Heteroaryl imidazolone derivatives as JAK inhibitors

A technology of heterocyclic group and solvate is applied in the field of heteroarylimidazolone derivatives as JAK inhibitors, which can solve the problems of abnormal lymphoid tissue proliferation and reduction of thymus gland size.

Inactive Publication Date: 2013-02-13
ALMIRALL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mice lacking JAK3 are fertile but display abnormal proliferation of their lymphoid tissue, which results in a reduced size of the thymus (10- to 100-fold smaller than wild-type)

Method used

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  • Heteroaryl imidazolone derivatives as JAK inhibitors
  • Heteroaryl imidazolone derivatives as JAK inhibitors
  • Heteroaryl imidazolone derivatives as JAK inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0724] imidazo[1,2-a]pyridine-6-carbonitrile

[0725]

[0726]A 50% aqueous solution of 2-chloroacetaldehyde (26.40 mL, 210 mmol) was added to a solution of 2-aminonicotinonitrile (10 g, 80 mmol) in acetonitrile (300 mL), and the resulting mixture was stirred and heated to reflux temperature. After 20 hours, saturated aqueous sodium bicarbonate solution was added to partially saturate the resulting mixture, and additional saturated aqueous sodium bicarbonate solution was added until pH 7 was reached. The mixture was extracted with dichloromethane, and the organic layer was dried (MgSO 4 ) and evaporated, the residue was triturated with diethyl ether to give the title compound (10.75 g, 89%) as a brown solid.

[0727] LRMS(m / z):144(M+1) + .

[0728] 1 H NMR (300MHz, DMSO-d 6 ) δ ppm 7.49 (dd, 1H), 7.72 (s, 1H), 7.75-7.78 (m, 1H), 8.07 (s, 1H), 9.37 (s, 1H).

preparation example 2

[0730] 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one

[0731]

[0732] a) 2-chloro-5-nitro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine

[0733] Under nitrogen atmosphere, diisopropylethylamine (19.80 mL, 110 mmol) was added dropwise to stirred 2,4-dichloro-5-nitropyrimidine (11.56 g, 60 mmol) at -78 °C over 15 minutes and tetrahydro-2H-pyran-4-amine hydrochloride (prepared as described in WO200424728-A2, 7.81 g, 60 mmol) in dichloromethane (400 mL). The reaction mixture was stirred at -78°C for 2 hours and then allowed to warm to room temperature. The solvent was evaporated, water was added and the resulting solid was filtered, washed with water and dried to give the title compound (13.62 g, 93%) as a yellow solid.

[0734] LRMS(m / z):259(M+1) + .

[0735] 1 H NMR (300MHz, CDCl 3 ( s, 1H).

[0736] b) 2-Chloro-N 4 -(tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine

[0737] Zinc bromide (2.37g, 10.5mmol) and 5% platinum on carbon (5.13g, 25.7mmol...

preparation example 3

[0745] 2-Chloro-9-(tetrahydro-2H-pyran-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7,9-dihydro-8H- Purin-8-one

[0746]

[0747] Sodium hydride (60% dispersion in mineral oil, 0.40 g, 10.0 mmol) was added portionwise to the stirred 2-chloro-9-(tetrahydro-2H-pyran- 4-yl)-7,9-dihydro-8H-purin-8-one (Preparation Example 2, 1.98g, 7.8mmol) in N,N'-dimethylformamide (30mL) solution. After 15 minutes, trimethylsilane (1.53 mL, 8.6 mmol) was added and the mixture was warmed to room temperature and stirred for 4 hours. The mixture was separated into an aqueous layer and an ethyl acetate layer, and the organic layer was washed with water and brine, dried (MgSO 4 ) and evaporate the solvent under reduced pressure. The residue was purified by flash chromatography (99:1 dichloromethane / methanol) to afford the title compound (2.94 g, 98%) as a pale yellow oily residue.

[0748] LRMS(m / z):385(M+1) + .

[0749] 1 H NMR (300MHz, CDCl 3 )δppm-0.20-0.08(m, 9H), 0.92(m, 2H), 1.73(m, 2H...

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Abstract

New heteroaryl imidazolone derivatives having the chemical structure of formula (I) disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Janus Kinases (JAK).

Description

Background technique [0001] Cytokines play a pivotal role in regulating many aspects of immunity and inflammation, which can range from the development and differentiation of immune cells to the suppression of immune responses. Type I and type II cytokine receptors lack intrinsic enzymatic activity to mediate signal transduction and, therefore, require association with tyrosine kinases for this purpose. The JAK family of kinases includes four distinct members, namely JAK1, JAK2, JAK3 and TYK2, which control signal transduction by binding type I and type II cytokine receptors (Murray PJ, (2007). The JAK-STAT signaling pathway: input and output integration. J Immunol, 178:2623). Each JAK kinase is selective for a particular cytokine receptor. In this regard, JAK-deficient cell lines and mice have demonstrated the following important roles for each JAK protein in the receptor pathway: JAK1 binds type II cytokine receptors (IFN and IL-10 families), which share the gp130 chain (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/522A61P29/00
CPCA61K31/785A61K31/59A61K38/13A61K39/3955A61K31/5377A61K31/58C07D519/00A61K38/215A61K31/137C07D487/04A61K31/439A61K31/277A61K31/522A61K31/4704A61P1/04A61P11/00A61P11/02A61P11/06A61P17/00A61P17/06A61P19/02A61P21/02A61P25/00A61P27/02A61P27/14A61P29/00A61P35/00A61P35/02A61P37/00A61P37/06A61P37/08A61P43/00C07D471/04C07D473/02
Inventor 保罗·罗伯特·伊斯威特雅各布·冈萨雷斯罗德里格斯埃莱安娜·戈麦斯·卡斯帝罗乔迪·巴赫塔纳
Owner ALMIRALL
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