JAK kinase inhibitor and application thereof

A solvate, selected technology, applied in the field of medicine, can solve the problem of loss, painful movement, etc.

Active Publication Date: 2020-11-06
JIANGSU CAREFREE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, loss of articular cartilage causes the bones to rub against each other, causing pain and loss of motion

Method used

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  • JAK kinase inhibitor and application thereof
  • JAK kinase inhibitor and application thereof
  • JAK kinase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Embodiment 1: the preparation of compound EXP-1

[0077] The synthetic route is as follows:

[0078]

[0079] Step 1.1 Preparation of compound 1

[0080]

[0081] 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (SM1) (2 g, 9.4 mmol) and triethylamine (2.4 g, 23.5 mmol) were dissolved in acetonitrile ( 10 mL), cyclopropylformyl chloride (SM2) (2.45 g, 23.5 mmol) was added dropwise at 0° C., and the mixture was naturally raised to room temperature and stirred for 16 hours. The reaction solution was concentrated in vacuo to obtain the bisacylated intermediate N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-N-(cyclopropanecarbonyl)cyclopropane Formamide (1) (3.3 g crude, yellow solid) was used in the next step without further purification.

[0082] LCMS:t R =0.785min in 5-95AB_1.5min_220&254_Shimadzu.lcmchromatography (Agilent Pursult 5C18 20*2.0mm), MS (ESI) m / z=350.9[M+2+H] + .

[0083] Step 1.2 Preparation of Compound Int-1

[0084]

[0085] N-(5-Bromo-[1,2,...

Embodiment 2

[0101] Embodiment 2: the preparation of compound EXP-3

[0102] The synthetic route is as follows:

[0103]

[0104] Step 2.1 Preparation of compound 22

[0105]

[0106] 6-Bromopyridin-2-amine (SM16) (5 g, 28.90 mmol) and ethyl bromopyruvate (SM17) (6.20 g, 31.79 mmol) were dissolved in ethanol (30 mL), and stirred at 85 degrees for 16 hours. The reaction solution was filtered, and the filter cake was collected, slurried with petroleum ether / ethyl acetate (5 / 1, v / v, 50mL), solid filtered, and dried to obtain 5-bromoimidazole[1,2-a]pyridine-2-carboxylic acid Ethyl ester (22) (8.41 g, 83% yield, hydrogen bromide salt, yellow solid).

[0107] 1 H NMR (400MHz, DMSO-d 6 ):δ=8.56(s,1H),7.75(d,J=8.8Hz,1H),7.52-7.44(m,2H),4.36(q,J=7.2Hz,2H),1.34(t,J= 7.2Hz, 3H).

[0108] Step 2.2 Preparation of compound 23

[0109]

[0110] Dissolve ethyl 5-bromoimidazol[1,2-a]pyridine-2-carboxylate (22) (2 g, 5.71 mmol, hydrogen bromide salt) in water, 5 ml each of tetrahydrofuran and ...

Embodiment 3

[0135] Embodiment 3: the preparation of compound EXP-4

[0136] The synthetic route is as follows:

[0137]

[0138] Step 3.1 Preparation of compound 3

[0139]

[0140] Dissolve 2-methylthiazol-5-boronate (SM5) (100mg, 0.444mmol) in carbon tetrachloride (2mL), add N-bromosuccinimide (103mg, 0.577mmol) and azobisisobutyronitrile (7.3 mg, 0.0444 mmol). The reaction solution was stirred at 80° C. for 0.5 hour under the protection of nitrogen. The reaction solution was filtered, and the filtrate was concentrated in vacuo to obtain a crude product, which was then dissolved in tetrahydrofuran (2mL), and diisopropylethylamine (0.1mL) and diethyl phosphite (74uL) were added successively, and stirred at 10°C for 25 minutes to obtain 2- Bromomethylthiazole-5-boronate (3) (135 mg, crude, brown solution in 2 mL THF) was used directly in the next step.

[0141] LCMS:t R =0.590min in 5-95AB_1.5min_220&254_Shimadzu.lcmchromatography(Merk RP18e 25-3mm), MS(ESI)m / z=221.7[M-81] + ....

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PUM

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Abstract

The invention discloses a JAK kinase inhibitor and an application thereof. The JAK kinase inhibitor is a compound represented by a formula I or a stereoisomer, a tautomer or pharmaceutically acceptable salt or a solvate or a prodrug of the compound; the invention further provides the application of the compound represented by the formula I in preparation of drugs for preventing or treating JAK kinase related diseases, and in particular, relates to the application in preparing medicines for preventing and/or treating diseases related to cartilage degeneration and bone and/or joint degeneration,diseases related to inflammation or immune response, endotoxin-driven disease states, cancers and organ transplantation rejection.

Description

technical field [0001] The invention belongs to the field of medical technology, and in particular relates to a novel nitrogen-containing five-membered heterocyclic pyridine compound, a preparation method thereof and a pharmaceutical composition containing the same, and its use for regulating Janus kinase (JAK) activity and for treating And / or use to prevent diseases associated with JAK activity. Background technique [0002] Chondrocytes are the main cellular component of avascular tissue. In normal articular cartilage, chondrocytes account for about 5% of the tissue volume, while the extracellular matrix accounts for the remaining 95% of the tissue. Chondrocytes secrete matrix components, mainly proteoglycans and collagen, which in turn provide chondrocytes with an environment suitable for their survival under mechanical stress. In cartilage, type II collagen and type IX protein collagen form a fibrous structure that provides cartilage with great mechanical strength. Pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P19/08A61P19/02A61P17/06A61P11/00A61P1/00A61P35/00A61P35/02A61P19/00A61P37/06A61P37/08A61K31/437A61K31/4545A61K31/54
CPCC07D471/04A61P19/08A61P19/02A61P17/06A61P11/00A61P1/00A61P35/00A61P35/02A61P19/00A61P37/06A61P37/08
Inventor 秦引林苏梅王德忠
Owner JIANGSU CAREFREE PHARM CO LTD
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