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Mifepristone derivative and application thereof

A technology of mifepristone and its derivatives, which is applied in the field of medicine, can solve the problems of no targeted therapy drug, limited clinical application, and no anti-tumor activity, and achieves strong drug activity, strong anti-tumor activity, and small dosage. Effect

Active Publication Date: 2017-02-15
KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Triple Negative Breast Cancer (TNBC) is a special type of breast cancer that is negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) , is the most malignant subtype of breast cancer, accounting for about 10%-25% of all breast cancers, and no effective targeted therapy drugs have been found so far
However, a large number of research data and preliminary activity test results have shown that mifepristone must be at a higher dose to produce anti-tumor activity, and the main metabolite of mifepristone, monodesmethylmifepristone (RU-42633, US tapristone) has no obvious antitumor activity
In view of the fact that mifepristone is quickly metabolized into monodesmethylmifepristone in the body, and the concentration of this main metabolite in the blood after 0.5-2 hours after administration far exceeds that of the parent compound, which greatly limits the efficacy of mifepristone. Ketone may be used as an ideal targeted antineoplastic drug for further clinical application

Method used

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  • Mifepristone derivative and application thereof
  • Mifepristone derivative and application thereof
  • Mifepristone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 FZU-0000-005

[0024] 2-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2, 3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylacetamide

[0025] 28mg, 0.24mmol 2-chloroacetyl chloride, 84mg, 0.2mmol metapristone and 42mg, 0.4mmol Et 3 N was added into 2.0 mL EtOAc and stirred for 16 hours, PE / EtOAc=1:1, 90 mg of product was prepared according to method (a), the yield was 92%, the product was a white solid, mp: 124.3–125.5°C.

[0026] The resulting product was subjected to hydrogen spectroscopy 1 HNMR, carbon spectrum 13 CNMR and HRMS detection, the results are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.27(d, J=6.0Hz, 2H), 7.16(d, J=7.7Hz, 2H), 5.80(s, 1H), 4.47(d, J=6.9Hz, 1H), 3.82(s, 2H),3.27(s,3H),2.85–2.75(m,1H),2.67–2.56(m,2H),2.53–2.38(m,4H),2.37–2.15(m,4H),2.10–2.01( m,1H),2.01–1.94(m,1H),1.91(s,3H),1.79–1.72(m,2H),1.56–1.47(m,1H),1.41–1.32(m,1H),0.50( s,3H).

[0027] 13 C N...

Embodiment 2

[0030] 2-Chloro-N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2, 3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N-methylpropanamide(FZU-0010-001)

[0031] The difference from Example 1 is: 2-chloroacetyl chloride is 30mg, Et 3 N was 40 mg, 80 mg of product was obtained in 79% yield, where PE / EtOAc = 2:1. The product was a white solid, mp: 124.6-125.6 °C.

[0032] 1 H NMR (400MHz, CDCl 3 )δ7.27(d, J=7.9Hz, 2H), 7.18(d, J=8.0Hz, 2H), 5.80(s, 1H), 4.48(d, J=6.8Hz, 1H), 4.26(q, J=6.3Hz,1H),3.28(s,3H),2.90–2.74(m,1H),2.68–2.58(m,2H),2.54–2.38(m,4H),2.32–2.19(m,2H) ,2.13–1.95(m,4H),1.91(s,3H),1.83–1.67(m,2H),1.56(d,J=6.5Hz,3H),1.53–1.44(m,1H),1.40–1.28 (m,1H),0.51(s,3H). 13 CNMR (101MHz, CDCl 3 )δ199.43,169.57,156.55,145.37,145.09,140.51,129.98,128.61,127.30,123.37,82.82,82.26,80.11,49.85,47.01,40.25,39.29,39.19,39.02,38.15,36.85,31.16,27.41,26.04,23.44 ,21.36,14.00,13.99,3.94.

[0033] HRMS(ESI-TOF):calcd for ...

Embodiment 3

[0035] N-(4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-yn-1-yl)-2,3,6, 7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)-N,4-dimethylbenzonesulfonamide(FZU-0025-008)

[0036] The difference from Example 1 is that 28mg, 0.24mmol of 2-chloroacetyl chloride was replaced with 46mg, 0.24mmol of p-toluenesulfonyl chloride, and 83mg of white solid was obtained according to method a, with a yield of 73%, mp: 121.8–122.9 ℃.

[0037] 1 H NMR (400MHz, CDCl 3 )δ7.33(d, J=7.9Hz, 2H), 7.19(d, J=7.9Hz, 2H), 7.11(d, J=8.2Hz, 2H), 7.01(d, J=8.2Hz, 2H) ,5.78(s,1H),4.42(d,J=6.8Hz,1H),3.11(s,3H),2.87–2.66(m,1H),2.66–2.56(m,2H),2.51–2.36(m ,6H),2.34–2.18(m,4H),2.14–1.97(m,3H),1.91(s,3H),1.82–1.68(m,2H),1.55–1.44(m,1H),1.35–1.28 (m,1H),0.51(s,3H).

[0038] 13 C NMR (101MHz, CDCl 3 )δ199.42,156.61,145.44,143.74,143.60,139.14,133.03,129.62,129.24,127.81,127.34,126.24,123.07,82.65,82.20,80.02,49.71,46.93,40.07,39.17,39.12,38.87,37.78,36.78,31.08 ,...

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Abstract

The invention discloses a mifepristone derivative and application thereof. The structural formula of the mifepristone derivative is represented by a formula (I) where R is acyl or sulfonyl. The invention further relates to application of the mifepristone derivative in preparation of a medicine for treating KLF5 (Kruppel-like factor 5) regulating tumors, in particular to application in preparation of a medicine for treating the triple-negative breast cancer. The compound is simple in structure and easy to prepare, has the anti-tumor activity higher than mifepristone, is small in dosage, and can be used for preparing a tumor medicine which is used for treating the triple-negative breast cancer and is closely related to the KLF5; meanwhile, the mifepristone derivative which is researched and synthesized according to the invention and has high druggability supplies a novel solution and scheme to synthesis of other compounds of the same type.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to mifepristone derivatives and uses thereof. Background technique [0002] Studies have found that transcription factor KLF5 (Kruppel-like factor 5, zinc finger protein transcription factor 5) is a family of transcriptional regulators that bind to DNA domains. In normal tissues, KLF5 participates in the biological processes of many cells, including cell proliferation, differentiation, migration, inflammation and potential. The expression and function of KLF5 are changed in cancer tissues, and it is involved in the regulation of cancer cell proliferation, regulation, metastasis, tumor microenvironment and tumor stem cells. KLF5 is mainly involved in many important signaling pathways that control cell proliferation, and it has the effect of promoting cell proliferation in both normal cells and many human cancer cells. Triple Negative Breast Cancer (TNBC) is a special t...

Claims

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Application Information

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IPC IPC(8): C07J41/00C07J43/00A61P35/00
CPCC07J41/0033C07J43/003
Inventor 陈策实陈海军刘蓉林雨琦郑政赵平杨传雨
Owner KUNMING INST OF ZOOLOGY CHINESE ACAD OF SCI