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Azaindole derivatives, their preparation method and their application in medicine

A technology of drugs and compounds, applied in the field of azaindole derivatives, their preparation and their application in medicine, can solve problems such as infection, increased risk of cancer and heart failure, and short half-life

Active Publication Date: 2019-12-13
SHANGHAI BIODURO BIOLOGICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, tofacitinib can cause some adverse reactions clinically, such as serious infection and increased risk of cancer and heart failure
These adverse reactions may be due to the strong inhibitory effect of tofacitinib on JAK1, JAK2 and JAK3
In addition, tofacitinib has a short half-life in the human body and needs to be taken twice a day

Method used

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  • Azaindole derivatives, their preparation method and their application in medicine
  • Azaindole derivatives, their preparation method and their application in medicine
  • Azaindole derivatives, their preparation method and their application in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)acrylamide

[0080]

[0081] first step

[0082] tert-Butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate

[0083] Compound 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 1a (154mg, 1.0mmol), tert-butylpiperidin-3-ylcarbamate 1b (200mg, 1.0mmol), N, N -Diisopropylethylamine (387mg, 3.0mmol) and 1,4-dioxane (5mL) were mixed, and heated to 120° C. for 0.5 hour in microwave to react. Cool to room temperature and desolvate under reduced pressure. The residue was added with water (20 mL), extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, precipitated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol=30 / 1). The target product tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate 1c (210 mg, white solid) w...

Embodiment 2

[0095] N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)acryloylamide

[0096]

[0097] Example 2 was synthesized with reference to the operation steps of Example 1, but in the first step, tert-butylpiperidin-4-ylcarbamate was used to replace tert-butylpiperidin-3-ylcarbamate.

[0098] MS m / z(ESI):272[M+1]

[0099] 1 H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.14(s,1H),8.05(d,J=7.8Hz,1H),7.18(s,1H),6.59(s,1H) ,6.19(dd,J=17.2,10.0Hz,1H),6.09(d,J=18.9Hz,1H),5.58(d,J=11.9Hz,1H),4.58(d,J=13.2Hz,2H) , 4.05-3.92 (m, 1H), 3.27-3.22 (m, 2H), 1.88 (d, J=10.0Hz, 2H), 1.45-1.37 (m, 2H).

Embodiment 3

[0101] 1-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-1-yl)prop-2-en-1-one

[0102]

[0103] first step

[0104] tert-butyl 5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydropyridine-1(2H)-carboxylate

[0105] The mixture 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 1a (1.0g, 6.5mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate 3a (1.0 g, 6.5 mmol), sodium carbonate (1.4 g, 13.0 mmol), PdCl 2 (dppf) (475mg, 0.65mmol), 1,4-dioxane (20mL) and water (10mL) were heated to 95°C and stirred overnight under nitrogen protection. After the reaction solution was cooled to room temperature, water (50 mL) was added and extracted with ethyl acetate (30 mL×3). The organic phase was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and the solvent was precipitated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol=50 / 1) to obtain the target product tert-b...

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Abstract

The present invention relates to azaindole derivatives, their preparation methods and their applications in medicine. Specifically, the present invention relates to a new derivative represented by general formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, and a preparation method thereof. The present invention also relates to the use of said derivatives and pharmaceutically acceptable salts thereof or pharmaceutical compositions containing them in the preparation of therapeutic agents, in particular Janus kinase 3 (JAK3) inhibitors, and in the preparation of agents for the treatment and / or prevention of inflammation-related diseases. Uses in medicines. Each substituent of general formula (I) is the same as the definition in the specification.

Description

technical field [0001] The present invention relates to a novel azaindole derivative and its pharmaceutically acceptable salt or a pharmaceutical composition containing it, and a preparation method thereof. The present invention also relates to the use of said derivatives and their pharmaceutically acceptable salts or pharmaceutical compositions containing them in the preparation of therapeutic agents, Janus kinase 3 inhibitors, and medicines for the treatment and / or prevention of inflammation-related diseases . Background technique [0002] Janus-activated kinase signal transducers and activators of transcriprion (JAK / STAT) is an intracellular signal transduction pathway closely related to cytokines discovered in recent years. When a cytokine, such as interferon, growth hormone, interleukin, etc., binds to its receptor, JAK will phosphorylate the cytokine receptor, and further phosphorylate and activate the STAT protein recruited by the phosphorylated cytokine receptor. A...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61K31/4985A61P29/00
Inventor 陈向阳高英祥
Owner SHANGHAI BIODURO BIOLOGICS
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