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Oxygen bridge bicyclo-[2.2.1]-heptene compound containing different functional side chain structures, as well as preparation and application thereof

A compound and functional technology, applied in the field of oxygen-bridged bicyclo-[2.2.1]-heptene compounds containing different functional side chain structures and their preparation and application, can solve the problem of no protein degradation activity

Active Publication Date: 2019-06-28
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds do not have proteolytic activity

Method used

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  • Oxygen bridge bicyclo-[2.2.1]-heptene compound containing different functional side chain structures, as well as preparation and application thereof
  • Oxygen bridge bicyclo-[2.2.1]-heptene compound containing different functional side chain structures, as well as preparation and application thereof
  • Oxygen bridge bicyclo-[2.2.1]-heptene compound containing different functional side chain structures, as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] [Example 1] 6-(4-(2,3-dihydroxypropoxy)phenyl)-N-ethyl-5-(4-hydroxyphenyl)-N-phenyl-7-oxo bridge bicyclic Preparation of [2.2.1]-5-heptene-2-sulfonamide (17a)

[0118]

[0119] Weigh 3-(4-(4-(4-hydroxyphenyl)furan-3-yl)phenoxy)propane-1,2-diol (1eq.) and N-ethyl-N-phenylethylene Sulfonamide (1eq.) was placed in a 25mL single-necked round-bottom bottle and then slowly heated to 90°C. After 12 hours of reaction, it was spin-dried, and directly separated and purified by column chromatography. The ratio of eluent was dichloromethane:methanol=60: 1. A yellow solid was obtained with a yield of 61%. 61% yield, mp 96-98℃. 1 H NMR (400MHz, MeOD) δ7.34–7.27 (m, 5H), 7.24–7.16 (m, 2H), 7.12 (dt, J=14.9, 7.5Hz, 2H), 6.88 (dd, J=17.1, 8.7 Hz, 2H), 6.73(dd, J=18.5, 8.6Hz, 2H), 5.44(d, J=10.7Hz, 1H), 5.28(t, J=3.8Hz, 1H), 4.08–4.02(m, 1H ),4.02–3.95(m,2H),3.84–3.75(m,2H),3.67(ddd,J=12.3,10.2,5.0Hz,2H),3.46(td,J=8.4,4.5Hz,1H), 2.20(dd,J=7.6,4.5Hz,1H),1.99(s,1H),1.04(t,J=7.0Hz,3...

Embodiment 2

[0120] [Example 2] 6-(4-(2,3-dihydroxypropoxy)phenyl)-5-(4-hydroxyphenyl)-N-(4-methoxyphenyl)-N-( Preparation of 2,2,2-trifluoroethyl)-7-oxobicyclo[2.2.1]-5-heptene-2-sulfonamide (17b)

[0121]

[0122] The preparation method is as in Example 1, and the product is a yellow solid with a yield of 74%. 1 H NMR (400MHz, MeOD) δ7.32–7.18(m,4H),7.18–7.08(m,2H),7.00–6.90(m,2H),6.87(d,J=8.8Hz,1H),6.83– 6.78(m,2H),6.73–6.68(m,1H),5.47(d,J=5.3Hz,1H),5.31(s,1H),4.42(q,J=8.5Hz,2H),4.08–4.03 (m,1H),4.02–3.95(m,2H),3.78(s,3H),3.73–3.65(m,2H),3.51–3.42(m,1H),2.28–2.19(m,1H),2.09 –2.03(m,1H). 13 C NMR(101MHz,MeOD)δ159.66,159.01,157.38,131.36,130.15,129.24,129.01,128.18,127.98,124.66,115.43,115.14,114.64,114.37,114.18,84.40,82.70,70.36,68.95,62.73,61.30,60.16 , 54.61, 19.49. HRMS (ESI) calcd for C 30 h 30 f 3 NO 8 S[M+Na] + ,644.1536; found 644.1531.

Embodiment 3

[0123] [Example 3] N-(4-chlorophenyl)-6-(4-(2,3-dihydroxypropoxy)phenyl)-5-(4-hydroxyphenyl)-N-(2, Preparation of 2,2-trifluoroethyl)-7-oxobicyclo[2.2.1]-5heptene-2-sulfonamide (17c)

[0124]

[0125] The preparation method is as in Example 1, and the product is a yellow solid with a yield of 56%. 1 H NMR (400MHz, MeOD) δ7.42–7.26(m,4H),7.21(dd,J=12.8,6.1Hz,2H),7.17–7.08(m,2H),6.98–6.86(m,2H), 6.81–6.69(m,2H),5.45(d,J=18.9Hz,1H),5.32(s,1H),4.50(dd,J=16.3,8.1Hz,2H),4.06(dd,J=12.5, 7.5Hz, 1H), 4.03–3.94(m, 2H), 3.69(dd, J=11.2, 4.9Hz, 2H), 3.50(d, J=7.8Hz, 1H), 2.22–2.13(m, 1H), 2.03(s,1H). 13 C NMR(101MHz,MeOD)δ159.02,157.42,140.79,137.96,136.37,134.01,130.20,129.23,129.11,128.88,128.23,128.04,124.61,123.56,115.41,115.14,114.63,114.37,84.38,82.73,70.36,68.94 ,62.74,61.83,60.16,30.18,19.48.HRMS(ESI)calcd for C 29 h 27 CIF 3 NO 7 S[M+Na] + ,648.1041; found 648.1038.

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Abstract

The invention discloses an oxygen bridge bicyclo-[2.2.1]-heptene compound containing different functional side chain structures, as well as preparation and application thereof. The preparation comprises the following steps that furan derivatives which contain different functional side chain structures (2,3-glycol butyl, N,N-diethoxy ethylamino, 2-pyrrolidinyl ethyl, 2-piperidine ethyl and alkyl acid) and are synthesized from 3,4-bis(4-methyoxy-phenyl)furan reacts with vinyl sulfonamide derivatives at 90 DEG C for 12 hours in one step without solvent or catalyst to prepare the oxygen bridge bicyclo-[2.2.1]-heptene compound containing basic side chains and other functional side chain groups. In-vitro experiments indicate that, compared with an existing anti-breast cancer drug tamoxifen, thenovel sulfamide type oxygen bridge bicyclo-[2.2.1]-heptene compound has stronger inhibiting activity on MCF-7 cells, and has excellent protein degrading activity and equivalent degrading performance as that of existing drug fulvestrant.

Description

technical field [0001] The invention belongs to the field of compounds based on oxygen-bridged bicyclo-[2.2.1]-heptene structures, and specifically relates to a class of oxygen-bridged bicyclo-[2.2.1]-heptenes with different functional side chain structures, which have protein degradation activity and anti-breast cancer activity. [2.2.1]-Heptene compounds and their preparation and application. Background technique [0002] Breast cancer is one of the most common malignant tumors in women and the number one killer of women aged 35-55. According to statistics, 1.2 million women in the world suffer from breast cancer every year, and 500,000 die from the disease, and the incidence rate accounts for 7-10% of various malignant tumors in the whole body. The incidence of breast cancer is increasing year by year worldwide, and it is getting younger. Current research shows that breast cancer has a very close relationship with estrogen and estrogen receptor (Estrogen Receptor, ER). ...

Claims

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Application Information

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IPC IPC(8): C07D493/08A61K31/343A61K31/4025A61K31/4525A61P35/00A61P5/32
Inventor 周海兵吴叔文蓝柯李媛媛张思龙董春娥
Owner WUHAN UNIV
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