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Application of 3,5-(E)-diarylmethylene-N-cyclopropyl piperidin-4-one compounds as Hsp90 depressant

A technology of cyclopropylpiperidine and ketone compounds, which is applied in the application field of 3,5-dibenzylidene-N-cyclopropylpiperidin-4-one compound, in the preparation of anti-tumor drugs, can Solve the problems of weak activity and unclear targets, and achieve the effect of strong inhibitory activity and strong proliferation inhibitory activity

Active Publication Date: 2016-11-09
FUJIAN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the weak activity of these compounds in vivo and unclear targets, their clinical application is limited.

Method used

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  • Application of 3,5-(E)-diarylmethylene-N-cyclopropyl piperidin-4-one compounds as Hsp90 depressant
  • Application of 3,5-(E)-diarylmethylene-N-cyclopropyl piperidin-4-one compounds as Hsp90 depressant
  • Application of 3,5-(E)-diarylmethylene-N-cyclopropyl piperidin-4-one compounds as Hsp90 depressant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] 3,5-( E )- two (2-pyridine) methylene- N - Preparation of cyclopropylpiperidin-4-one (compound 1)

[0015] N -Cyclopropyl-4-piperidone 348 mg (2.5 mmol), sodium hydroxide 20 mg (0.5 mmol), absolute ethanol 20 mL, mix and stir at room temperature, add 2-pyridinecarbaldehyde 535 mg (5 mmol ), reacted at room temperature for 2h~24h, and solid precipitated out. Suction filtration, the filter cake was washed with absolute ethanol, passed through a silica gel column, eluent petroleum ether: ethyl acetate (3:1) gradient elution, to obtain 348 mg of light yellow solid, yield 47%, melting point 137-138 ° C .

[0016]

[0017] 1 H NMR (400 MHz, Chloroform- d ) δ 8.76 (d, J = 1.8 Hz, 2H), 7.75-7.70(m, 2H), 7.61 (s, 2H), 7.47 (d, J = 7.8 Hz, 2H), 7.24-7.21 (m, 2H), 4.38 (s,4H), 2.06-2.00 (m, 1H), 0.56-0.53(m, 2H), 0.48-0.46 (m, 2H). MS[M+H] + 318.2

Embodiment 2

[0019] 3,5-( E )- two (3-pyridine) methylene- N - Preparation of cyclopropylpiperidin-4-one (compound 2)

[0020]

[0021] This product consists of the aforementioned N -Cyclopropyl-4-piperidone 348 mg (2.5 mmol) and 3-pyridinecarbaldehyde 535 mg (5 mmol) were synthesized according to the method of Example 1 to obtain 79 mg of light yellow solid, yield 9%, melting point 158-160 ° c.

[0022] 1 H NMR (400 MHz, Chloroform- d ) δ 8.70 (s, 2H), 8.60 (d, J =1.6 Hz,2H), 7.74-7.71(m, 4H), 7.39 (d, J = 8.0, 2H), 3.98 (s, 4H), 1.97-1.93 (m,1H), 0.53-0.48 (m, 2H), 0.40 – 0.36 (m, 2H). MS[M+H] + 318.2

Embodiment 3

[0024] 3,5-( E )- two (4-pyridine) methylene- N - Preparation of cyclopropylpiperidin-4-one (compound 3)

[0025]

[0026] This product consists of the aforementioned N -Cyclopropyl-4-piperidone 348 mg (2.5 mmol) and 4-pyridinecarbaldehyde 535 mg (5 mmol) were synthesized according to the method of Example 1 to obtain 74 mg of light yellow solid, yield 8%, melting point 139-140 ° c.

[0027] 1 H NMR (400 MHz, Chloroform- d ) δ 8.76 – 8.63 (m, 2H), 7.65 (d, J =2.0 Hz, 1H), 7.32 (d, J = 5.6 Hz, 0H), 7.30 – 7.25 (m, 2H), 3.96 (s, 4H),1.95 -1.93(m, 1H), 0.54-0.50 (m, 2H), 0.41 – 0.37(m, 2H).

[0028] MS[M+H] + 318.2

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Abstract

The invention discloses an application of 3,5-(E)-diarylmethylene-N-cyclopropyl piperidin-4-one compounds as an Hsp90 depressant. The invention discloses use of the 3,5-(E)-diarylmethylene-N-cyclopropyl piperidin-4-one compounds 1-4 represented by formulae shown in the description and compositions thereof in preparation of drugs for treating or preventing Hsp90 induced diseases. According to the use disclosed by the invention, the Hsp90 induced diseases are leukemia, colon cancer, liver cancer, lymphoma, nasopharyngeal carcinoma or breast cancer. According to the application, the compounds have powerful Hsp90 depression activity, and in vitro, the depression activity of the compounds 1-4 to six kinds of tumor cells is higher than that of 2F by 2 to 20 times. In vivo, relatively high nude-mouse transplantation tumor propagation depression activity is shown, so that the compounds can be used for preparing drugs for treating the leukemia, the colon cancer, the liver cancer, the lymphoma, the nasopharyngeal carcinoma and the breast cancer.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of 3,5-(E)-dibenzylidene-N-cyclopropylpiperidin-4-one compounds with Hsp90 inhibitory activity and their use in the preparation of antitumor drugs Applications. Background technique [0002] Heat shock protein 90 (hsp90) is an ATP-dependent molecular chaperone that is highly expressed in tumor cells and can stabilize and activate many cancer-related kinases and transcription factors. Hsp90 participates in the activation of client protein and promotes its maturation, maintains the conformation and function of various proteins in cells, and is closely related to cell proliferation, apoptosis, carcinogenesis and tumor development, and has become one of the important targets of antitumor drugs . Inhibition of hsp90 can inhibit multiple targets in the tumor growth and metastasis signaling pathway, and simultaneously disable many different cancer growth-promoting client pro...

Claims

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Application Information

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IPC IPC(8): C07D213/68A61K31/4545A61P35/00A61P35/02
CPCC07D213/68
Inventor 刘洋许建华叶敏吴丽贤高剑滨林巧发朱丽萍何佳敏
Owner FUJIAN MEDICAL UNIV
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