Substituted hydrazide compound, and its preparation method, medicinal compositions and application

A kind of compound, hydrazide technology, applied in substituted hydrazide compound and preparation method thereof, field of pharmaceutical composition

Inactive Publication Date: 2012-11-14
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many studies have shown that the B-Raf/MEK/ERK pathway is likely to be in

Method used

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  • Substituted hydrazide compound, and its preparation method, medicinal compositions and application
  • Substituted hydrazide compound, and its preparation method, medicinal compositions and application
  • Substituted hydrazide compound, and its preparation method, medicinal compositions and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1 Preparation of p-methoxycinnamic acid (intermediate 2a)

[0083]

[0084] Dissolve 6.8 grams of p-methoxybenzaldehyde (Shanghai Pure Chemical Reagents) in anhydrous pyridine, then add 10.4 grams of malonic acid and 0.5 milliliters of piperidine in turn, heat and react at 100°C for 3 hours, and dissolve the Quickly pour the reaction liquid into the prepared cold dilute hydrochloric acid (30 ml concentrated hydrochloric acid + 200 ml ice water), stir, and precipitate a white solid, let it stand, filter, slowly wash the filter cake with ice water, and dry it at an appropriate temperature to obtain a powder Recrystallized with ethanol to obtain 7.8 g of p-methoxycinnamic acid (intermediate 2a), with a yield of 87%. 1 H NMR (400MHz, DMSO-d 6 )δ12.20(s, 1H), 7.63(d, J=8.4Hz, 2H), 7.54(d, J=16.0Hz, 1H), 6.96(d, J=8.8Hz, 2H), 6.37(d, J = 16.0 Hz, 1H), 3.79 (s, 3H).

Embodiment 2

[0085] Example 2 Preparation of 3-chloro-6-methoxybenzothiophene-2-formyl chloride (intermediate 3a)

[0086]

[0087] Under argon atmosphere at room temperature, add 3.56 g of compound intermediate 2a to 20 ml of chlorobenzene, then add 0.16 ml of pyridine and 7.3 ml of thionyl chloride, heat the reaction solution under reflux for 11 hours, then cool to about 40°C , filtered, and the solvent was evaporated under reduced pressure. The residue was heated and dissolved with 150 ml of 60-90°C petroleum ether, filtered while it was hot, and the filtrate was cooled in the refrigerator overnight, and a solid precipitated, filtered, the filter cake was washed with cold petroleum ether, and vacuum-dried to obtain 1.10 g of 3-chloro-6- Methoxybenzothiophene-2-carbonyl chloride (intermediate 3a), yield 21%.1 H NMR (400MHz, CDCl 3 )δ7.90(d, J=9.2Hz, 1H), 7.24(d, J=2.4Hz, 1H), 7.16(dd, J 1 =2.0Hz,J 2 =8.8Hz, 1H), 3.95(s, 3H).

Embodiment 3

[0088] Embodiment 3 Preparation of ethyl p-aminobenzoate (intermediate 4)

[0089]

[0090] Under ice-bath conditions, 11 milliliters of thionyl chloride was added dropwise to the ethanol suspension of 13.7 grams of p-aminobenzoic acid, the reaction solution was heated to reflux for 5.5 hours, cooled, and solids were precipitated, and the ethanol in the reaction solution was evaporated under reduced pressure , Dissolve the residue obtained with 100 ml of ethyl acetate, neutralize with saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with ethyl acetate several times, and combine the organic phases. The organic phase was washed successively with saturated brine, anhydrous Na 2 SO 4 Dry and concentrate under reduced pressure to obtain a solid, which is recrystallized from ethyl acetate / petroleum ether to obtain 15.4 g of ethyl p-aminobenzoate (intermediate 4), with a yield of 93%. 1 H NMR (400MHz, CDCl 3 )δ7.87(d, J=8.4Hz, 2H), 6.65(d, J...

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Abstract

The invention relates to a substituted hydrazide compound with a structure shown in the following general formula I, its preparation method, medicinal compositions and application thereof. The compound can be used for preparing medicines treating diseases caused by B-Raf and its isoenzymes or mutants (such as B-RafV600E).

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, and more specifically relates to substituted hydrazide compounds and their preparation methods, pharmaceutical compositions and applications. This type of compound can be used for preparing and treating B-Raf and its isoenzymes or mutants (such as B-Raf V600E ) of the disease caused by the drug. Background technique [0002] Raf kinase and its mediated Raf / MEK / ERK (MAPK) pathway play a significant role in tumor progression and metastasis. It is currently known that the transduction pathway MAPK exists in all eukaryotic cells, and it transmits signals from the extracellular to the nucleus through the specific cascade phosphorylation of Ras, Raf, MEK and ERK. In many tumor cells, this pathway is up-regulated, and Raf is a key kinase in this pathway, which can exert its signal transduction regulation in a Ras-dependent or Ras-independent manner. As a downstream...

Claims

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Application Information

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IPC IPC(8): C07D333/70C07D495/04C07C243/38C07C241/04A61K31/381A61K31/166A61P35/00A61P1/00
Inventor 朱维良曾步斌王贺瑶闫桂蕊黄贤贵徐志建罗成张奇军王改红杨卓张小东李波徐炜均罗小民蒋华良陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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