Oxygen-bridged bicyclo-[2.2. 1]-heptene compounds containing different covalent warhead structures and preparation and application thereof

A technology of compounds and oxygen bridges, applied in the direction of active ingredients of heterocyclic compounds, organic chemistry, drug combinations, etc., can solve problems affecting drug efficacy, achieve strong inhibitory activity, and down-regulate estrogen receptor levels

Active Publication Date: 2021-11-02
WUHAN UNIV
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Problems solved by technology

However, these non-covalent bindings are reversible and will be competed by endogenous substrates, affecting drug efficacy

Method used

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  • Oxygen-bridged bicyclo-[2.2. 1]-heptene compounds containing different covalent warhead structures and preparation and application thereof
  • Oxygen-bridged bicyclo-[2.2. 1]-heptene compounds containing different covalent warhead structures and preparation and application thereof
  • Oxygen-bridged bicyclo-[2.2. 1]-heptene compounds containing different covalent warhead structures and preparation and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0137] Preparation of Ethylene Sulfonate Derivatives 13b~13l

[0138] Referring to the preparation method of vinylsulfonate derivative 13a containing a covalent warhead, compound 12 and As starting materials, ethylene sulfonate derivatives 13b-13l were prepared.

[0139] 4. Synthesis of vinylsulfonamide derivatives 16a-16j:

[0140]

[0141] (1) Weigh 1.0eq. of aminophenyl derivatives in a 100mL one-mouth bottle, add 25mL of DCM, dropwise add 1.2eq. of trifluoroacetic anhydride (14g is synthesized by adding acetic anhydride), and react at room temperature for 12 hours. The reaction was quenched by adding 10 mL of water, extracted with DCM, saturated NaHCO 3 Solution washing, organic layer anhydrous NaSO 4 Drying and precipitation under reduced pressure gave crude products, and column chromatography (eluent, petroleum ether / ethyl acetate=10:1~1:1) gave compounds 14a~14g.

[0142] (2) Weigh 1.0eq. compound 14a-14g and 50mL two-necked flask, add 20mL DCM, replace with a...

Embodiment 1

[0146] [Example 1] 4-acrylamide phenyl-5,6-bis(4-hydroxyphenyl)-7-oxo bridge bicyclo-[2.2.1]-hept-5-ene-2-sulfonic acid ester 17a preparation

[0147]

[0148] Weigh 3,4-bis(4-hydroxyphenyl)furan 1.0e.q and 4-acrylamide phenylethylene sulfonate (13a) 1.0e.q into a 25mL single-necked round-bottom bottle, add 1mL tetrahydrofuran, and then slowly raise the temperature After reaction at 90°C for 12 hours, it was spin-dried, separated and purified by direct column chromatography, the eluent ratio was dichloromethane:methanol=60:1, and a yellow solid was obtained with a yield of 61%.

[0149] 1 H NMR (400MHz, Acetone-d 6 )δ9.59(s,1H),8.82(d,J=3.2Hz,1H),8.75(d,J=3.0Hz,1H),7.81–7.67(m,2H),7.30–7.13(m,6H ),6.89–6.74(m,4H),6.39(m,J=16.9,6.0Hz,2H),5.72(dd,J=9.7,2.3Hz,1H),5.64–5.62(m,1H),5.43( d,J=4.3Hz,1H),3.77(dd,J=8.3,4.5Hz,1H),2.40(dt,J=12.0,4.4Hz,1H),2.27(dd,J=12.1,8.4Hz,1H ).

[0150] 13 C NMR (101MHz, Acetone-d 6 )δ163.46,162.32,157.71,157.56,145.09,141.29,138.19,136.96,...

Embodiment 2

[0151] [Example 2] 4-(2-butenamido)phenyl-5,6-bis(4-hydroxyphenyl)-7-oxo-bridge bicyclo-[2.2.1]-hept-5-ene-2 - Preparation of sulfonate 17b

[0152]

[0153] Referring to the preparation method of Example 1, using 3,4-bis(4-hydroxyphenyl)furan and ethylenesulfonate derivative 13b as raw materials, the product was a yellow solid with a yield of 53%.

[0154] 1 H NMR (400MHz, Acetone-d 6 )δ9.39(s,1H),8.76(s,2H),7.77(dd,J=34.6,9.0Hz,2H),7.38–7.12(m,6H),6.97–6.88(m,1H),6.87 –6.74(m,4H),6.12(dd,J=15.1,1.5Hz,1H),5.65–5.60(m,1H),5.40(t,J=18.0Hz,1H),3.80–3.56(m,1H ),2.40(dt, J=12.0,4.4Hz,1H),2.27(dd,J=12.1,8.4Hz,1H),1.85(dd,J=6.9,1.2Hz,3H).

[0155] 13 C NMR (101MHz, Acetone-d 6 )δ163.76,157.58,157.44,144.89,141.34,140.61,138.45,137.02,129.20,128.60,125.70,124.12,123.32,122.57,120.39,115.73,115.51,84.38,82.77,60.50,30.60,16.94.

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Abstract

The invention discloses oxygen-bridged bicyclo-[2.2. 1]-heptene compounds containing different covalent warhead structures and preparation and application thereof, and belongs to the technical field of targeted drugs. The structure of the compounds disclosed by the invention is shown as a general formula (I) or a general formula (II), and a furan derivative and a vinyl sulfonamide derivative or a vinyl sulfonate derivative containing different covalent warheads are subjected to Diels-Alder reaction to prepare the compounds disclosed by the invention. The compounds provided by the invention can be used for preparing anti-breast cancer medicines, medicines for degrading estrogen receptors and medicines for mutant estrogen receptors. Compared with the existing anti-breast cancer drug tamoxifen, the compounds provided by the invention have stronger inhibitory activity on MCF-7 cells and have the ability to down-regulate the level of an estrogen receptor, and the activity of the compounds on a mutant estrogen receptor is 5-10 times that of 4-hydroxytamoxifen.

Description

technical field [0001] The invention belongs to the technical field of targeted drugs, and relates to a compound based on an oxygen-bridged bicyclo-[2.2.1]-heptene structure, in particular to an oxygen-bridged bicyclo-[2.2.1]-heptene structure containing different covalent warhead structures. Heptene compound and its preparation method and application in anti-breast cancer. 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 WHO statistics, 1.7 million women around the world suffer from breast cancer every year, and 500,000 die from the disease, accounting for 7-10% of all malignant tumors in the whole body. The incidence of breast cancer is increasing year by year worldwide, and it is getting younger. Two-thirds of the patients were estrogen receptor positive. The mechanism of estrogen mainly regulates the growth, differentiation and functionalization of mammary glands...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/00A61K31/34A61P35/00
CPCC07D307/00A61P35/00Y02P20/55
Inventor 董春娥周海兵王禹博冯甜程艳
Owner WUHAN UNIV
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