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1,3,4-thiadiazole heterocyclic compound having hedgehog pathway antagonist activity

A technology of heterocyclic compounds and hedgehog pathway, applied in the field of 1,3,4-thiadiazole heterocyclic compounds, can solve the problems of low solubility and poor physical and chemical properties of vismodegib, and achieve the treatment of tumor diseases and block the metastasis and regeneration of tumor cells. Effect

Active Publication Date: 2019-04-23
SUZHOU YUNXUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, vismodegib has poor physical and chemical properties, low solubility, strong side effects and has developed drug resistance, etc.

Method used

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  • 1,3,4-thiadiazole heterocyclic compound having hedgehog pathway antagonist activity
  • 1,3,4-thiadiazole heterocyclic compound having hedgehog pathway antagonist activity
  • 1,3,4-thiadiazole heterocyclic compound having hedgehog pathway antagonist activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] This example provides a 1,3,4-thiadiazole heterocyclic compound D1 with hedgehog signaling pathway antagonistic activity, which is synthesized by the following method:

[0044]

[0045] 1) Synthesis of intermediate D1-1:

[0046] 2-Amino 1,3,4-thiadiazole (10g, 100mmol) and sodium bicarbonate (16g, 190mmol) were added to methanol (140mL), and bromine (5.5mL, 110mmol) was slowly added dropwise at 0°C ), and then stirred at this temperature for 0.5 hours. Concentrate under reduced pressure to remove most of the methanol, add water (150 mL) to the reaction system to dilute, filter, and vacuum dry to obtain a brown solid (16 g, 89%). 1 H NMR (400MHz, DMSO-d6) δ7.51 (s, 2H).

[0047] 2) Synthesis of intermediate D1-2:

[0048] Intermediate D1-1 (5.0g, 27.8mmol), ethyl 4-piperidinecarboxylate (5.2g, 33.3mmol) and potassium carbonate (7.7g, 55.6mmol) were added to isopropanol (100mL) at 90 Stir at °C for 3 hours. Cool to room temperature, concentrate under reduced pres...

Embodiment 2

[0060] This example provides a 1,3,4-thiadiazole heterocyclic compound D2 with hedgehog signaling pathway antagonistic activity, which is synthesized by the following method:

[0061]

[0062] Intermediate D1-6 (80mg, 0.2mmol), isopropylamine (18mg, 0.3mmol), DIPEA (77mg, 0.6mmol) and HATU (91mg, 0.24mmol) were added to DMF (1mL), stirred at room temperature for 12 hours . The reaction solution was diluted with ethyl acetate (50 mL), and washed with saturated aqueous sodium chloride solution (30 mL*5). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a white solid (25 mg, 28%). After nuclear magnetic spectrum analysis (see Table 1 for spectral data), the obtained solid was compound D2.

Embodiment 3

[0064] This example provides a 1,3,4-thiadiazole heterocyclic compound D3 with hedgehog signaling pathway antagonistic activity, which is synthesized by the following method:

[0065]

[0066] Intermediate D1-6 (70mg, 0.18mmol), cyclopropylamine (15mg, 0.26mmol), DIPEA (70mg, 0.54mmol) and HATU (82mg, 0.22mmol) were added to DMF (1mL), stirred at room temperature for 12 hours . The reaction solution was diluted with ethyl acetate (50 mL), and washed with saturated aqueous sodium chloride solution (30 mL*5). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a yellow solid (45 mg, 58%). After nuclear magnetic spectrum analysis (see Table 1 for spectral data), the obtained solid was compound D3.

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Abstract

The present invention discloses a 1,3,4-thiadiazole heterocyclic compound having hedgehog pathway antagonist activity, wherein the compound has a structure represented by a general formula I defined in the specification. According to the present invention, the 1,3,4-thiadiazole heterocyclic compound having hedgehog pathway antagonist activity can block tumor cell metastasis regeneration by antagonizing hedgehog pathway so as to achieve significant antitumor effect.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a 1,3,4-thiadiazole heterocyclic 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. The research and development of anticancer drugs has undergone tremendous changes in recent years. In the past, anticancer drugs commonly used in clinical treatment were mainly cytotoxic drugs. This type of anticancer drugs has unavoidable disadvantages such as poor selectivity, strong side effects, and easy drug resistance . In recent years, with the rapid development of life science research, various basic processes such as signal transduction in malignant tumor cells, regulation of cell cycle, induction of apoptosis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/454A61K31/4545A61K31/506A61K31/496A61K31/501A61P35/00A61P35/02A61P35/04
CPCC07D417/14
Inventor 张小虎郑计岳马海阔田盛
Owner SUZHOU YUNXUAN PHARMA
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