Salicylamide ester type derivative and preparation method and application thereof

A technology of salicylamide and derivatives, which is applied in the field of salicylamide ester derivatives, and can solve problems such as researches that have not been reported in the literature

Inactive Publication Date: 2011-04-13
李家明
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The histone deacetylase inhibitor short-chain fatty acid and the protein tyrosine kinase inhibitor salicylic amide

Method used

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  • Salicylamide ester type derivative and preparation method and application thereof
  • Salicylamide ester type derivative and preparation method and application thereof
  • Salicylamide ester type derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The synthesis of embodiment 1 niclosamide valproate

[0022] 1.1 Preparation of valproyl chloride

[0023] Reaction formula

[0024]

[0025] In reaction flask, add valproic acid (5.0g, 20.8mmol), SOCl 2 (40mL), add 2 drops of DMF as a catalyst, stir the reaction at 85°C for 4h, then distill off excess SOCl under reduced pressure 2 , and added a small amount of benzene and distilled twice to remove residual SOCl 2 , to obtain valproyl chloride for subsequent use.

[0026] 1.2 Synthesis of niclosamide valproate

[0027] Reaction formula

[0028]

[0029] reaction steps

[0030] Add niclosamide (7.0 g, 21.0 mmol), acetone (60 mL), and triethylamine (4 mL) into the reaction flask, and heat to dissolve under stirring. Then the valproyl chloride (3.4g, 0.021mol) prepared in 1.1 was dissolved in 15mL of dry acetone, and was added dropwise to the niclosamide acetone solution with a constant pressure dropping funnel. TLC detection [V (petroleum ether): V (ethyl ac...

Embodiment 2

[0031] The synthesis of embodiment 2N-(3-chlorophenyl)-2-hydroxyl-4-methoxybenzamide valproate

[0032] 2.1 Synthesis of N-(3-chlorophenyl)-2-hydroxyl-4-methoxybenzamide

[0033] Reaction formula

[0034]

[0035] reaction steps

[0036] Add 4-methoxysalicylic acid (6.0g, 35.7mmol), m-chloroaniline (5.0g, 39.2mmol) and solvent chlorobenzene (80mL) in 250mL three-necked bottle, install reflux condenser, heat and stir until After complete dissolution, the temperature was raised to 135°C to maintain reflux. Phosphorus trichloride (2.4g, 17.5mmol) dissolved in chlorobenzene was slowly added dropwise, and kept at 135°C for a constant temperature reaction for 3h, and detected by TLC [V (petroleum ether): V (ethyl acetate) = 3:1 as developing solvent] Shows complete reaction. Suction filtration while hot, cool and precipitate solid, filter to obtain white solid, wash 2-3 times with 50ml, drain and recrystallize with acetone, the final white crystal, after drying, obtain N-(3-c...

Embodiment 3

[0042] The synthesis of embodiment 3N-(3-bromophenyl)-2-hydroxyl-4-methoxybenzamide valproate

[0043] 3.1 Synthesis of N-(3-bromophenyl)-2-hydroxy-4-methoxybenzamide

[0044] Reaction formula

[0045]

[0046] reaction steps

[0047] According to the method of 2.1 in Example 2, white crystals of N-(3-bromophenyl)-2-hydroxy-4-methoxybenzamide were obtained with a yield of 64.0%, m.p.163.0-163.8°C. 1 H NMR (DMSO, 300MHz) δ: 12.18 (s, 1H, OH), 10.29 (s, 1H, NH), 8.03 (s, 1H, ArH), 7.97 (d, J=9.0Hz, 1H, ArH), 7.68~7.64(m, 1H, ArH), 7.35(d, J=7.8Hz, 2H, ArH), 6.59(dd, J=9.0Hz, J=2.4Hz, 1H, ArH), 6.51(d, J= 2.4Hz, 1H, ArH), 3.80(s, 3H, OCH 3 ); 13 C-NMR (DMSO, 75MHz) δ: 167.7, 164.4, 162.0, 140.3, 131.0, 130.7, 127.0, 123.8, 121.9, 120.2, 109.5, 106.9, 101.8, 55.9; IR (KBr, cm -1 )υ: 3319.7, 3073.6, 2363.6, 1631.4, 1475.3, 1435.7, 1320.5, 1202.7, 1131.0, 1096.4, 1031.3, 994.0, 961.8, 858.8, 830.6, 774.1; ESI-Mass for C 14 h 12 BrNO 3 : m / z(M + +H)322.16.

[0048] 3.2 ...

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Abstract

The invention discloses a salicylamide ester type derivative and a preparation method thereof. The salicylamide ester type derivative has a general formula 1. The salicylamide ester type derivative can be disassociated into a salicylamide type compound with anti-tumor activity and a short-chain fatty acid type compound such as valproic acid, butyric acid and the like with effect of suppressing histone deacetylase activity; thus, the salicylamide ester type derivative disclosed by the invention can be used as an antineoplastic medicament with a double action mechanism.

Description

(1) Technical field [0001] The invention relates to salicylamide ester derivatives used for tumor treatment, a preparation method, and a pharmaceutical composition containing them, belonging to the technical field of medicines. (2) Background technology [0002] The treatment of malignant tumors has long been a worldwide problem. In recent years, with the rapid development of tumor molecular biology and related disciplines, people have gradually realized that the essence of cell carcinogenesis may be the infinite proliferation of cells caused by the imbalance of cell signal transduction pathways. Cytotoxic drugs (mainly acting on DNA, RNA and tubulin) have been transferred to new anti-tumor drugs targeting intracellular signal transduction pathways (see Lu Peng, Li Zeng. Research progress of new target anti-tumor drugs, modern medicine and health , 2010, 26(5): 732-734; Zhu Yijing, Jiang Fengchao. Research progress of anticancer drugs targeting Ras signal transduction, Acta...

Claims

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Application Information

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IPC IPC(8): C07C235/64C07C231/12A61K31/616A61P35/00
Inventor 李家明周鹏袁明许勤龙
Owner 李家明
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