Thiadiazole amide compounds and their applications

A technology of thiadiazole amides and compounds, which is applied in the field of preparation of drugs for the treatment of prostate cancer, can solve the problems of reducing drug efficacy, multi-drug resistance, limiting clinical treatment options and benefits, etc., and achieve good safety and high Antagonize the activity of androgen receptor transcription, the effect of good biological activity

Active Publication Date: 2022-07-05
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 same time, when drug-resistant mutations occur, multidrug resistance often occurs, which severely limits the options and benefits of clinical treatment.

Method used

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  • Thiadiazole amide compounds and their applications
  • Thiadiazole amide compounds and their applications
  • Thiadiazole amide compounds and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] Example 1: Synthesis of target molecules A-1 to A-23

[0122] The synthetic route of compound A-1~A-23 is as follows figure 1 shown.

[0123] 2-Methyl-5-(3-(trifluoromethyl)phenyl)-N-(3-(2-oxopropyl)-1,2,4-thiadiazol-5-yl)furan- 3-Carboxamide (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] NBS (1.04 g, 5.9 mmol) and p-toluenesulfonic acid (458 mg, 2.7 mmol) were dissolved in acetonitrile (20 mL), and m-trifluoromethylacetophenone (1-1-1, 1.00 g, 5.3 mmol) was added , 55 ℃ stirring reaction 1h. An appropriate amount of ethyl acetate was added to the system, washed with water and saturated brine successively, and the organic layer was washed with anhydrous Na 2 SO 4 Dry and concentrated. The residue was obtained by column chromatography to obtain light yellow oily liquid, yield 88%; ESA-MS: m / z=267.0 [M+H] + .

[0127] (b) Synthesis of ...

Embodiment 2

[0181] Example 2: Synthesis of Compounds A-24 to A-30

[0182] The synthetic routes of compounds A-24~A-30 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 (215 mg, 0.56 mmol) was dissolved in ethanol and water (3:1, 12 mL), iron powder (225 mg, 4.0 mmol) and ammonium chloride (89 mg, 1.7 mmol) were added, and the reaction was carried out at 75° C. for 6 h. Saturated sodium bicarbonate solution was added to the system to adjust the pH to weakly alkaline, then an appropriate amount of ethyl acetate was added, washed with water and saturated brine in turn, and the organic layer was washed with anhydrous Na 2 SO 4 After drying and concentration, the residue was subjected to column chromatography to obtain a pale 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, ...

Embodiment 3

[0197] Example 3: Synthesis of Compounds A-31 to 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 routes 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, 122 μL, 1.27 mmol), methyl 2-methylfuran-3-carboxylate (317 μL, 2.53 mmol), potassium acetate (248 mg, 2.53 mmol) and palladium acetate (0.1%) equiv.) was added to DMA (5 mL) and stirred overnight at 150°C. An appropriate amount of ethyl acetate was added to the system, washed with water and saturated brine successively, and the organic layer was washed with anhydrous Na 2 SO 4 After 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)

[...

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Abstract

The invention discloses thiadiazole amide compounds and applications thereof, and belongs to the field of medicine. The general structural formula of the compound is shown in formula (I), which is a new type of compound with androgen receptor antagonistic activity, and one of the key targets is the binding between the androgen receptor ligand binding domain dimer interface. Pocket, which can block androgen receptor dimerization and antagonize androgen receptor. The compounds provided by the present invention have higher activity of antagonizing androgen receptor transcription, exhibit better biological activities at molecular level, cellular level and animal level, and have better safety. Therefore, it can be used in the preparation of medicines for the treatment of tumors with abnormal expression of androgen receptor 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, and 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 late stages of cancer when they are diagnosed. Both normal prostate cells and cancer cells depend on androgens for growth. Surgery or drug castration can greatly reduce androgen levels in early-stage prostate cancer patients, thereby inhibiting androgen-androgen receptor (AR)-dependent signaling pathways, and ultimately inhibiting Growth of prostate cancer cells. However, as the disease progresses, the vast majority of prostate cancer patients dev...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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