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Aromatic ring and cyclic lactone thiohydantoin compound as well as preparation method and application thereof

A technology of compounds, hydrates, used in drug synthesis and pharmacology, the field of pharmacy

Pending Publication Date: 2022-04-12
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, enzalutamide has only moderately strong androgen receptor antagonistic activity, so it is necessary to develop androgen receptor antagonists with stronger AR antagonistic activity and stronger antitumor activity to further improve the clinical treatment of prostate cancer.

Method used

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  • Aromatic ring and cyclic lactone thiohydantoin compound as well as preparation method and application thereof
  • Aromatic ring and cyclic lactone thiohydantoin compound as well as preparation method and application thereof
  • Aromatic ring and cyclic lactone thiohydantoin compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1: 4-(4,4-dimethyl-5-oxo-3-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-thioimidazolidine -1-yl)-2-(trifluoromethyl)benzonitrile (compound 1)

[0074] 5-Aminoisobenzofuran-1(3H)-one (22)

[0075]

[0076] Copper sulfate (35mg, 0.22mmol, 0.007eq) was dissolved in 1.5mL of water, then zinc powder (5.5g, 84.11mmol, 2.8eq) was added to the solution, and then 12.75g of 20% sodium hydroxide solution was added. After stirring the reaction in the bath for several minutes, 5-aminoisoindoline-1,3-dione (5.00 g, 30.84 mmol, 1 equiv) was added. The reaction mixture was stirred at 60 °C for 4 h, TLC monitoring indicated the reaction was complete. The reaction was cooled to room temperature for suction filtration, and then the filter cake was washed with a small amount of water to obtain a filtrate, and then the pH was adjusted to 3-4 with concentrated hydrochloric acid. At this time, a large amount of solid precipitated out, and suction filtration was performed to obtain a y...

Embodiment 2

[0086] Example 2: 5-(4,4-Dimethyl-5-oxo-3-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-thioimidazolidine -1-yl)-3-(trifluoromethyl)pyridinecarbonitrile (compound 2)

[0087] 5-isothiocyanato-3-(trifluoromethyl)pyridinecarbonitrile (25)

[0088]

[0089] Thiophosgene (0.489mL, 6.4mmol, 1.2eq) was dissolved in 20mL of water and stirred at room temperature, and 5-amino-3-(trifluoromethyl)cyanopyridine (1g, 5.37mmol, 1eq) was dissolved in batches added to the solution. The reaction mixture was stirred at room temperature for 4 h, TLC monitoring showed that the reaction was complete. Then the solution was extracted with dichloromethane, the organic phase was washed twice with saturated brine, washed with anhydrous Na 2 SO 4 After drying, filtration, the organic phase was concentrated by adding silica gel and purified by automatic column passer (0-10% ethyl acetate / petroleum ether) to obtain the desired product. Finally, 540 mg of light yellow oil was obtained, with a yield of 44...

Embodiment 3

[0093] Example 3: 4-(4,4-Dimethyl-5-oxo-3-(1-oxoisopyran-6-yl)-2-thioimidazolidin-1-yl)-2- (Trifluoromethyl)benzonitrile (Compound 3)

[0094] Methyl 4-amino-2-bromobenzoate (26)

[0095]

[0096] 2-Bromo-4-nitrobenzoic acid methyl ester (10g, 38.46mmol, 1 equivalent) was dissolved in 80mL ethanol and 20mL water, stirred at room temperature for several minutes, and then Fe (6.44g, 115.3mmol, 3 equivalents ) and NH 4 Cl (8.23g, 153.8mmol, 4eq) was added to the solution, and the temperature was slowly raised to 70°C. The reaction mixture was stirred at 70 °C for 5.5 h, TLC monitoring indicated the reaction was complete. The solution was then filtered with celite to obtain the filtrate, which was extracted with ethyl acetate, and the organic phase was washed twice with saturated brine, washed over anhydrous Na 2 SO 4 After drying, filtration and concentration, the desired product is obtained. Finally, 8.05 g of white solid was obtained with a yield of 90.99%. 1 H NMR (4...

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Abstract

The invention discloses an aromatic ring and cyclic lactone thiohydantoin compound as well as a preparation method and application thereof, the structure is as shown in formula I. In the formula, the definition of each substituent group is as described in the specification and claims. The compound provided by the invention has excellent antagonistic activity on androgen receptors, and can be used as an androgen receptor antagonist for treating prostate cancer patients.

Description

technical field [0001] The invention relates to the field of pharmacy, and relates to the fields of drug synthesis and pharmacology. More specifically, it relates to an aromatic ring and ring lactone thiohydantoin compound and its preparation method and application, especially for the treatment of prostate cancer patients. Background technique [0002] Prostate cancer (PCa) is a common malignant tumor of the male genitourinary system and the second most deadly cancer in American men. In my country, with the aging population and changes in diet structure, the morbidity and mortality of prostate cancer patients have increased significantly in recent years, and the incidence rate increases with age. According to the national cancer statistics released by the National Cancer Center in 2019, prostate cancer has ranked sixth in the incidence of male cancer in my country, with about 60,000 new cases every year. Compared with developed countries in Europe and the United States, mo...

Claims

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Application Information

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IPC IPC(8): C07D405/04C07D405/14C07D491/048C07D491/107A61P13/08A61P35/00A61P1/00A61P19/10A61K31/4178A61K31/4355A61K31/4184A61K31/4188
Inventor 杨玉社王傲王雅琬罗湘港
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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