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Diaryl thioether compound, preparation method and antitumor application thereof

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

Inactive Publication Date: 2014-08-27
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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 undergoing phase III clinical trials

Method used

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  • Diaryl thioether compound, preparation method and antitumor application thereof
  • Diaryl thioether compound, preparation method and antitumor application thereof
  • Diaryl thioether compound, preparation method and antitumor application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Preparation of O-ethyl-S-(3,4,5-trimethoxyphenyl)dithiocarbonate (ZLM-1)

[0076]

[0077] Dissolve 3,4,5-trimethoxyaniline (22.3g) in 30.5mL of concentrated hydrochloric acid and 250mL of water, cool in an ice bath to about 0°C, 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). Slowly add this diazonium salt solution dropwise to KS at about 80°C 2 In COEt aqueous solution (48.7g dissolved in 120mL water), react 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 (400M...

Embodiment 2

[0079] Preparation of 3,4,5-trimethoxy-1-[(3-amino-4-nitrophenyl)thio]benzene (ZLM-2)

[0080]

[0081] Dissolve O-ethyl-S-(3,4,5-trimethoxyphenyl)dithiocarbonate ZLM-1 (4.0g) in THF (66mL), slowly add LiAlH4 (2.11g ), refluxed for 1 h, cooled to room temperature, adjusted to pH = 5 with 10% HCl, then extracted 100 mL×3 with EA, combined the organic phases, dried with anhydrous sodium sulfate for 1 h, and then filtered with suction to obtain the filtrate, which was spun off from the solvent. In 3,4,5-trimethoxythiophenol. Under nitrogen protection, K 2 CO3 (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 with EA (200 mL...

Embodiment 3

[0083] Preparation of 3,4,5-trimethoxy-1-[(3-acetamido-4-nitrophenyl)thio]benzene (ZLM-3)

[0084]

[0085] Add 3,4,5-trimethoxy-1-[(3-amino-4-nitrophenyl)thio]benzene ZLM-2 (50 mg) to a mixture of acetic anhydride (17 μL) and acetic acid (9 μL) In the solvent, reflux at 85-90°C for 2h. The low boiling point substances were evaporated under reduced pressure to obtain 61mg of yellow solid with a yield of 93%, mp168.1-170.2℃. 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 CNMR (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 new drug research and development field, especially to a diaryl thioether compound, a preparation method and antitumor application thereof. The structure of the diaryl thioether compound is shown as general formula I. Specifically, A is selected from 4-nitro substituted phenyl with a structure shown as formula II, 4-alkoxy substituted phenyl with a structure shown as formula III, substituted heterocycle with a structure shown as formula IV or substituted heterocycle with a structure shown as formula V, wherein R1, R2, R3, R4, R5, R6, R7, R8, R10, R11, R12, R13, R14, R15, R16, R18, R17, and X, Y are all as described in the specification. The compound has anti-abnormal neovascularization and tubulin polymerization inhibiting mechanisms, and has the advantages of high activity and low toxicity. (formula I, formula II, formula III, formula IV and formula V).

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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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/37C07C323/20C07C329/20C07D213/70C07D333/70C07C319/14A61K31/136A61K31/16A61K31/44A61K31/381A61P35/00
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