A kind of substituted steroid compound and its application

A compound and composition technology, applied in the field of medicine, can solve the problems of stimulating tumor growth, unable to inhibit androgen, etc., and achieve the effects of improving drug concentration, improving the characteristics of pharmacokinetic parameters, and improving drug efficacy and safety.

Active Publication Date: 2021-04-30
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In men with prostate cancer, the hormone testosterone stimulates tumor growth. Castration therapy, including drugs or surgery, can reduce testosterone producti

Method used

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  • A kind of substituted steroid compound and its application
  • A kind of substituted steroid compound and its application
  • A kind of substituted steroid compound and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1 Preparation of 3β-17-(1H-benzo[d]imidazol-2-d-1-yl)androst-5,16-dien-3-ol (compound 7)

[0061]

[0062] Step 1: Synthesis of (3β)-3-(acetoxy)-17-chloroandrost-5,16-diene-16-carbaldehyde (compound 2).

[0063] N,N-Dimethylformamide (15 mL, 192 mmol) was slowly added dropwise to a solution of phosphorus oxychloride (15 mL, 165 mmol) in chloroform (45 mL) under ice-cooling and nitrogen protection. After the dropwise addition, a solution of dehydroepiandrosterone acetate (3.00 g, 9.00 mmol) in chloroform (45 mL) was slowly added dropwise. After the dropwise addition was completed, the temperature was raised to room temperature, and the reaction was refluxed for 5 hrs. The reaction solution was concentrated under reduced pressure, the residue was added to ice water, extracted with ether / ethyl acetate (8 / 2, v / v) mixed solvent, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concent...

Embodiment 2

[0072] Example 2 Preparation of 3β-17-(1H-benzo[d]imidazole-5,6,7-d 3 -1-yl)androst-5,16-dien-3-ol (compound 13)

[0073]

[0074] At room temperature, under nitrogen protection, anhydrous dimethyl sulfoxide (6 mL) was added to 17-iodoandrost-5,16-dien-3β-ol (300 mg, 0.75 mmol), 1H-benzo[d]imidazole- 4, 5, 6, 7-d 4 (110mg, 0.90mmol), L-proline (35mg, 0.3mmol), cuprous iodide (30mg, 0.15mmol) and potassium carbonate (259mg, 1.87mmol) mixture, the reaction solution was overnight at 120°C. Cool to room temperature, add water (25mL) to quench the reaction, filter through celite, extract the filtrate with ethyl acetate (30mLx3), combine the organic layers, wash the organic layer with saturated brine (30mL), dry over anhydrous sodium sulfate, reduce The organic layer was concentrated under pressure, and purified by column chromatography of the concentrate to obtain 80 mg of white solid, yield: 27.2%, purity: 99.37%. LC-MS(APCI): m / z=393.0[M+1] + ; 1 H NMR (300MHz, MeOD-d...

Embodiment 3

[0075] Example 3 Preparation of 3β-17-(1H-benzo[d]imidazole-4,5,6,7-d 4 -1-yl)androst-5,16-dien-3-ol (compound 15)

[0076]

[0077] At room temperature, under nitrogen protection, anhydrous dimethyl sulfoxide (6 mL) was added to 17-iodoandrost-5,16-dien-3β-ol (300 mg, 0.75 mmol), 1H-benzo[d]imidazole- 4, 5, 6, 7-d 4 (110mg, 0.90mmol), L-proline (35mg, 0.3mmol), cuprous iodide (30mg, 0.15mmol) and potassium carbonate (259mg, 1.87mmol) mixture, the reaction solution was overnight at 120°C. Cool to room temperature, add water (25mL) to quench the reaction, filter through celite, extract the filtrate with ethyl acetate (30mLx3), combine the organic layers, wash the organic layer with saturated brine (30mL), dry over anhydrous sodium sulfate, reduce The organic layer was concentrated under pressure, and purified by column chromatography of the concentrate to obtain 80 mg of white solid, yield: 27.2%, purity: 99.37%. LC-MS(APCI): m / z=393.0[M+1] + ; 1 H NMR (300MHz, MeOD...

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Abstract

The invention provides a substituted steroid compound and its application. Specifically, the substituted steroid compound of the present invention is a steroid compound represented by formula (I), or its crystal form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate or solvent compound. The substituted steroidal compound disclosed in the present invention and the composition containing the compound have excellent inhibitory properties on CYP17 enzyme and androgen receptor (AR), and have better pharmacokinetic parameter characteristics, and can improve the Drug concentration in animals to improve drug efficacy and safety.

Description

technical field [0001] The invention belongs to the field of medicine. Specifically, the present invention relates to steroidal compounds and uses thereof, more specifically, to steroidal compounds and as irreversible inhibitors of CYP17 enzymes and androgen receptor (AR) antagonists, which can be used for the treatment and prevention of CYP17-related Enzyme and androgen receptor (AR) related diseases. Background technique [0002] Prostate cancer (PCa for short) is a common malignant tumor in the male reproductive system. In 2008, there were 903,500 new cases of prostate cancer and 258,400 deaths from prostate cancer worldwide. Among them, new cases of prostate cancer accounted for 14% of all new cases of male tumors, ranking the second among new cases of male cancer; death cases of prostate cancer accounted for 6% of male cancer deaths, ranking sixth among male cancer deaths . Prostate cancer deaths account for 9% of male cancer deaths, second only to lung cancer, rank...

Claims

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Application Information

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IPC IPC(8): C07J43/00C07B59/00A61K31/58A61P35/00A61P29/00A61P31/00A61P37/00A61P9/00A61P3/00
CPCC07J43/003C07B59/007C07B2200/05A61K31/58C07B59/00C07J43/00
Inventor 王义汉任兴业
Owner SHENZHEN TARGETRX INC
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