has the advantages of high activity and low toxicity.

Description

technical field [0001] The invention relates to the field of research and development of new drugs, in particular to the field of research and development of new anti-tumor drugs. Background technique [0002] Combretum caffrum (Combretaceae) is a plant of the genus Combretum in South Africa, which has very important medical application value. In 1988, Pettit et al. isolated a series of active group Combretastatins from it. This series of compounds can bind to the colchicine site to inhibit tubulin polymerization, among which Combretastatin A4 (Combretastatin A4, CA4) has the best activity. CA4 has a simple structure, which is somewhat similar to the structure of colchicine. It has a high inhibitory activity on cell mitosis. At the same time, it has a competitive inhibitory effect on the microtubule polymerization promoted by colchicine, and it can inhibit the mitosis of tumor cells. , disrupting the formation of the mitotic spindle, thereby causing G 2 / M block. At the s...

Claims

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Application Information

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IPC IPC(8): C07C323/37C07C323/41C07C323/20C07C319/14C07D213/70C07D333/70A61K31/145A61K31/165A61K31/10A61K31/44A61K31/381A61P35/00
Inventor 刘苏友罗志勇李杰马大友刘丽君吕恒佳谭小宁曾江陈湘晖李群
Owner CENT SOUTH UNIV
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