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Preparation method and application of tamoxifen twin drug

A technology of tamoxifen and twin drugs, which is applied in the field of new tamoxifen twin drugs and its preparation, can solve the problems of threatening women's lives and unsatisfactory overall treatment effects, and achieve improved specificity, reduced dosage, The effect of reducing toxicity

Active Publication Date: 2012-07-25
THE SECOND AFFILIATED HOSPITAL OF NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

With the advancement of tumor radiotherapy and chemotherapy, molecular targeted therapy, and endocrine therapy, the treatment of breast cancer has achieved certain curative effect, but there are primary drug resistance and secondary drug resistance in the endocrine therapy of ER-positive breast cancer, and the overall therapeutic effect cannot be achieved. Satisfactory, but still seriously threatening women's lives, it is urgent to find new anti-tumor drugs with good targeting, high efficiency and low toxicity

Method used

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  • Preparation method and application of tamoxifen twin drug
  • Preparation method and application of tamoxifen twin drug
  • Preparation method and application of tamoxifen twin drug

Examples

Experimental program
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Effect test

Embodiment 1

[0019] Synthesis of 4-Hydroxy-4'-(trimethylacetoxy)benzophenone and 4,4'-bis(trimethylacetoxy)benzophenone

[0020] Dissolve 4,4'-dihydroxybenzophenone (7.5g, 35mmol) in dry THF (100mL), add NaH (2.5g, 38mmol), stir at room temperature for 1h, cool to 0°C, add PvCl (5mL), Remove the ice-water bath and stir for 3h. The reaction mixture was poured into distilled water (100 mL) and extracted with ethyl acetate (3 x 100 mL). Combined organic phases, anhydrous Na 2 SO 4 Dry overnight and concentrate. The two compounds were separated by column chromatography (hexane-dichloromethane 9:1), and both compounds were white powders. Wherein 4-hydroxy-4'-(trimethylacetoxy) benzophenone, 1H NMR (δ, CDCl3): 1.32 (s, 9H), 6.830 (d, 2H), 7.19 (d, 2H), 7.72 (d, 2H), 7.79 (d, 2H); 4,4'-two (trimethylacetoxy) benzophenone, 1H NMR (δ, CDCl3): 1.20 (s, 18H), 7.22 ( d, 4H), 7.82 (d, 4H).

Embodiment 2

[0022] Synthesis of (E)-4-(1-(4-hydroxyphenyl)-2-phenyl-1-enyl)phenyl pivalate

[0023] Disperse Zn powder (1.0g, 15mmol) in 20mL dry THF, add TiCl4 (0.8mL, 7mmol) dropwise under argon protection, reflux for 3h, add 20mL containing 4-hydroxy-4'-(trimethylacetoxy ) a solution of benzophenone (1.0 g, 3.5 mmol) and propiophenone (1.0 mL, 11 mmol) in dry THF. Reflux for 5h, cool to room temperature, add 10% K 2 CO 3 (40 mL), extracted with ethyl acetate (3 x 100 mL). Combine the organic phases to 10% K 2 CO 3 (2×50 mL) and saturated NaCl solution (50 mL), concentrated, and recrystallized from methanol to obtain a white powder. E / Z ratio greater than 100:1. 1H NMR (δ, CD3OD): 0.95(t, 3H), 1.26(s, 9H), 2.26(q, 2H), 6.40(d, 2H), 6.66(d, 2H ), 7.22-7.45(m, 9H)

Embodiment 3

[0025] Synthesis of (E)-4-[1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-2-phenylpropyl-1-ene]phenylpivalate Get the product (0.60g, 1.5mmol) in Example 2, fresh distillation 2-dimethylaminochloroethane (0.32g, 3.0mmol) and K 2 CO 3 (0.27g, 1.9mmol) was poured into a mixed solution of acetone:water (19:1, 20mL), and refluxed for 6h in the dark. Cool to room temperature, dry, evaporate the solvent, separate by column chromatography (dichloromethane-methanol 19:1), and recrystallize from isopropanol to obtain a white powder. 1H NMR (δ, CDCl3): 0.95(t, 3H), 1.28(s, 9H), 2.29(s, 6H), 2.46(q, 2H), 2.68(t, 2H), 3.93(t, 2H), 6.56(d, 2H), 6.80(d, 2H), 7.14-7.32(m, 9H);

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Abstract

The invention provides a preparation method and application of a tamoxifen twin drug, wherein a tamoxifen-neogambogic acid twin drug is formed through ester bond combination of tamoxifen and neogambogic acid. The twin drug has a high degree of mammary tissue specificity, has higher curative effect compared with the tamoxifen and is expected to be a new high-efficacy and low-toxicity anti-tumor drug.

Description

technical field [0001] The invention relates to a novel tamoxifen drug and a preparation method thereof, and also relates to the application of the tamoxifen drug as an anti-tumor disease drug. Background technique [0002] Breast cancer is the most common malignant tumor with the highest mortality rate among women, and it is also the most common estrogen-dependent tumor clinically. According to the phenotype difference of estrogen receptor (ER), breast cancer is divided into two types: ER-positive breast cancer and ER-negative breast cancer. About 2 / 3 breast cancer patients are ER-positive, and the growth of tumor cells depends on in estrogen. With the advancement of tumor radiotherapy and chemotherapy, molecular targeted therapy, and endocrine therapy, the treatment of breast cancer has achieved certain curative effect, but there are primary drug resistance and secondary drug resistance in endocrine therapy for ER-positive breast cancer, and the overall therapeutic effect...

Claims

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Application Information

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IPC IPC(8): C07D493/20A61K31/352A61P35/00A61P15/14
Inventor 王科明许贯虹周晶何烨
Owner THE SECOND AFFILIATED HOSPITAL OF NANJING MEDICAL UNIV
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