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Alpha, beta-unsaturated ketone compound containing thiazole heterocycle, its preparation method and application

A ketone compound, unsaturated technology, applied in the field of thiazole-containing heterocycle α, can solve the problem of lack of isozyme specificity

Active Publication Date: 2014-09-03
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Ethacrynic acid (EA for short, formula I) is the first GST Pi inhibitor used clinically, but its diuretic, ototoxic and other toxic side effects, and lack of isoenzyme specificity all limit its clinical application. For application, see: Zhao G. Wang X: Advance in antitumor agents targeting glutathione-S-transferase. Curr Med Chem 2006, 13(12): 1461-1471

Method used

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  • Alpha, beta-unsaturated ketone compound containing thiazole heterocycle, its preparation method and application
  • Alpha, beta-unsaturated ketone compound containing thiazole heterocycle, its preparation method and application
  • Alpha, beta-unsaturated ketone compound containing thiazole heterocycle, its preparation method and application

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preparation example Construction

[0040] The preparation method of the thiazole heterocyclic α, β-unsaturated ketone compound containing general formula 8 of the present invention, with R 1 is hydrogen or methyl, R 2 is methyl or chlorine, R 3 is methyl or ethyl, R 4 is phenyl, p-nitrophenyl, p-trifluoromethylphenyl or 2-naphthyl, R 5 For hydrogen as an example, the steps are as follows:

[0041] (1) Mix 2-(substituted phenoxy)acetic acid 1 and thionyl chloride at a molar ratio of 1:10, heat to 80°C, react for 4 hours, distill off thionyl chloride under reduced pressure, and dilute with anhydrous toluene , add the obtained toluene solution to ammonia water under ice-bath conditions, continue to stir for 1.5h, filter, and recrystallize the filter cake with ethanol-water to obtain intermediate compound 2: 2-(substituted phenoxy)acetamide 2 ;

[0042] (2) Add the above-mentioned intermediate compound 2 and phosphorus pentasulfide into tetrahydrofuran in a molar ratio of 1:2, use 250 ml of tetrahydrofuran per...

Embodiment 1

[0054] Embodiment 1. Preparation of Compounds 8a~8o

[0055] (1) Preparation of 2-(substituted phenoxy)acetamide 2

[0056] Add 2-(substituted phenoxy)acetic acid 1 (20mmol) and thionyl chloride 15mL (200mmol) into a 50mL round-bottomed flask, stir and mix, slowly heat the oil bath to 80°C, reflux for 4h, evaporate under reduced pressure Remove the residual thionyl chloride in the reaction solution, add 10 mL of dry toluene to dilute and directly use it in the next reaction.

[0057] Take a 100mL three-necked flask (with a drying tube) and place it in an ice-water bath, add 10mL of ammonia water, and slowly add the reaction solution treated in the previous step into the ammonia water. Remove to filtrate. The filter cake was transferred to hot acetone, fully dissolved and filtered, the filter residue was washed with hot acetone, the lotion and filtrate were combined, and the solvent was evaporated under reduced pressure. The obtained white solid was recrystallized with ethano...

Embodiment 2

[0119] Embodiment 2: Determination of compound's inhibitory activity on GST Pi and growth inhibitory activity on HL-60 cells

[0120] Compounds 8a-8o prepared in Example 1 were tested for their inhibitory activity by the following method, and the results are listed in Table 1.

[0121] For the assay method of GST Pi inhibitory activity, according to the prior art, refer to Example 5 on page 11 of CN1706789 "α, β-unsaturated ketone compound and its preparation method and its inhibition of GSTπ activity" (200510043573.3).

[0122] For the assay method of HL-60 cell growth inhibitory activity, according to the prior art, refer to page 3 of CN101108832 "five-membered heterocyclic compounds, preparation method and application" (200710015199.5).

[0123] Table 1. Determination data of compounds inhibiting GST Pi activity and inhibiting HL-60 cell growth activity

[0124]

[0125]

[0126]

[0127] The experimental results show that the 15 kinds of α, β-unsaturated ketone c...

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Abstract

The invention relates to an alpha, beta-unsaturated ketone compound containing thiazole heterocycle, its preparation method and application. The alpha, beta-unsaturated ketone compound containing thiazole heterocycle is shown by the general formula 8, wherein R1 represents hydrogen, methyl or chlorine, R2 represents methyl or chlorine, R3 represents methyl or ethyl, R4 represents hydrogen, phenyl, p-nitro phenyl, p-benzotrifluoride or naphthyl, R5 represents hydrogen, phenyl, p-nitro phenyl, p-benzotrifluoride or naphthyl. The invention also provides the preparation method and application of the compound. The compound has excellent activity for inhibiting GST Pi and activity for inhibiting HL-60 cell growth, and is used for preparing antitumor drugs.

Description

technical field [0001] The invention relates to the fields of organic compounds and medical applications, in particular to a preparation method and application of thiazole-containing heterocyclic alpha, beta-unsaturated ketone compounds. Background technique [0002] Malignant tumors are one of the major diseases that threaten human health. The development of molecular biology provides new targets for the research of antitumor drugs. Glutathione transferases (GSTs) are a large family of phase II metabolic enzymes widely present in animals and plants. Compounds combine to form complexes with high water solubility and low toxicity, which are easily inactivated by phase III metabolic enzymes. See: Townsend DM. Tew KD: The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 2003, 22(47): 7369-7375. GSTs can be divided into membrane-bound microsomal family and cytoplasmic family. Mammalian cytoplasmic GSTs have gene polymorphisms and can be divided into se...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/24A61P35/00
Inventor 赵桂森李婷刘古月杨新美景永奎李红彩
Owner SHANDONG UNIV
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