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Pyrimidine antitumor compound with Hedgehog antagonist activity

A hedgehog pathway and compound technology, applied in the field of pyrimidine anti-tumor compounds, can solve the problems of tumor metastasis and regeneration with little efficacy, and achieve the effect of blocking metastasis and regeneration and inhibiting abnormal cell growth.

Active Publication Date: 2014-02-19
SUZHOU KINTOR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Metastasis and regeneration are the characteristics of malignant tumors, and they are also difficult problems in the treatment of malignant tumors. Even the new generation of targeted drugs have little effect on tumor metastasis and regeneration

Method used

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  • Pyrimidine antitumor compound with Hedgehog antagonist activity
  • Pyrimidine antitumor compound with Hedgehog antagonist activity
  • Pyrimidine antitumor compound with Hedgehog antagonist activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] This embodiment provides an antitumor compound A1, the synthesis method of which is as follows:

[0054]

[0055] 1) Synthesis of intermediate A1-2:

[0056] Dissolve 4-tert-butoxycarbonylpiperidone (A1-1, 10g, 50.2mmol) in 40ml of N,N-dimethylformamide, and add N,N-dimethylformamide dimethyl After the addition of acetal (6 g, 50 mmol), the reaction was carried out at 80°C for 12 hours. Cooled to room temperature, added to ethyl acetate (150mL) and water (50mL), the organic phase was washed twice with saturated brine (50mL), dried and filtered over anhydrous sodium sulfate, and rotary evaporated to obtain an orange crude product (13g). Vote for the next response.

[0057] 2) Synthesis of intermediate A1-3:

[0058] At room temperature, dissolve hemimethylthiourea sulfate (6.98g, 25.1mmol) and sodium ethoxide (3.28g, 40mmol) in 40ml of ethanol, stir for half an hour, then add the intermediate A1-2 (13g, 50.2 mmol) in 10 ml of ethanol solution, reflux for 12 h, coo...

Embodiment 2

[0071] This embodiment provides an antitumor compound A2, the synthesis method of which is as follows:

[0072]

[0073] 1) Synthesis of intermediate A2-1:

[0074] A1-4 (1g, 3.19mmol) and ethylamine aqueous solution (71%, 1mL, 15.8mmol) were successively dissolved in ethanol (10mL) under stirring, heated to reflux, after 12 hours, cooled to room temperature, and decompressed to spin off The solvent and the concentrate were purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 4:1) to obtain a white solid (400mg, 45%).

[0075] 2) Synthesis of intermediate A2-2:

[0076] Dissolve A2-1 (400mg, 1.44mmol) in a small amount of dichloromethane, add hydrogen chloride in saturated ethyl acetate solution (3mL), stir at room temperature for 3 hours, spin off the solvent under reduced pressure, and add the concentrate to saturated aqueous sodium bicarbonate solution (5mL) and dichloromethane (20mL), the organic phase was washed with saturated brine (10mL...

Embodiment 3

[0081] This embodiment provides an antitumor compound A3, the synthesis method of which is as follows:

[0082]

[0083] 1) Synthesis of intermediate A3-1:

[0084] A1-4 (1g, 3.19mmol) and cyclopropylamine (300mg, 5.26mmol) were successively dissolved in ethanol (10mL) under stirring, heated to reflux, after 12 hours, cooled to room temperature, decompressed to spin off the solvent, and concentrate After purification by column chromatography (mobile phase: petroleum ether: ethyl acetate = 4:1), a white solid (460mg, 50%) was obtained.

[0085] 2) Synthesis of intermediate A3-2:

[0086] Dissolve A3-1 (460mg, 1.58mmol) in a small amount of dichloromethane, add hydrogen chloride in saturated ethyl acetate solution (3mL), stir at room temperature for 3 hours, spin off the solvent under reduced pressure, and add the concentrate to saturated aqueous sodium bicarbonate solution (5 mL) and dichloromethane (20 mL), the organic phase was washed with saturated brine (10 mL), dried ...

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Abstract

The invention discloses a pyrimidine antitumor compound with Hedgehog antagonist activity, comprising the compound and pharmaceutically acceptable salts, various isotopes, various isomers or various crystal structures thereof. The pyrimidine antitumor compound has the structure shown as the general formula I, wherein, A refers to nitrogen atom or C-R9, n is 0, 1, 2, 3, 4, 5 or 6; the R1, R2, R3, R4, R5, R6, R7, R8 and R9 are independently selected from hydrogen atom, alkyl, alkenyl, alkynyl, aromatic ring group, heterocyclic radical or heteroatom functional group-containing substituent group, respectively. The antitumor compound provided by the invention can block Hedgehog through blocking an SMO (Smoothened receptor) so as to inhibit cell abnormal growth and block tumor cell migration generation, and has an obvious antitumor effect.

Description

technical field [0001] The present invention relates to the technical field of medicine, in particular to a pyrimidine antitumor compound with hedgehog pathway antagonist activity. Background technique [0002] Malignant tumors are one of the most important diseases that endanger human health. There are about 10.9 million new cases of malignant tumors in the world every year, and about 6.7 million patients die of malignant tumors every year [1]. The research and development of anti-tumor drugs has undergone tremendous changes after years of research and exploration; the anti-tumor drugs commonly used in clinical treatment in the past are mainly cytotoxic drugs, which have poor selectivity, strong toxic and side effects, and are easy to treat. In recent years, with the rapid development of life science research, the signal transduction in malignant tumor cells, the regulation of cell cycle, the induction of apoptosis, angiogenesis and the interaction between cells and extrace...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D487/04A61K31/519A61K31/53A61K31/4985A61K31/4375A61K31/55A61K31/5025A61P35/00A61P35/02
CPCC07D471/04C07D487/04
Inventor 张小虎
Owner SUZHOU KINTOR PHARMA
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