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Oxygen-bridge bicyclo-[2.2.1]-heptylene compound and application thereof

A compound, oxygen bridge technology, applied in organic chemistry, drug combination, medical preparations containing active ingredients, etc., can solve problems such as unsatisfactory treatment effect

Active Publication Date: 2014-12-24
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the effect of TAM treatment is not satisfactory: in estrogen receptor negative (ER - ) patients (accounting for about 1 / 3 of the total number of breast cancer patients), only 5% benefit from endocrine therapy; even if the estrogen receptor positive (ER + ) patients (about 2 / 3 of the total number of breast cancer patients), only 50% of them benefit from endocrine therapy (references: A.M.Brzozowski, A.C.Pike, Z.Dauter, R.E.Hubbarde, T.Bonn, O. Engstrom, L. Ohman, G.L. Greene, J.A. Gustafsson, M. Carquist, Molecular basis of agonism and antagonist in the estrogen receptor, Nature, 389(1997) 753-758.)
In addition, the problem of drug resistance of patients to SERMs is a serious deficiency in the current endocrine therapy for breast cancer

Method used

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  • Oxygen-bridge bicyclo-[2.2.1]-heptylene compound and application thereof
  • Oxygen-bridge bicyclo-[2.2.1]-heptylene compound and application thereof
  • Oxygen-bridge bicyclo-[2.2.1]-heptylene compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1: 5,6-bis(4-hydroxyl)-7-oxobicyclo-[2.2.1]-5-heptene-2-sulfonic acid-4-(7-anicarboyl heptanoic acid methyl ester )-Preparation of ester (1)

[0069]

[0070] Weigh 3,4-bis(4-hydroxy-phenyl)furan (200mg, 0.793mmol) and ethylenesulfonic acid-4-(7-anicarboylheptanoic acid methyl ester)-ester (351.4mg, 0.952mmol) Place in a 50mL two-necked round-bottom bottle and then slowly heat up to 90°C, spin dry after reacting for 3 hours, separate and purify directly by column chromatography, the eluent ratio is dichloromethane:methanol=60:1, and obtain 413.6mg of white Solid, yield 90.1%. 1 H NMR (400MHz, Acetone-d 6 )δ7.53(d, J=9.2Hz, 2H), 7.12(m, 6H), 6.74(d, J=8.4Hz, 2H), 6.66(d, J=8.8Hz, 2H), 5.57(s, 1H), 5.34(d, J=4.0Hz, 1H), 4.09(m, 2H), 3.66(m, 1H), 3.60(m, 3H), 2.31(m, 4H), 1.65(m, 2H), 1.58(m,2H),1.34(m,4H). 13 C NMR (101MHz, CDCl 3 )δ175.98,174.63,158.91,158.77,146.51,142.52,139.02,138.02,130.33,129.73,125.13,124.40,123.69,122.25,116.81,116.56,85.82,84.18,...

Embodiment 2

[0071] Example 2: 5,6-bis(4-hydroxy)-7-oxobicyclo-[2.2.1]-5-heptene-2-sulfonic acid-(3-anicarboylheptanoic acid methyl ester)- Preparation of ester (2)

[0072]

[0073] The preparation method was as in Example 1, and the product was a white solid with a yield of 65.3%. 1 H NMR (400MHz, Acetone-d 6 )δ9.30(s,1H,-CONH-),8.63(s,2H,-OH),7.79(s,1H),7.60(d,J=8.0Hz,1H),7.30(d,J=8.4 Hz,1H),7.22(m,4H),6.95(d,J=8.4Hz,1H),6.83(m,4H),5.64(s,1H),5.45(d,J=4.0Hz,1H), 3.83(m,1H),3.60(s,-OMe),2.45(m,1H),2.40(t,J=7.6Hz,2H),2.30(m,3H),1.65(m,2H),1.55( m,2H),1.35(m,4H). 13 C NMR (101MHz, Acetone-d 6 )δ174.18,172.38,158.36,158.32,150.65,142.32,141.86,137.98,130.71,129.96,129.62,125.03,124.30,118.33,117.35,116.57,116.42,113.89,85.20,83.71,61.79,51.53,37.62,34.27,31.54 , 29.57, 29.32, 25.92, 25.51; HRMS (ESI) calcd for C 33 h 36 NO 9 S,622.2128 (M+H + ); found 622.2105.

