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5-member and 6-member rings heterocyclic compound, its preparation method, pharmaceutical composition and its application

A six-membered heterocyclic compound technology, applied in the field of five-membered and six-membered heterocyclic compounds

Active Publication Date: 2014-07-23
GUANGZHOU MAXINOVEL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, inflammatory mediators and cytokines can also lead to the activation of multiple signaling pathways in the body, which directly or indirectly mediate the expression of inflammatory mediators, resulting in damage to the intestinal mucosa, but many of the intricate signaling mechanisms remain to be elucidated

Method used

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  • 5-member and 6-member rings heterocyclic compound, its preparation method, pharmaceutical composition and its application
  • 5-member and 6-member rings heterocyclic compound, its preparation method, pharmaceutical composition and its application
  • 5-member and 6-member rings heterocyclic compound, its preparation method, pharmaceutical composition and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0138] Example 1 3-{4-[2-(Benzylamino)thieno[3,2-d]pyrimidin-4-yl]-1H-pyrazol-1-yl}butyronitrile T-01

[0139] The synthetic route is as follows:

[0140]

[0141] Synthesis of compound 1-a

[0142] Cesium carbonate (13.3g, 41.2mmol) was added to a solution of 3-bromobutylcyanide (2.0g, 10.3mmol) and 4-pyrazole borate pinazolate (2.3g, 15.5mmol) in acetonitrile (100mL), and the mixture Heat to 90°C and stir for 3 hours. After cooling to room temperature, water (100 mL) was added to quench the reaction. Extracted with ethyl acetate (100mL×3), the organic phases were combined, washed with water (60mL×3) and saturated brine (60mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless liquid 1- a (2.3g), the crude product was directly put into the next reaction. LC-MS(ESI): m / z=262[M+H] + .

[0143] Synthesis of compound 1

[0144] Under nitrogen atmosphere, sodium carbonate (318 mg, 3....

Embodiment 2

[0148] Example 2 3-{4-[2-(phenylamino)thieno[3,2-d]pyrimidin-4-yl]-1H-pyrazol-1-yl}butyronitrile T-02

[0149] The synthetic route is as follows:

[0150]

[0151] Compound 1 (30mg, 0.1mmol), aniline (55mg, 0.6mmol) and p-toluenesulfonic acid monohydrate (76mg, 0.4mmol) were dissolved in isobutanol (8mL), and the mixture was stirred at 110°C for 16 hours . The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethanol (30 mL), washed successively with saturated aqueous sodium bicarbonate (30 mL), water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and reduced pressure The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to obtain compound T-02 (20 mg, yield: 55%). LC-MS(ESI): m / z=361[M+H] + .

[0152] 1 HNMR (400MHz, CDCl 3 )δ: 8.35(s, 1H), 8.32(s, 1H), 7.88(d, J=5.6Hz, 1H), 7.75(d, J=8.0Hz, 1H), 7.33~7.39(m, 4H)...

Embodiment 3

[0153] Example 3 3-cyclopentyl-3-{4-[2-(phenylamino)thieno[3,2-d]pyrimidin-4-yl]-1H-pyrazol-1-yl}propionitrile T- 03 The synthetic route is as follows:

[0154]

[0155] Synthesis of compound 3-b

[0156] Under a nitrogen atmosphere, the suspension of cyanomethyltriphenylphosphine bromide (12g, 31.49mmol) in anhydrous tetrahydrofuran (100mL) was cooled to 0°C, and a 2.5M n-butyllithium n-hexane solution (13mL, 34.64 mmol). After continuing stirring at 0°C for 30 minutes, cyclopentylcarbaldehyde (3.1 g, 31.49 mmol) was added and stirred at room temperature for 1 hour. Add saturated ammonium chloride solution (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×3), combine organic phases, wash with water (60 mL×3) and saturated brine (60 mL) successively, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=...

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Abstract

The invention discloses a 5-member and 6-member rings heterocyclic compound shown as a formula I, its pharmaceutically acceptable salt, a metabolite, a metabolism precursor or its medicine precursor, a preparation method, a pharmaceutical composition and an application. The 5-member and 6-member rings heterocyclic compound has activity by being as a Janus kinases (JAK) inhibitor, and be used for treating diseases due to abnormal activity of kinases, such as cell proliferation diseases such as cancer, and can be used for preparing the medicines for treating the disease.

Description

technical field [0001] The present invention relates to a five-membered and six-membered heterocyclic compound, its preparation method, pharmaceutical composition and application. Background technique [0002] The JAK-STAT (Janus kinase-signal transducer and activator of transcription) signaling pathway is a signal transduction pathway stimulated by cytokines discovered in recent years, which is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Process (Aaronson, D.S. et al. Science 2002, 296, 1653-1655; O'Shea, J.J. et al. Nat. Rev. Drug Discovery 2004, 3, 555-564). Compared with other signaling pathways, the transmission process of this signaling pathway is relatively simple, and it mainly consists of three components, namely tyrosine kinase-associated receptors, tyrosine kinase JAK and transcription factor STAT. [0003] Cytokines (such as interferon IFN and interleukin IL, etc.) and growth facto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04C07D491/048A61K31/519A61K31/5377A61P35/00A61P29/00A61P37/02A61P31/00
CPCC07D487/04C07D491/048C07D495/04A61P29/00A61P31/00A61P35/00A61P37/02A61P37/06A61P43/00A61K31/519
Inventor 许祖盛张农孙庆瑞汪廷汉
Owner GUANGZHOU MAXINOVEL PHARMA CO LTD
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