Sulfo-imidazole diketone androgen receptor antagonist and applications thereof

A technology of thioimidazolidine and halogen, which is applied in the field of medicine and can solve the problems of reduced affinity activation

Inactive Publication Date: 2018-05-04
刘秀云
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The newly marketed androgen receptor antagonist, enzalutamide (trade name Xtandi), has a higher affinity to androgen receptor than b...

Method used

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  • Sulfo-imidazole diketone androgen receptor antagonist and applications thereof
  • Sulfo-imidazole diketone androgen receptor antagonist and applications thereof
  • Sulfo-imidazole diketone androgen receptor antagonist and applications thereof

Examples

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Comparison scheme
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preparation example Construction

[0048] The preparation of compounds of formula (I) according to the invention is illustrated by Scheme A.

[0049] Option A:

[0050]

[0051] In scheme A, the compound of formula (IV) is non-limitingly selected from compound IV-1, which can be obtained commercially.

[0052]

[0053] In scheme A, the compound of formula (V) is non-limitingly selected from acetone, cyclobutanone and dihydro-3(2H)-furanone.

[0054] In certain embodiments, the compound of formula (II) is selected from: Y is carbon, R 3 Is amino meta-fluorine, Z is cyano, COOCH 3 、CONH 2 、CONHCH 3 , imidazol-2-yl or oxazol-2-yl.

[0055] In certain embodiments, the compound of formula (II) is selected from: Y is nitrogen, R 3 is hydrogen, Z is COOCH 3 、CONH 2 , oxazol-2-yl, thiazol-2-yl, or

[0056]

Embodiment 1

[0058] 4-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1 Preparation of -yl)-2-fluorophenyl)butanoic acid methyl ester (WX-101)

[0059]

[0060] Preparation of compound II-1: add compound 1 (12.05g, 0.05mol), ammonium chloride (45g), iron powder (30g), methanol (350mL) and water (250mL) into the reaction flask, stir, heat to reflux and Leave on for 1 hour. Cool down, filter, concentrate under reduced pressure to remove methanol, add dichloromethane for extraction. The organic phase was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain compound II-1 (9.10 g, yield 86.1%) as light yellow oil. 1 H-NMR (400MHz, CDC1 3 ): δ1.83-1.88(m,2H), 2.32(t,2H,J=7.2Hz), 2.52(t,2H,J=7.2Hz), 3.63(s,3H), 5.44(bs,2H) , 6.31-6.37 (m, 1H), 6.90-6.98 (m, 2H).

[0061] Preparation of compound III-1: add compound II-1 (1.06g, 5mmol), zinc chloride (10...

Embodiment 2

[0064] 4-(4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioimidazolidine-1 Preparation of -yl)-2-fluorophenyl)butyramide (WX-102)

[0065]

[0066] Preparation of compound II-2: Add compound II-1 (2.11 g, 10 mmol) and methanol (30 mL) into a reaction flask, stir, add ammonia water (30 mL), and continue stirring for 24 hours. Concentrate under reduced pressure to remove methanol, add water to the residue, and extract with dichloromethane. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain compound II-2 (1.54 g, yield 78.5%) as a white solid, which was directly used in the next step.

[0067] Preparation of compound III-2: According to the similar method for preparing compound III-1, compound III-2 (1.46 g) was synthesized from compound II-2 as light yellow oil, which was directly used in the next step.

[0068] Preparation of compound WX-102: According to the sim...

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Abstract

The invention discloses a sulfo-imidazole diketone compound represented by the formula (I). The sulfo-imidazole diketone compound can be used as an androgen receptor and can be used to prepare drugs for treating diseases or disorders related with androgen receptors such as cancer, and the like.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to novel substituted thioimidazole diketone compounds and their use as androgen receptor antagonists for preventing and treating diseases or disorders related to androgen receptors. Background technique [0002] Androgen receptor (AR) is a ligand-dependent trans-transcriptional regulatory protein with a molecular weight of 110,000 Daltons. One of its key functions is androgen-activated gene transcription. The androgen receptor plays an important role in many androgen related diseases such as prostate cancer, benign prostatic hypertrophy, androgen alopecia, sarcopenia and hirsutism. [0003] Prostate cancer is one of the most common cancers in men and one of the leading causes of cancer death in men. The current standard of care for prostate cancer is surgery or hormone therapy. Often, hormone therapy is also combined with drugs that act as androgen receptor antagonists, such as flu...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D413/14C07D401/14C07D491/107C07D417/14A61P35/00A61P17/14A61P17/10A61P17/00A61P5/26
CPCC07D401/04C07D401/14C07D413/14C07D417/14C07D491/107
Inventor 刘秀云
Owner 刘秀云
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