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Potential ezh2 small molecule inhibitors and methods for their synthesis

A technology of a small molecule inhibitor and a synthesis method, which is applied in the field of medicine and chemical industry, and achieves the effects of simple synthesis route, simple separation process and good EZH2 inhibitory activity

Inactive Publication Date: 2019-03-19
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although no clinically or therapeutically approved compounds have emerged, more efforts should be made to develop methyltransferase inhibitors of EZH2

Method used

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  • Potential ezh2 small molecule inhibitors and methods for their synthesis
  • Potential ezh2 small molecule inhibitors and methods for their synthesis
  • Potential ezh2 small molecule inhibitors and methods for their synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] FTCI-2362

[0032]

[0033] Take 1.78g (0.01mol) of 1-phenyl-5-mercapto-1H-tetrazolium into a round bottom flask, add 30ml of methanol dropwise, and stir until the white solid is completely dissolved. Under stirring, 1.81 g (0.011 mol) of ethyl 4-chloroacetoacetate was added dropwise and stirred at room temperature for 5 h, and the spot reaction was complete. Spin the methanol to dryness under reduced pressure, add 5ml of deionized water to the residual oil to dissolve, then add ethyl acetate to extract the water phase three times, combine the organic phases, dry, and recover the ethyl acetate under reduced pressure to obtain 2.82g of a colorless oily liquid (93%).

[0034] Take 1.5g (4.9×10-3mol) of the oil obtained in the previous step, add an appropriate amount of absolute ethanol and stir, add 0.94g (9.8×10-3mol) of guanidine hydrochloride under stirring, add 0.53g (9.8×10-3mol) After the ethanol solution of sodium methoxide was heated to reflux for 8 hours, th...

Embodiment 2

[0037] FTCI-2377

[0038]

[0039] Take 1.78g (0.01mol) of 1-phenyl-5-mercapto-1H-tetrazolium into a round bottom flask, add 30ml of methanol dropwise, and stir until the white solid is completely dissolved. Under stirring, 1.81 g (0.011 mol) of ethyl 4-chloroacetoacetate was added dropwise and stirred at room temperature for 5 h, and the spot reaction was complete. Spin the methanol to dryness under reduced pressure, add 5ml of deionized water to the residual oil to dissolve, then add ethyl acetate to extract the water phase three times, combine the organic phases, dry, and recover the ethyl acetate under reduced pressure to obtain 2.82g of a colorless oily liquid (93%).

[0040] Take 1.5g (4.9×10-3mol) of the oil obtained in the previous step, add an appropriate amount of absolute ethanol and stir, add 0.94g (9.8×10-3mol) of guanidine hydrochloride under stirring, add 0.53g (9.8×10-3mol) After the ethanol solution of sodium methoxide was heated to reflux for 8 hours, th...

Embodiment 3

[0043] FTCI-2369

[0044]

[0045] Take 1.78g (0.01mol) of 1-phenyl-5-mercapto-1H-tetrazolium into a round bottom flask, add 30ml of methanol dropwise, and stir until the white solid is completely dissolved. Under stirring, 1.81 g (0.011 mol) of ethyl 4-chloroacetoacetate was added dropwise and stirred at room temperature for 5 h, and the spot reaction was complete. Spin the methanol to dryness under reduced pressure, add 5ml of deionized water to the residual oil to dissolve, then add ethyl acetate to extract the water phase three times, combine the organic phases, dry, and recover the ethyl acetate under reduced pressure to obtain 2.82g of a colorless oily liquid (93%).

[0046] Take 1.5g (4.9×10-3mol) of the oil obtained in the previous step, add an appropriate amount of absolute ethanol and stir, add 0.94g (9.8×10-3mol) of guanidine hydrochloride under stirring, add 0.53g (9.8×10-3mol) After the ethanol solution of sodium methoxide was heated to reflux for 8 hours, th...

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Abstract

The invention discloses a potential EZH2 small molecule inhibitor and a synthetic method thereof. The synthetic method includes the specific steps: (1) subjecting 5-mercapto-1-phenyltetrazole and ethyl 4-chloroacetoacetate to reaction under the action of strong base to obtain a first intermediate; (2) subjecting the first intermediate to reaction with guanidine hydrochloride under the action of strong base to obtain a second intermediate; (3) subjecting the second intermediate and isocyanates or isothiocyanate compounds to reaction to generate a target compound. The separation process is simple, column chromatography separation is not needed, the steps are simple, and convenience is brought to industrial production. The synthesized target compound has good EZH2 inhibitory activity, a kind of novel small molecule structure is provided for research and development of antineoplastic drugs, the small molecule structure has diversity, and further research is conducive to development of the medicinal value of the inhibitor.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to an EZH2 small molecule inhibitor and a synthesis method thereof. Background technique [0002] In the past few years, epigenetic modifications such as DNA methylation, histone methylation, and acetylation have shown promise for cancer therapy. Studies have found that overexpression of EZH2 has been found in blood diseases and solid tumors, such as Hodgkin's disease, non-Hodgkin's tumor, prostate cancer, breast cancer, and throat cancer, which indicates that the overexpression of EZH2 is related to tumor There is a close relationship between generation and deterioration. Therefore, many researchers list it as an important target for cancer treatment and develop corresponding inhibitors. In recent years, several effective drugs have been used as new clinical anti-tumor drugs, such as 5-azacytidine, 5-aza-2-deoxycytidine, and GSK126. Further stu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12A61K31/513A61P35/00
CPCA61K31/513C07D403/12
Inventor 姚志艺张晓攀
Owner SHANGHAI INST OF TECH
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