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Androgen receptor antagonist for resisting prostate cancer

A halogen and compound technology, used in antitumor drugs, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of limited efficacy, limited side effects, and nervous system toxicity.

Active Publication Date: 2010-09-01
SUZHOU KINTOR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The latest research shows that the reactivation of androgen receptor signaling pathway may be the root cause of resistance to hormone therapy, which limits the efficacy of androgen receptor antagonist drugs commonly used in the market, such as bicalutamide, in the treatment of prostate cancer. Especially for advanced resistant prostate cancer
In addition, the efficacy of these androgen receptor antagonist drugs is generally limited by their significant side effects, such as toxicity to the liver or central nervous system

Method used

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  • Androgen receptor antagonist for resisting prostate cancer
  • Androgen receptor antagonist for resisting prostate cancer
  • Androgen receptor antagonist for resisting prostate cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0052] Synthesis of Example 1

[0053]

[0054] Synthesis of 4-isothiocyanate-3-trifluoromethoxy-benzonitrile (intermediate 3a)

[0055] To an aqueous suspension (30 mL) of thiophosgene (4.21 g, 36.6 mmol) was slowly added 4-amino-2-methyl-benzonitrile la (5 g, 34.9 mmol). The resulting mixture was stirred at room temperature (25°C) for one hour and extracted three times with ethyl acetate (3 x 25 mL). The organic layers were combined, washed with water (1×50 mL), dried (MgSO 4 ), and vacuum-dried to give 3a (Intermediate 7, 6.5 g, 100% yield) as a beige solid, which was directly used in the next reaction.

[0056] Synthesis of 2-fluoro-N-methyl-4-nitro-benzamide (intermediate 8)

[0057]

[0058] Thionyl chloride (15 g, 130 mmol) was slowly dropped into a solution of 2-fluoro-4-nitro-benzoic acid 7 (20 g, 110 mmol) in dimethylformamide (DMF, 20 mL) at -5°C. After stirring for 1 hour, methylamine (400 mL, 800 mmol) was added dropwise. Warm slowly to room temperat...

example 2

[0072] Example 2 was obtained by reacting intermediate 10 and 7b by a method similar to Synthesis Example 1 (yield: 23%), and 7b was obtained from the corresponding aniline by a method similar to Synthesis 7a. 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 8.30 (1H, dd, J = 8.6, 3.5Hz), 7.57 (3H, m), 7.26 (1H, m), 7.15 (1H, dd, J = 12.0, 2.0Hz), 6.71(1H, br s), 3.00(3H, d, J=5Hz), 2.65(2H, m), 2.52(2H, m), 2.27(1H, m), 1.70(1H, br m). Mass spectrum: 427(M+H + ).

example 3

[0076] Example 3 was obtained by the reaction of intermediate 10 and 7c (yield: 21%) by a method similar to Synthesis Example 1, and 7c was obtained from the corresponding aniline by a method similar to Synthesis 7a. 1 H NMR (CDCl 3 , 500MHz): δ (ppm) 8.30 (1H, dd, J = 8.6, 3.5Hz), 7.67 (2H, m), 7.38 (1H, d, J = 8.0Hz), 7.26 (1H, m), 7.20 ( 1H, dd, J = 11.5, 2.0Hz), 6.71 (1H, br s), 3.00 (3H, d, J = 5Hz), 2.65 (2H, m), 2.52 (2H, m), , 2.15 (3H, s), 2.15 (1H, m), 1.68 (1H, br m). Mass spectrum: 423 (M+H + ).

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Abstract

The invention provides an androgen receptor antagonist for resisting the prostate cancer, relates to a sulfoimidazoledione with substituted groups on two nitrogen atoms, and relates to a use of such the compounds as a medicament for treating the diseases or disorders related to the androgen receptor, such as prostate cancer, alopecia or whelk.

Description

technical field [0001] The present invention relates to a class of thioimidazole diketones having substituent groups on both nitrogen atoms; and to the use of such compounds as drugs for the treatment of Androgen Receptor ('AR') related diseases or disorders, such as Prostate cancer, hair loss, or acne. Background technique [0002] Androgen receptor (AR) is a ligand-dependent trans-transcriptional regulatory protein with a molecular weight of 110,000 Daltons, a member of the steroid hormone nuclear receptor superfamily, and mainly exists in the nucleus of target cells . Androgen receptor plays a very important role in both the pathogenesis of prostate cancer and its progression. It binds to a specific steroid hormone ligand such as testosterone or more effectively dihydrotestosterone (DTH) in the ligand-binding domain, resulting in a conformational change that dissociates from the heat shock protein (hsp), causing androgen stimulation. The activation of the body increase...

Claims

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Application Information

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IPC IPC(8): C07D235/02C07D233/86C07D471/04C07D401/04A61K31/4184A61K31/4166A61K31/437A61K31/4709A61K31/4439A61P35/00A61P17/14A61P17/10
Inventor 童友之
Owner SUZHOU KINTOR PHARMA
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