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Triazole derivative having HSP90 (Heat Shock Protein) inhibiting activity, as well as preparation method and application of triazole derivative

A technology of triazole derivatives and stereoisomers, applied in the field of triazole derivatives and their preparation, can solve the problems of preventing clinical development and toxicity

Active Publication Date: 2017-01-25
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • 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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  • Triazole derivative having HSP90 (Heat Shock Protein) inhibiting activity, as well as preparation method and application of triazole derivative
  • Triazole derivative having HSP90 (Heat Shock Protein) inhibiting activity, as well as preparation method and application of triazole derivative
  • Triazole derivative having HSP90 (Heat Shock Protein) inhibiting activity, as well as preparation method and application of triazole derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0124] 4-(7-Bromo-4,5-dihydro-[1,2,4]triazol[4,3-a]quinolin-1-yl)-6-isopropylbenzene-1,3-di phenol

[0125]

[0126] Step 1: 6-bromo-3,4-dihydroquinolin-2(1H)-one

[0127] Compound 3,4-dihydro-2(1H)-quinolinone (10.0 g, 67.95 mmol) was dissolved in N,N-dimethylformamide (100 mL). After cooling to 0°C, N-bromosuccinimide (12.7 g, 71.34 mmol) was added in batches, and the reaction was stirred for 6 hours while slowly raising the temperature. The reaction solution was concentrated to dryness, added with ethyl acetate, washed with sodium bicarbonate solution and brine successively. The organic phase was dried, filtered and concentrated to dryness to obtain 6-bromo-3,4-dihydroquinolin-2(1H)-one (14g) with a yield of 90%.

[0128] Step 2: 6-bromo-3,4-dihydroquinoline-2(1H)-thione

[0129] Compound 6-bromo-3,4-dihydroquinolin-2(1H)-one (10.0g, 44.23mmol) was dissolved in toluene (100mL), Lawson's reagent (8.95g, 22.12mmol) was added, and the suspension The solution was heated...

Embodiment 2

[0162] 4-isopropyl-6-(7-((2-morpholinoethyl)amine)-4,5-dihydro-[1,2,4]triazol[4,3-a]quinoline- 1-yl)benzene-1,3-diol

[0163]

[0164] Step 1: 1-(5-isopropyl-2,4-dimethoxybenzene)-N-(2-morpholinoethyl)-4,5-dihydro-[1,2,4]triazole [4,3-a]quinolin-7-amine

[0165] The compound 7-bromo-1-(5-isopropyl-2,4-dimethoxyphenyl)-4,5-dihydro-[1,2,4]triazol[4,3-a] Quinoline (70 mg, 0.16 mmol), 2-morpholinoethyl-1-amine (43 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (15 mg, 0.013 mmol), 4,5-diphenylene Phosphine-9,9-dimethylxanthene (15 mg, 0.013 mmol) and sodium tert-butoxide (35 mg, 0.36 mmol) were dissolved in anhydrous toluene (2 mL). Under the protection of nitrogen, microwave heating to 100° C. was performed for 2 hours. Concentrated to dryness under reduced pressure, the crude product was separated by column chromatography (dichloromethane / methanol=100:0~90:10, v / v) to obtain 1-(5-isopropyl-2,4-dimethoxybenzene) -N-(2-morpholinoethyl)-4,5-dihydro-[1,2,4]triazol[4,3...

Embodiment 3

[0172] 4-isopropyl-6-(7-(morpholinylmethyl)-4,5-dihydro-[1,2,4]triazol[4,3-a]quinolin-1-yl)benzene- 1,3-diphenol

[0173]

[0174] Step 1: 2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde

[0175] Under nitrogen protection, in a 100mL three-necked flask, the compound 6-bromo-3,4-dihydroquinolin-2(1H)-one (2.5g, 11.06mmol) and N,N-dimethylformamide (2.5g , 11.06 mmol) was dissolved in dry tetrahydrofuran (50 mL) and cooled to -78 °C. Slowly add tert-butyllithium solution (24.1mL, 38.7mmol, 1.6M in pentane) dropwise, continue to react at -78°C for 4 hours after the dropwise addition, add acetic acid (2.5mL, slowly warm up to room temperature. Diluted with ethyl ester (100mL), washed successively with saturated sodium bicarbonate solution and brine. The organic phase was dried, filtered and concentrated to dryness to obtain 2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (0.6 g), yield 30%.

[0176] ESI-MS m / z: 176.2.

[0177] Step 2: 6-(morpholinylmethyl)-3,4-dihydroqui...

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Abstract

The invention discloses a triazole derivative having an HSP90 (Heat Shock Protein) inhibiting activity, as well as a preparation method and an application of the triazole derivative. Specifically, the invention relates to the triazole derivative having a structure as shown in a formula (I), a stereisomer of the triazole derivative and a pharmaceutically acceptable salt, wherein the definition of each substituent group in the formula (I) and the definition in a description are the same. The compound with a novel structure has the HSP90 inhibiting activity, can be used to cure cancers, neurodegenerative disorders, inflammation diseases, autoimmune diseases, ischemic brain injuries and the like, and has a broad application prospect.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a triazole derivative with HSP90 inhibitory activity and its preparation method and application. 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 inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04C07D498/04C07D471/14A61K31/5377A61K31/55A61K31/4985A61K31/5517A61K31/5383A61K31/553A61P25/28A61P35/00A61P29/00A61P37/02A61P9/10
CPCC07D471/04C07D471/14C07D487/04C07D498/04Y02P20/55
Inventor 赵志明邓向君黄志强喻红平徐耀昌潘忠宗包如迪
Owner SHANGHAI HANSOH BIOMEDICAL
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