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1-(pyrimidin-4-yl) 3-aminopiperidine derivatives and their preparation methods and uses

A kind of technology of aminopiperidine and derivatives, applied in the field of 1-3-aminopiperidine derivatives and preparation thereof

Active Publication Date: 2019-01-25
CHENGDU ZENITAR BIOMEDICAL TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since JAK3 and the same family of JAK1 and JAK2 kinases have very high homology and are very similar in structure and function, all existing JAK3 inhibitors have side effects of inhibiting JAK1 and JAK2

Method used

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  • 1-(pyrimidin-4-yl) 3-aminopiperidine derivatives and their preparation methods and uses
  • 1-(pyrimidin-4-yl) 3-aminopiperidine derivatives and their preparation methods and uses
  • 1-(pyrimidin-4-yl) 3-aminopiperidine derivatives and their preparation methods and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1 Synthesis of (R)-tert-butyl (1-(9H-purin-6-yl) piperidin-3-yl) carbamate (compound 1)

[0091]

[0092] At room temperature, 6-chloropurine (1 mmol) and R-3-Boc aminopiperidine (1.2 mmol) were added to methanol, stirred for 5 minutes, then slowly heated to 50 degrees Celsius, and precipitated after stirring for 7 hours to stop the reaction. Cool to room temperature, filter the reaction solution, wash the filter cake with a little methanol, collect the filter cake, and drain to obtain a crude product, which is purified by column chromatography to obtain the final target compound 1, with a yield of 42%.

[0093] 1 H NMR (400MHz, DMSO-d6): δ12.98(s, 1H), 8.20(s, 1H), 8.11(s, 1H), 6.94(d, 1H, J=6.4Hz), 5.16-5.04(m ,2H), 3.34(s,1H), 3.23-3.05(m,2H), 1.90-1.79(m,2H), 1.50(t,2H, J=4.2Hz), 1.39(s,9H). MS(ESI),m / z:317.4[M-H] - .

Embodiment 2

[0094] Example 2 Synthesis of (R)-N-(1-(9H-purin-6-yl)piperidin-3-yl)acetamide (compound 2)

[0095]

[0096] Compound 1 (1 mmol) was added into dichloromethane (2 mL) and trifluoroacetic acid (2 mL), stirred at room temperature for 4 hours, and the reaction was monitored by thin-layer chromatography. After the reaction is complete, spin the reaction solution to dryness, add diethyl ether, precipitate out, and filter to obtain the trifluoroacetate intermediate of compound 1. Add trifluoroacetic acid salt (1 mmol) of compound 1 into tetrahydrofuran, add triethylamine (3 mmol), slowly add acetyl chloride (1.2 mmol) under ice bath, and react at room temperature. After the reaction is completed, the solution is spin-dried at low temperature. Add methanol to dissolve, and purify by column chromatography to obtain compound 2, yield: 40%.

[0097] 1 H NMR (400MHz, DMSO-d6): δ10.01(s, 1H), 8.19(s, 1H), 8.10(s, 1H), 7.91(d, 1H, J=8.0Hz), 5.34-4.66(m ,2H),3.72-3.71(m,1H),3.43-3.36...

Embodiment 3

[0098] Example 3 Synthesis of (R)-N-(1-(9H-purin-6-yl)piperidin-3-yl)palmitamide (compound 3)

[0099]

[0100] Compound 1 (1 mmol) was added into dichloromethane (2 mL) and trifluoroacetic acid (2 mL), stirred at room temperature for 4 hours, and the reaction was monitored by thin-layer chromatography. After the reaction is complete, spin the reaction solution to dryness, add diethyl ether, precipitate out, and filter to obtain the trifluoroacetate intermediate of compound 1. Add the trifluoroacetic acid salt (1 mmol) of compound 1 into tetrahydrofuran, add triethylamine (3 mmol), slowly add pivaloyl chloride (1.2 mmol) under ice bath, and react at room temperature. After the reaction is completed, the solution is spin-dried at low temperature , added methanol to dissolve, and purified by column chromatography to obtain compound 3, yield: 35%.

[0101] 1 H NMR (400MHz, DMSO-d6): δ8.37(s, 1H), 7.98(s, 1H), 6.16(d, 1H, J=4.2Hz), 4.64-4.28(m, 2H), 4.23-4.01 (m,3H),2.00-1.8...

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Abstract

The invention relates to the field of chemical medicines and concretely relates to a 1-(pyrimidine-4-yl)-3-aminopiperdine derivative and its preparation method and use. The invention provides the 1-(pyrimidine-4-yl)-3-aminopiperdine derivative. The 1-(pyrimidine-4-yl)-3-aminopiperdine derivative has a structure shown in the formula IV. The invention also provides a preparation method and a use of the 1-(pyrimidine-4-yl)-3-aminopiperdine derivative. The 1-(pyrimidine-4-yl)-3-aminopiperdine derivative can selectively inhibit JAK3 and provide a novel choice for treating JAK3-related diseases such as rheumatoid arthritis, asthma, chronic obstructive pulmonary diseases and tumors.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and specifically relates to 1-(pyrimidin-4-yl)3-aminopiperidine derivatives and their preparation methods and applications. Background technique [0002] Tyrosine protein kinase (TPK) is a kind of kinase that catalyzes the transfer of γ-phosphate on ATP to protein tyrosine residues, and can catalyze the phosphorylation of various substrate protein tyrosine residues. Signal transduction pathways play a very important role in regulating a series of physiological and biochemical processes such as cell growth, differentiation, and death. There are two types of tyrosine kinases: receptor-type and non-receptor-type. Receptor tyrosine kinases are single-pass transmembrane proteins, and non-receptor tyrosine kinases are cytoplasmic proteins that play important roles in signal transduction from extracellular to intracellular. Dysregulation of protein tyrosine kinases will lead to a series of diseas...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D473/34C07D473/16C07D473/40A61P19/02A61P11/06A61P11/00A61P35/00
CPCC07D473/16C07D473/34C07D473/40C07D487/04
Inventor 陈俐娟魏于全
Owner CHENGDU ZENITAR BIOMEDICAL TECH CO LTD
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