Abiraterone derivative and preparation method and application thereof

A technology of abiraterone and derivatives, applied in the field of preparation of abiraterone derivatives, can solve the problems of low activity of prostate cancer cells and limited clinical treatment effect of abiraterone

Inactive Publication Date: 2019-09-24
CHENGDU BIOBEL BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although abiraterone has great clinical value, the clinical therapeutic effect of abiraterone is still limited, and its activity in inhibiting prostate cancer cells is not high, and new therapeutic drugs are still needed clinically

Method used

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  • Abiraterone derivative and preparation method and application thereof
  • Abiraterone derivative and preparation method and application thereof
  • Abiraterone derivative and preparation method and application thereof

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preparation example Construction

[0028] The present application also provides a preparation method of the abiraterone derivative shown in formula (I), including:

[0029] Abiraterone and solid phosgene are reacted in a solvent to obtain an intermediate product;

[0030] The intermediate product is reacted with dichloroethylamine hydrochloride to obtain the abiraterone derivative shown in formula (I);

[0031]

[0032] In the above process of preparing the abiraterone derivatives shown in formula (I), first, abiraterone and solid phosgene are initially reacted under alkaline conditions in a solvent to obtain an intermediate, and the solvent is dichloromethane , the base is triethylamine; after the above reaction is complete, dichloroethylamine hydrochloride is added, and the abiraterone derivative shown in formula (I) is obtained after the reaction. In above-mentioned reaction process, the mol ratio of described Abiraterone and described solid phosgene is 1:(1~2.5); The mol ratio of described intermediate ...

Embodiment 1

[0045] Embodiment 1 Preparation of Abiraterone Derivative 1

[0046] Add 1 gram of abiraterone (commercially available, HPLC purity 98%) to 40 milliliters of DCM, 0.8 grams of triethylamine, cool to 0-5 degrees, slowly add 1.5 grams of solid phosgene, stir for 1-2 hours, and confirm the raw material by TLC The reaction is complete; then add 0.5 g of dichloroethylamine hydrochloride, stir for 4-5 hours, TLC monitors to confirm the complete reaction of the raw materials, then add 50 ml of water and DCM, stir for 2 min, separate the liquids, add 50 ml of sodium bicarbonate aqueous solution to wash Organic phase, concentrated organic phase, 10-20 ml of ethyl acetate, stirred and crystallized to obtain 0.7 g of white solid.

[0047] 1 HNMR (400MHz, CDCl3): δ8.62 (d, J = 2.1Hz, 1H), 8.45 (dd, J = 4.8, 1.5Hz, 1H), 7.64 (dt, J = 7.9, 2.0Hz, 1H), 7.21 (dd,J=7.9,4.8Hz,1H), 5.99(dd,J=3.4,1.8Hz,1H), 5.41-5.37(m,1H), 4.5(m,1H), 3.6-3.7(m,8H ), 2.36-2.20(m,3H), 2.12-2.00(m,3H), 1.89-1.81...

Embodiment 2

[0050] Embodiment 2 Preparation of Abiraterone Derivative 2

[0051] Add 1 gram of Abiraterone to 40 milliliters of DCM, add 0.8 grams of triethylamine, cool down to 0-5 degrees, slowly add 0.5 grams of dichloroacetyl chloride dropwise, stir for 5-6 hours after dripping, add 50 milliliters of water, and stir After 2 minutes, the organic phase was washed once with 50 ml of sodium bicarbonate solution, dried, and the organic phase was concentrated, and the residue was passed through a silica gel chromatography column with ethyl acetate:petroleum ether=1:1 eluent to obtain 0.5 g of the product.

[0052] 1HNMR (400MHz, CDCl3): δ8.62 (d, J = 2.1Hz, 1H), 8.45 (dd, J = 4.8, 1.5Hz, 1H), 7.64 (dt, J = 7.9, 2.0Hz, 1H), 7.21 (dd, J=7.9, 4.8Hz, 1H), 6.2(m, 1H), 5.99(dd, J=3.4, 1.8Hz, 1H), 5.41-5.37(m, 1H), 4.6(m, 1H), 2.36 -2.20(m,3H), 2.12-2.00(m,3H), 1.89-1.81(m,2H), 1.80-1.43(m,7H), 1.15-1.10(m,2H), 1.07(s,3H) , 1.05(s,3H);

[0053] ESI-MS m / z:460.44[M+H] + .

[0054]

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Abstract

The invention provides an abiraterone derivative shown in a formula (I) or a formula (II), provides a preparation method of the abiraterone derivative shown in the formula (I), provides a preparation method of the abiraterone derivative shown in the formula (II), and also provides application of the abiraterone derivative in preparing drugs for treating prostatic cancer. The abiraterone derivative has the advantages that a specific chlorine-containing group is introduced into the provided abiraterone derivative so that the abiraterone derivative can significantly inhibit the proliferation of prostatic cancer cells and have stronger inhibitory activity against the prostatic cancer cells.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to abiraterone derivatives, their preparation methods and applications. Background technique [0002] Abiraterone (Abiraterone), chemical name 17-(3-pyridyl) androsta-5,16-dien-3β-ol, molecular formula C 24 h 31 NO is specifically shown in formula (i). [0003] The mechanism of action of abiraterone in prostate cancer is: the growth of prostate cancer cells mostly requires the supply of androgen, CYP17 is the rate-limiting enzyme in the biosynthesis of androgen, and abiraterone achieves anti-prostate cancer by inhibiting CYP17 role. Clinically, Abiraterone is mainly suitable for the combination with prednisone to treat patients with metastatic castration-resistant prostate cancer who previously received docetaxel-containing chemotherapy. In addition, in order to improve its absorption in the body, abiraterone is orally administered in the form of its prodrug abiraterone acetate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J43/00A61K31/58A61P35/00
CPCA61P35/00C07J43/003
Inventor 广兵阳泰董韧涵覃传军刘进黄胜谢建彭向阳赖永新许庆占伟
Owner CHENGDU BIOBEL BIOTECHNOLOGY CO LTD
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