3,4-diphenyl-4H-1,2,4-triazole derivative as well as preparation method and application thereof

A technology of triazole derivatives and diphenyl, applied in the field of drug synthesis, can solve problems such as toxicity and prevention of clinical development

Active Publication Date: 2017-01-25
SHANGHAI HANSOH BIOMEDICAL +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The natural antibiotic Geldanamycin has shown potential inhibitory effect on the growth of human cancer cells, but the obvious toxicity of this compound has prevented its further clinical development (Whitesell L., et al., Cancer Res., 1992,52,1721; SupkoJ .G., et al., Cancer Chemother. Pharmacol., 1995, 36, 305)
[0005] At present, the FDA has not approved a HSP90 inhibitor as an anticancer drug, and HSP90 as a promising anticancer drug target still attracts the medical community to develop new HSP90 inhibitors

Method used

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  • 3,4-diphenyl-4H-1,2,4-triazole derivative as well as preparation method and application thereof
  • 3,4-diphenyl-4H-1,2,4-triazole derivative as well as preparation method and application thereof
  • 3,4-diphenyl-4H-1,2,4-triazole derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] 5-(2,4-diphenolhydroxy-5-isopropylbenzene)-N-ethyl-4-(4-methyl-2,3,4,5-tetrahydrobenzo[b][1, 4] Oxazepine-8-yl)-4H-1,2,4-triazole-3-carboxamide

[0119]

[0120] Step 1: 2-(Hydroxymethyl)-5-nitrophenol

[0121] Compound 2-hydroxyl-4-nitrobenzoic acid (15g, 82mmol) was added to dry tetrahydrofuran (100mL), and the concentration of 10M borane dimethyl sulfide solution (82mL, 820mmol) was slowly added dropwise under ice bath, and the dropwise addition was completed Afterwards, the temperature was raised to room temperature and reacted for 16 h. Cool to 0°C, slowly add methanol dropwise to quench. The temperature was raised to 70° C. and refluxed for 1 h. After concentration, ethyl acetate was added, washed with brine, dried and concentrated to obtain 2-(hydroxymethyl)-5-nitrophenol (13.5 g) with a yield of 97.5%.

[0122] MS m / z (ESI): 168.1.

[0123] Step 2: 2-Hydroxy-4-nitrobenzaldehyde

[0124] Compound 2-(hydroxymethyl)-5-nitrophenol (13g, 77mmol) and manganese...

Embodiment 2

[0150] 4-(4-Cyclohexyl-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-8-yl)-5-(2,4- Diphenol hydroxy-5-isopropylphenyl)-N-ethyl-4hydro-1,2,4-triazole-3-carboxamide

[0151]

[0152] Step 1: 2-((cyclopropylamine)methyl)-5-nitrophenol

[0153] The compound 2-hydroxy-4-nitrobenzaldehyde (1.8 g, 10.8 mmol) was dissolved in methanol (50 mL), and cyclopropylamine (800 mg, 14 mmol) and acetic acid (650 mg, 10.8 mmol) were added. After reacting at room temperature for 0.5h, sodium cyanoborohydride (1.35g, 21.6mmol) was added in batches, and the reaction was continued for 3h. After concentration, dichloromethane was added, washed with saturated sodium bicarbonate and brine, dried and concentrated to obtain 2-( (Cyclopropylamine)methyl)-5-nitrophenol (2.1 g) yield 93.6%.

[0154] MS m / z (ESI): 209.2.

[0155] Step 2: 2-Chloro-N-cyclopropyl-N-(2-hydroxy-4-nitrobenzyl)acetamide

[0156] The compound 2-((cyclopropylamine) methyl)-5-nitrophenol (1.6g, 7.7mmol) and triethylamine (2.2mL...

Embodiment 3

[0172] 5-(2,4-diphenolhydroxy-5-isopropylbenzene)-N-(3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (Zen-8-yl)-N-ethyl-4hydro-1,2,4-triazole-3-carboxamide

[0173]

[0174] Step 1: 2-(((2,4-dimethoxybenzyl)amino)methyl)-5-nitrophenol

[0175] The compound 2-hydroxyl-4-nitrobenzaldehyde (4g, 23.9mmol) was dissolved in methanol (100mL), and 2,4-dimethoxybenzylamine (4.8g, 28.7mmol) and acetic acid (1.44g, 23.9 mmol). After reacting at room temperature for 0.5h, sodium cyanoborohydride (3g, 47.8mmol) was added in batches, and the reaction was continued for 2h. After concentration, dichloromethane was added, washed with saturated sodium bicarbonate and saturated brine, dried and concentrated, and the crude product was beaten (dichloro Methane / petroleum ether=1:10) gave 2-(((2,4-dimethoxybenzyl)amino)methyl)-5-nitrophenol (6.5 g) with a yield of 85.3%.

[0176] MS m / z (ESI): 319.1.

[0177] Step 2: 2-chloro-N-(2,4-dimethoxybenzyl)-N-(2-hydroxy-4-nitrobenzyl)acetamide

[017...

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Abstract

The invention discloses a 3,4-diphenyl-4H-1,2,4-triazole derivative as well as a preparation method and application thereof. Specifically, the invention relates to a 3,4-diphenyl-4H-1,2,4-triazole derivative of a structure represented by the formula (I), and a stereisomer or pharmaceutically acceptable salt of the derivative, wherein the definition of each substituent in the formula (I) is the same as that in a specification. Compounds of novel structures have the activity of inhibiting heat shock proteins HSP90, can be used for treating cancers, neurodegenerative diseases, inflammatory diseases, autoimmune diseases and ischemic brain injuries, and has wide application prospect.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a 3,4-diphenyl-4H-1,2,4-triazole derivative and a preparation method and application thereof. Background technique [0002] Heat shock proteins play a key protective role against various cellular stress factors (such as toxic foreign bodies, chemotherapy, radiation), and can prevent key proteins involved in maintaining normal cell functions from misfolding. Heat shock protein HSP90 plays an important role in the conformational maturation, stabilization and functionalization of a series of client proteins, many of which belong to the proto-oncogene protein family, such as Bcr-Abl, Raf-1, Akt, ErbB2, EGFR, Hif and other proteins and steroid hormone receptors. Inhibition of heat shock protein HSP90 can trigger the depolymerization of heat shock protein and client protein complexes, and then lead to the degradation of client proteins and loss of efficacy, thereby inhibiting...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D413/04C07D403/04A61K31/4245A61K31/553A61K31/55A61P35/00A61P25/28A61P29/00A61P37/02A61P9/10
CPCC07D403/04C07D413/04C07D413/12Y02P20/55
Inventor 赵志明林昇黄志强喻红平徐耀昌潘忠宗包如迪
Owner SHANGHAI HANSOH BIOMEDICAL
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