Thiadiazole amide compound and application thereof

A technology of thiadiazole amide and compound is applied in the application field of preparing drugs for the treatment of prostate cancer, which can solve the problems of multidrug resistance, reduce drug efficacy, limit clinical treatment options and benefits, etc., and achieve high antagonistic androgen receptors. The effect of in vivo transcriptional activity, good biological activity, and good safety

Active Publication Date: 2021-09-28
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These drug resistance mutations will directly affect the binding of the drug to the ligand binding pocket and reduce the efficacy of the drug
At the...

Method used

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  • Thiadiazole amide compound and application thereof
  • Thiadiazole amide compound and application thereof
  • Thiadiazole amide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Embodiment 1: Synthesis of Target Molecules A-1~A-23

[0122] The synthetic routes of compounds A-1~A-23 are as follows: figure 1 shown.

[0123] 2-Methyl-5-(3-(trifluoromethyl)phenyl)-N-(3-(2-oxopropyl)-1,2,4-thiadiazol-5-yl)furan- 3-Formamide (Compound A-1)

[0124] The specific synthetic route is as figure 2 shown.

[0125] (a) Synthesis of 2-bromo-1-(3-trifluoromethylphenyl)ethan-1-one (compound I-2-1)

[0126] Dissolve NBS (1.04g, 5.9mmol) and p-toluenesulfonic acid (458mg, 2.7mmol) in acetonitrile (20mL), add m-trifluoromethyl acetophenone (I-1-1, 1.00g, 5.3mmol) , Stir the reaction at 55°C for 1h. Add an appropriate amount of ethyl acetate to the system, wash with water and saturated brine successively, and wash the organic layer with anhydrous Na 2 SO 4 Dried and concentrated. The residue was subjected to column chromatography to obtain a light yellow oily liquid with a yield of 88%; ESA-MS: m / z=267.0[M+H] + .

[0127] (b) Synthesis of ethyl 2-acetyl...

Embodiment 2

[0181] Embodiment 2: the synthesis of compound A-24~A-30

[0182] Compounds A-24~A-30 synthetic routes are as follows: image 3 shown.

[0183] 2-methyl-5-(3-aminophenyl)-N-(3-(2-oxopropyl)-1,2,4-thiadiazol-5-yl)furan-3-carboxamide ( Compound A-24)

[0184] Compound A-2 (215mg, 0.56mmol) was dissolved in ethanol and water (3:1, 12mL), iron powder (225mg, 4.0mmol) and ammonium chloride (89mg, 1.7mmol) were added, and reacted at 75°C for 6h. Add saturated sodium bicarbonate solution to the system to adjust the pH to weakly alkaline, then add an appropriate amount of ethyl acetate, wash with water and saturated brine in sequence, and wash the organic layer with anhydrous Na 2 SO 4 After drying and concentration, the residue was subjected to column chromatography to obtain a light yellow solid with a yield of 72%; 1 H NMR (500MHz, DMSO-d 6 ): δ13.12(s,1H),7.54(s,1H),7.10(t,J=8.0Hz,1H),6.87(t,J=2.0Hz,1H),6.80-6.76(m,1H) ,6.57-6.52(m,1H),5.30(s,2H),4.04(s,2H),2.68(s,3H),2.21(...

Embodiment 3

[0197] Embodiment 3: the synthesis of compound A-31~A-33

[0198] 2-Methyl-5-(pyridin-3-yl)-N-(3-(2-oxopropyl)-1,2,4-thiadiazol-5-yl)furan-3-carboxamide ( Compound A-31)

[0199] Synthetic route such as Figure 4 shown.

[0200] (a) Synthesis of methyl 2-methyl-5-(pyridin-3-yl)furan-3-carboxylate (compound II-2-1)

[0201] 3-bromopyridine (II-1-1, 122μL, 1.27mmol), 2-methylfuran-3-carboxylate methyl ester (317μL, 2.53mmol), potassium acetate (248mg, 2.53mmol) and palladium acetate (0.1% equivalent) was added to DMA (5 mL), and stirred overnight at 150°C. Add an appropriate amount of ethyl acetate to the system, wash with water and saturated brine successively, and wash the organic layer with anhydrous Na 2 SO 4 Drying and concentration, the residue was subjected to column chromatography to obtain a yellow solid with a yield of 88%; ESA-MS: m / z=218.1[M+H] + .

[0202] (b) Synthesis of 2-methyl-5-(pyridin-3-yl)furan-3-carboxylic acid (compound II-3-1)

[0203] A solutio...

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Abstract

The invention discloses a thiadiazole amide compound and application thereof, belonging to the field of medicines. The structural general formula of the compound is as shown in formula (I); the compound is a novel compound with androgen receptor antagonistic activity; and one of key targets is a binding pocket between dimer interfaces of an androgen receptor ligand binding domain, and the binding pocket can block androgen receptor dimerization so as to play a role in antagonizing an androgen receptor. The compound provided by the invention has relatively high activity of antagonizing androgen receptor transcription, shows relatively good biological activity at a molecular level, a cellular level and an animal level, and has relatively good safety. Therefore, the compound can be applied to preparation of drugs for treating androgen receptor abnormal expression tumors including but not limited to prostate cancer, metastatic prostate cancer, castration-resistant prostate cancer, breast cancer and ovarian cancer.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the medical use of thiadiazole amide compounds, in particular to the application in the preparation of drugs for treating prostate cancer. Background technique [0002] Prostate cancer is the second most common cancer in men worldwide and the fifth leading cause of cancer death, seriously threatening men's health. Prostate cancer patients generally have no obvious symptoms in the early stage, and most patients are already in the middle and advanced stages of cancer when they are diagnosed. Both normal prostate cells and cancer cells depend on androgen for growth. Surgery or drug castration can greatly reduce the level of androgen in patients with early prostate cancer, thereby inhibiting the androgen-androgen receptor (AR)-dependent signaling pathway, and finally inhibiting Growth of prostate cancer cells. However, as the disease progresses, the vast majority of prostate cancer patients...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07D417/14A61K31/433A61K31/4439A61K31/454A61K31/496A61K31/5377A61P35/00
CPCC07D417/12C07D417/14A61P35/00
Inventor 侯廷军李丹盛荣富炜涛胡陈娴杨浩张珉魁廖佳宁
Owner ZHEJIANG UNIV
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