Ferrocene-bridged bicyclic-[2.2.1]-heptyl diene compound

A ferrocene and compound technology, applied in the field of ferrocene-oxo bridge bicyclo-[2.2.1]-heptene compounds, can solve the problems of increasing the risk of endometrial cancer due to drug resistance

Active Publication Date: 2015-12-02

铱诺(武汉)药业有限公司

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AI-Extracted Technical Summary

Problems solved by technology

In addition, although SERMs have been successful in the treatment of breast cancer, the problem of drug resistance and problems such...

Abstract

The invention discloses a ferrocene-bridged bicyclic-[2.2.1]-heptyl diene compound that contains N-hydroxy-(i)N-benzene succinic amide or a similar structure. 3-(4-hydroxyphenyl)-4-suberic nonacylanilino-furan or similar analogs and a ferrocene vinyl sulfonate derivative are used as raw materials, and a solvent and a catalyst are not needed; the raw materials are reacted for 3 hours at 90 DEG C through one step to obtain a ferrocene-bridged bicyclic-[2.2.1]-heptyl diene compound that contains a suberic nonacylanilino group. According to an in vitro experiment, compared with a current anti-cancer drug Tamoxifen, the novel ferrocene-bridged bicyclic-[2.2.1]-heptyl diene compound has stronger inhibitory activity on hormone-dependent breast cancer MCF-7 cells and non-hormone-dependent breast cancer MDA-MB-231 cells, and has no toxicity on normal VERO cells while the current anti-cancer drug Tamoxifen has toxicity on normal VERO cells.

Application Domain

Organic active ingredientsAntineoplastic agents +1

Technology Topic

BenzenePerylene derivatives +23

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Examples

Experimental program(10)

Example Embodiment

[0063] Example 1: 3-(4-hydroxyphenyl)-4-pimelic acid monoanilide-7-oxo bridge bicyclo[2.2.1]-5-heptene-2-sulfonic acid-(3-ferrocene Preparation of carbonylphenyl)-ester (TC1)

[0064]

[0065] Weigh 3-(4-hydroxyphenyl)-4-pimelic acid anilide-furan (200mg, 0.509mmol) and ethylenesulfonic acid-3-(ferrocenecarbonylphenyl)-ester (241.7mg, 0.160 mmol) is placed in a two-necked round-bottomed bottle of 50mL and then slowly warmed up to 90°C, spin-dried after 3 hours of reaction, and directly separated and purified by column chromatography, the eluent ratio is dichloromethane:methanol=60:1, to obtain 374.5mg red solid, yield 93.2%, m.p.111-114°C; 1 HNMR (400MHz, Acetone- d 6 ) δ 9.34(s,1H),8.01(s,1H),7.86(d, J =7.6Hz,1H),7.65(t, J =7.2Hz,2H),7.55(m,1H),7.47(t, J =8.0Hz,1H),7.35(t, J =8.8Hz,2H),7.27(t, J =8.8Hz,2H),6.86(t, J =8.4Hz,2H),5.78(s,1H),5.51(s,1H),4.89(s,2H),4.66(s,2H),4.24(s,5H),3.98(m,1H),2.52 (m,1H),2.40(m,3H),2.29(t, J =6.8Hz,2H),1.71(t, J =6.8Hz,2H),1.62(t, J =7.2Hz,2H),1.41(m,2H). 13 CNMR (100MHz, Acetone- d 6 ) δ 197.45,175.10,172.50,158.66,158.59,149.98,143.61,142.30,141.97,140.15,139.23,137.53,131.12,130.19,129.80,128.98,128.59,127.58,125.99.124.61,122.98,120.40,116.56,85.19,83.82, 78.71, 73.91, 72.16, 71.17, 62.11, 37.64, 34.18, 31.68, 31.47, 26.02, 25.42; HRMS (ESI) calcdforC 42 h 38 54 FeNO 9 S[M-H] - ,786.6621;found786.6624.

Example Embodiment

[0066] Example 2: 3-(4-hydroxyphenyl)-4-pimelic acid monoanilide-7-oxo bridge bicyclo[2.2.1]-5-heptene-2-sulfonic acid-(4-ferrocene Preparation of carbonylphenyl)-ester (TC2)

[0067]

[0068] The preparation method is as in Example 1, and the product is a red solid with a yield of 90.6%, m.p.108-110°C. 1 HNMR (400MHz, Acetone- d 6 ) δ 9.31(s,1H),8.00(d, J =8.0Hz,2H),7.67(d, J =8.4Hz,1H),7.63(d, J =8.4Hz,1H),7.43(t, J =8.0Hz,2H),7.36(d, J =8.0Hz,1H),7.32(t, J =7.6Hz,2H),7.26(d, J =8.0Hz,1H),6.88(d, J =8.0Hz,1H),6.83(d, J=8.0Hz,1H),5.76(s,1H),5.50(s,1H),4.84(s,2H),4.66(s,2H),4.23(s,5H),3.95(m,1H),2.51 (m,1H),2.39(m,3H),2.32(t, J =7.2Hz,2H),1.70(m,2H),1.62(t, J =7.2Hz,2H),1.41(m,2H). 13 CNMR (100MHz, Acetone- d 6 ) δ 197.40,174.90,172.30,158.70,158.56,152.60,143.55,142.00,140.35,140.21,139.32,137.54,130.92,130.34,129.78,129.12,128.47,127.94,123.87.123.03,120.29,120.10,116.71,116.51,85.28, 83.73,78.93,73.66,72.17,71.07,61.81,37.61,34.12,31.57,31.36,25.98,25.41;HRMS(ESI)calcdforC 42 h 38 54 FeNO 9 S[M-H] - ,786.6627;found786.6624.

Example Embodiment

[0069] Example 3: 3-(4-hydroxyphenyl)-4-pimelic acid monoanilide-7-oxo bridge bicyclo[2.2.1]-5-heptene-2-sulfonic acid-(4-ferrocene Preparation of benzyl)-ester (TC3)

[0070]

[0071] The preparation method was as in Example 1, and the product was a red solid with a yield of 85.2%, m.p.96-98°C. 1 HNMR (400MHz, Acetone- d 6 ) δ 9.14(s,1H),7.53(t, J =8.8Hz,2H),7.17(d, J =7.6Hz,1H),7.15(d, J =7.2Hz,1H),7.11(d, J =7.6Hz,1H),7.09(d, J =7.6Hz,1H),7.05(d, J =8.8Hz,2H),7.00(d, J =7.2Hz,1H),6.99(d, J =7.2Hz,1H),6.71(d, J =8.8Hz,1H),6.68(d, J =8.8Hz,1H),5.53(s,1H),5.31(t, J =3.2Hz,1H),3.97(s,7H),3.92(s,2H),3.64(m,1H),3.60(m,2H),2.27(m,3H),2.17(m,3H),1.58 (t, J =7.6Hz,2H),1.46(t, J =7.6Hz,2H),1.30(m,2H). 13 CNMR (100MHz, Acetone- d 6 ) δ 174.83,172.18,158.56,158.42,148.63,142.13,141.90,140.21,140.09,139.24,137.59,130.60,130.29,129.11,128.46,127.95,124.71,123.90,122.84,120.23,116.40,88.54,85.22,83.64,69.43, 69.36, 68.39, 61.21, 37.55, 35.90, 34.08, 31.51, 31.31, 25.98, 25.39; HRMS (ESI) calcdforC 42 h 40 54 FeNO 8 S[M-H] - ,772.1820;found772.1824.

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