Embodiment 3

[0074] Example 3: 3-(4-Hydroxyphenyl)-4-suberylanilide-7-oxo-bridged bicyclo-[2.2.1]-5-heptene-2-sulfonic acid-(4-methoxy Preparation of phenyl)-ester (3)

[0075]

[0076] The preparation method is as in Example 1, and the product is light yellow powder with a yield of 67.6%. 1 H NMR (400MHz, MeO-d 4)δ7.54(t, J=8.4Hz, 2H), 7.24(d, J=8.4Hz, 2H), 7.16(d, J=8.8Hz, 2H), 7.09(d, J=8.8Hz, 1H) ,7.06(d,J=9.6Hz,1H),6.80(m,4H),5.61(s,1H),5.39(t,J=4.8Hz,1H),3.73(s,3H,-OMe),3.62 (m,1H),2.38(m,3H),2.26(t,J=7.2Hz,2H),2.19(m,1H),1.69(m,2H),1.61(m,2H),1.38(m, 4H). 13 C NMR (101MHz, MeO-d 4 )δ174.75,174.72,159.84,159.29,159.05,144.03,142.00,139.93,137.48,130.65,129.93,129.39,128.68,124.28,123.86,121.45,121.17,116.96,116.71,115.85,115.82,85.85,84.16,61.28,56.20 , 38.22, 35.86, 31.65, 30.08, 27.15, 26.80; HRMS (ESI) calcd for C 33 h 36 NO 9 S,622.2101(M+H + ); found 622.2105.

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Abstract

The invention belongs to the technical field of medicines, and particularly discloses an oxygen-bridge bicyclo-[2.2.1]-heptylene compound comprising N-hydroxy-N'-phenyloctanediamide (SAHA) or a like structure, wherein the oxygen-bridge bicyclo-[2.2.1]-heptylene compound has an activity of resisting breast cancer. 3-(4-hydroxy penyl)-4-octanedioic acid monoanilide-furan and a vinyl sulphonate derivative are taken as raw materials and are reacted without a solvent or a catalyst at the temperature of 90 DEG C for 3 hours to further prepare the oxygen-bridge bicyclo-[2.2.1]-heptylene compound comprising the octanedioic acid monoanilide, and then the compound is reacted with oxammonium hydrochloride to obtain the oxygen-bridge bicyclo-[2.2.1]-heptylene compound comprising the N-hydroxy-N'-phenyloctanediamide. The experiments in vitro show that the oxygen-bridge bicyclo-[2.2.1]-heptylene compound has a great inhibitory activity on an MCF-7 cell in comparison to an existing anti-breast-cancer medicine tamoxifen.

Description

technical field [0001] The present invention relates to the preparation and preparation of a class of oxygen-bridged bicyclo-[2.2.1]-heptene compounds containing N-hydroxy-N'-phenylsuberamide group (SAHA) or similar structures with anti-breast cancer activity application. Background technique [0002] Breast cancer is the most common malignant tumor in women. According to statistics, 1.2 million women around the world suffer from breast cancer every year, and 500,000 die from the disease. The incidence rate accounts for 7-10% of all kinds of malignant tumors in the whole body. On the one hand, studies have shown that breast cancer has a very close relationship with estrogen and estrogen receptor (Estrogen Receptor, ER). Estrogen regulates the growth, differentiation and functionalization of mammary glands through ER, and the ER signal transduction system plays a very important role in normal physiological functions such as development, maturation, and shrinkage of mammary g...

Claims

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Application Information

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IPC IPC(8): C07D493/08A61K31/343A61P35/00
CPCC07D493/08
Inventor 周海兵黄健唐初李长浩董春娥张思龙
Owner WUHAN UNIV
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