A class of pyrazole heterocycle-containing ursolic amide derivatives, synthesis and applications thereof

A synthesis method and compound technology, which can be applied to medical preparations containing active ingredients, drug combinations, steroids, etc., and can solve the problems of limited development, poor solubility, and low bioavailability.

Active Publication Date: 2017-07-14
SHANGHAI ADVANCED RES INST CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the poor solubility, unclear target and low bioavailability of ursolic acid compounds, their development in drug development is limited.

Method used

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  • A class of pyrazole heterocycle-containing ursolic amide derivatives, synthesis and applications thereof
  • A class of pyrazole heterocycle-containing ursolic amide derivatives, synthesis and applications thereof
  • A class of pyrazole heterocycle-containing ursolic amide derivatives, synthesis and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Dissolve 460mg of ursolic acid (1) and 280mg of anhydrous potassium carbonate in 10ml of N,N-dimethylamide, then add 300mg of BnBr, and heat the reaction mixture at about 60°C for 4 hours until the reaction is complete. The mixture was cooled to room temperature, and 50 mL of H 2 O, a white solid was precipitated. The obtained solid was successively filtered, washed with water, and vacuum-dried to obtain 0.50 g of intermediate (2), and the yield of intermediate (2) was 92%.

[0126] The spectrum identification result of intermediate (2) is as follows:

[0127] 1 H NMR (500MHz, CDCl 3 ):δ=7.36-7.29(m,5H),5.24-5.23(m,1H),5.10(d,J=12.5Hz,1H),4.98(d,J=12.5Hz,1H),3.20(dd, J=11.0,4.5Hz,1H),2.04-1.98(m,1H),1.89-1.76(m,3H),1.73-1.67(m,2H),1.64-1.55(m,4H),1.53-1.44( m,6H),1.37-1.26(m,6H),1.07(s,3H),1.05-1.02(m,2H),0.98(s,3H),0.93(d,J=6.0Hz,3H),0.89 (s,3H),0.85(d,J=6.5Hz,3H),0.78(s,3H),0.64(s,3H).

[0128] 13 C NMR (125MHz, CDCl 3 ):δ=177.3,138.1,136.3,128.4(2C),128.1(2C...

Embodiment 2

[0132] Dissolve 450 mg of intermediate (2) in 50 mL of anhydrous dichloromethane, cool to below 0°C, add 355 mg of PCC for reaction, and slowly warm the mixture to room temperature and stir for about 12 hours until the reaction is complete. The reaction mixture was filtered through diatomaceous earth to remove insoluble matter, the organic phase was concentrated under pressure, and the residue was separated and purified by silica gel column chromatography to obtain 375 mg of intermediate (3). Intermediate (3) was a white solid. The yield was 84%.

[0133] The spectrum identification result of intermediate (3) is as follows:

[0134] 1 H NMR (500MHz, CDCl 3 ):δ=7.37-7.29(m,5H),5.25(t,J=3.5Hz,1H),5.11(d,J=12.5Hz,1H),4.99(d,J=12.5Hz,1H),2.57 -2.50(m,1H),2.40-2.34(m,1H),2.27(d,J=11.5Hz,1H),2.04-1.98(m,1H),1.92-1.87(m,3H),1.82-1.68 (m,3H),1.64-1.54(m,3H),1.50-1.41(m,5H),1.35-1.28(m,4H),1.10-1.07(m,1H),1.08(s,6H),1.03 (d,J=9.0Hz,6H),0.93(d,J=6.0Hz,3H),0.85(d,J=6.5Hz,3H),0.68(s,...

Embodiment 3

[0139] 300 mg of intermediate (3) was dissolved in 20 mL of anhydrous tetrahydrofuran, the reaction solution was cooled to 0°C, 45 mg of sodium methoxide was added thereto, and then 45 mg of ethyl formate was added. The reaction mixture was stirred at room temperature for about 4 hours until the reaction was complete. A small amount of water was added to quench the reaction and the mixture was extracted three times with ethyl acetate (3 x 30ml). The combined organic phases were sequentially washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated, and the residue was quickly separated by silica gel column chromatography to obtain intermediate (4a).

[0140] The spectrum identification results of intermediate (4a) are as follows:

[0141] 1 H NMR (500MHz, CDCl 3 ): δ=14.92(br s,1H), 8.57(s,1H), 7.37-7.30(m,5H), 5.28(t,J=3.3Hz,1H), 5.12(d,J=12.5Hz,1H ),4.99(d,J=12.5,1H),2.32-2.28(m,2H),2.05-1.92(m,4H),1.82-1.69(m,3H)...

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Abstract

The present invention provides the structure general formula of a class of pyrazole heterocycle-containing ursolic amide derivatives, further a synthesis route and synthesis steps of the pyrazole heterocycle-containing ursolic amide derivatives, and uses of the pyrazole heterocycle-containing ursolic amide derivatives in preparation of tumor treatment drugs. According to the present invention, the in vitro ant-tumor activity test results show that the pyrazole heterocycle-containing ursolic amide derivatives can significantly kill tumor cell growth, and have the development potential in novel antitumor drugs.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, relates to a class of ursbutamide derivatives containing a pyrazole heterocycle and its synthesis and application, in particular to a class of ursbutamide derivatives containing a pyrazole heterocycle and a synthesis method thereof and is used in the treatment of Application of tumor drugs. Background technique [0002] Modern medicine has proved that tumors are caused by various physiological and biochemical factors such as environmental pollution, chemical pollution, ionizing radiation, free radical toxins, microorganisms (bacteria, fungi, viruses, etc.) and their metabolic toxins, genetic characteristics, endocrine imbalance, and immune dysfunction. Under the action, some cells in the local tissue lose their normal regulation of their growth at the gene level, and the new organisms formed by clonal abnormal proliferation. Clinically, tumor treatment mainly adopts various measures su...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00A61K31/58A61P35/00
CPCC07J71/0047
Inventor 苏小惠李斌孙琳魏万国
Owner SHANGHAI ADVANCED RES INST CHINESE ACADEMY OF SCI
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