Imidazopyridine derivatives as JAK inhibitors

A technology of solvates and compounds, applied in the field of imidazopyridine derivatives as JAK inhibitors, can solve problems such as disorders

Inactive Publication Date: 2012-09-26
ALMIRALL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, Grossman et al. (1999. Dysregulated myelopoiesis in mice lacking JAK3. Blood, 94:932:939) have shown th

Method used

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  • Imidazopyridine derivatives as JAK inhibitors
  • Imidazopyridine derivatives as JAK inhibitors
  • Imidazopyridine derivatives as JAK inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1717] 3-(4-{[(1S)-1-phenylethyl]amino}pyrimidin-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile

[1718]

[1719] From 3-(4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile (Preparation 4b, 0.175 g, 0.74 mmol) following the experimental procedure as described in Preparation 5a And (S)-1-phenyl-ethylamine (0.48 mL, 3.68 mmol) gave a yellow solid (0.102 g, 40%). The solvent was removed in vacuo and analyzed by reverse phase chromatography (C-18 silica from Waters, water / 1:1 acetonitrile-methanol as eluent [buffered with 0.1% v / v formic acid] 0% to 100%) to give the title compound (0.102 g, 40%) as a yellow solid.

[1720] LRMS(m / z):341(M+1) + .

[1721] 1 H-NMRδ(DMSO-d 6 ):1.53(d,3H),5.28(bs,1H),6.52(bs,1H),7.22(d,1H),7.36(d,2H),7.48(d,2H),7.67(d,1H) , 7.87 (d, 1H), 8.19 (d, 1H), 8.26 (bs, 1H), 8.42 (bs, 1H), 10.27 (bs, 1H).

Embodiment 2

[1723] 3-(4-{[(1R)-1-phenylethyl]amino}pyrimidin-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile

[1724]

[1725] Following the experimental procedure as described in Preparation 5a, from 3-(4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile (Preparation 4b) and (R)-1- Phenyl-ethylamine was obtained as a white solid (70%). After completion of the reaction, the mixture was partitioned between water and dichloromethane. The organic layer was washed with water, brine, and dried (MgSO 4 ) and evaporated, the residue was purified by flash chromatography (dichloromethane / methanol 98:2 to 96:4).

[1726] LRMS(m / z):341(M+1) + .

[1727] 1 H-NMRδ(DMSO-d 6 ):1.52(d,3H),5.30(bs,1H),6.52(d,1H),7.22(d,1H),7.34(t,2H),7.48(d,2H),7.68(d,1H) ,7.88(d,1H),8.19(d,1H),8.24(d,1H),8.43(s,1H),10.28(bs,1H)

Embodiment 3

[1729] 3-[4-(Benzylamino)pyrimidin-2-yl]imidazo[1,2-a]pyridine-6-carbonitrile

[1730]

[1731] Following the experimental procedure as described in Preparation 5a, yellow color was obtained from 3-(4-hydroxypyrimidin-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile (Preparation 4b) and phenylmethylamine Solids (60%). Reaction crude material was purified by reverse phase chromatography (C-18 silica from Waters, water / 1:1 acetonitrile-methanol as eluent [buffered with 0.1% v / v formic acid] 0% to 100%) After that, the desired compound is obtained.

[1732] LRMS(m / z):327(M+1) + .

[1733] 1 H-NMRδ(DMSO-d 6 ):5.76(bs,2H),6.61(bs,1H),7.25-7.4(m,5H),7.68(d,1H),7.89(d,1H),8.17-8.36(m,2H),8.48( s,1H),10.37(bs,1H)

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Abstract

New imidazopyridine derivatives having the chemical structure of formula (I) are 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 have important functions in regulating many aspects of immunity and inflammation, ranging 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 capable of mediating signal transduction and therefore require binding to tyrosine kinases for this purpose. The JAK kinase family includes four distinct members, JAK1, JAK2, JAK3, and TYK2, which bind to type I and type II cytokine receptors to control signal transduction (Murray PJ, (2007). The JAK-STAT signaling pathway: input and output integration. J Immunol, 178:2623). Each JAK kinase is selective for receptors for certain cytokines. In this regard, JAK-deficient cell lines and mice have demonstrated an important role for each JAK protein in receptor signaling: JAK1 is in the type II cytokine receptors (IFN and IL-10 families), these receptors Body-shared gp130 chain (IL-6 fam...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437
CPCA61K31/437A61K31/551A61K31/513A61K31/506C07D471/04A61K31/5377A61K31/497A61K31/517A61K45/06A61P1/04A61P11/00A61P11/02A61P11/06A61P17/00A61P17/04A61P17/06A61P19/00A61P25/00A61P27/02A61P27/14A61P29/00A61P35/00A61P35/02A61P35/04A61P37/00A61P37/06A61P37/08A61P43/00A61P7/00
Inventor 保罗·罗伯特·伊斯威特雅各布·冈萨雷斯罗德里格斯乔迪·巴赫塔纳路易·米克尔·佩吉斯圣卡娜琼·塔尔塔伍利莫尔胡安·弗朗西斯科·卡图尔拉哈瓦洛耶斯维克托·朱利奥·马塔萨
Owner ALMIRALL
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