Azaindole derivatives, preparation method and applications thereof in medicine

A compound, heterocyclic group technology, applied in the field of azaindole derivatives, its preparation and its application in medicine, can solve the problems of increasing the risk of cancer and heart failure, seriousness, short half-life, etc.

Active Publication Date: 2016-06-29
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, preparation method and applications thereof in medicine
  • Azaindole derivatives, preparation method and applications thereof in medicine
  • Azaindole derivatives, preparation method and applications thereof 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] MSm / z(ESI):272[M+1]

[0099] 1 HNMR(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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PUM

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Abstract

The invention relates to azaindole derivatives, a preparation method and applications thereof in medicine. Specifically, the invention relates to novel derivatives represented by the formula (I), pharmaceutically acceptable salts thereof, pharmaceutical composition containing the derivatives, and a preparation method of the derivatives. The invention also discloses an application of the derivatives, pharmaceutically acceptable salts thereof, or pharmaceutical composition containing the derivative in the preparation of drugs for treating and/or preventing inflammation related diseases, especially Janus kinase 3 (JAK3) inhibitor. The definitions of each substituent in the formula (I) are the same as the definitions in the description.

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 kinase\signal transducer and activator of transcription (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. After the act...

Claims

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Application Information

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