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Pi3k inhibitor for treatment of respiratory disease

A respiratory and compound technology, applied in the field of PI3K inhibitors for the treatment of respiratory diseases, can solve problems such as protein stability changes, expression level interaction changes, inappropriate PI3Kδ activity, etc.

Inactive Publication Date: 2016-06-08
GLAXOSMITHKLINE INTPROP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such mutations may result in changes in the stability of the folded protein, changes in expression levels and / or changes in interactions with other proteins
Therefore, mutations in PI3Kδ may result in inappropriate PI3Kδ activity, which may be increased or decreased compared to the wild-type protein

Method used

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  • Pi3k inhibitor for treatment of respiratory disease
  • Pi3k inhibitor for treatment of respiratory disease
  • Pi3k inhibitor for treatment of respiratory disease

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preparation example Construction

[0086] Compound preparation

[0087] The compounds used in accordance with the present invention and their pharmaceutically acceptable salts can be prepared by a variety of methods including standard chemistry. For example, 6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazole- 2-yl)-1H-indazole, N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3 -Oxazol-2-yl)-1H-indazol-6-yl]-2-(methoxy)-3-pyridyl]methylsulfonamide and their pharmaceutically acceptable salts can be as described in WO2010 / 125082 , as described in WO2012 / 055846 and / or WO2012 / 032067.

[0088] Instructions

[0089] The treatment method of the present invention comprises administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need.

[0090] The invention provides for treating or preventing respiratory infection, treating airway damage and / or preventing airway damage in a patient with a PI3Kδ mutation. ...

Embodiment 1

[0345] 6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazole-2- Base) -1H- Indazole hydrochloride for the treatment of Streptococcus pneumoniae

[0346] Germ-free C57BL / 6 male and female mice aged 10-12 weeks were intranasally administered 0.2% Tween-80 / saline vehicle or 0.2 mg / kg micronized 6-(1H- Indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1H- Indazole hydrochloride. Compound administration was performed twice daily for 11 days under anesthesia (induction with 3% isoflurane and maintenance with 2% isoflurane). Initially on day 2 and following administration of 6-(1H-indol-4-yl)-4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}- One hour after 1,3-oxazol-2-yl)-1H-indazole hydrochloride or vehicle, mice were anesthetized using isoflurane as above and dosed with 1×10 7 CFU of S. pneumoniae strain TIGR4 were infected intranasally. S. pneumoniae was obtained and prepared as previously described (see, eg, Infect. Immun. ...

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Abstract

The present invention is directed to compounds and pharmaceutically acceptable salts thereof which are inhibitors of the activity or function of the phosphoinositide 3'OH kinase family (hereinafter PI3K) for use in the treatment or prevention of respiratory infections, the treatment of airway damage, and / or the prevention of airway injury in patients with a PI3K Delta mutation.

Description

field of invention [0001] The present invention relates to compounds and pharmaceutically acceptable salts thereof as inhibitors of the activity or function of the phosphoinositide 3'OH kinase family (hereinafter PI3K), in particular PI3Kδ, for use in patients with PI3Kδ mutations Treat or prevent respiratory infections, treat airway damage, and / or prevent airway damage. Background of the invention [0002] The class I PI3 kinase family includes 4 separate isoforms (α, β, γ, and δ) that are distinguished by the sequence and structure of the p110 catalytic subunit. Several different genetic variants of PI3Kδ have been observed (Jou et al., International Journal of Immunogenetics, 2006, 33, 361 to 369; Angulo et al., Science DOI: 10.1126 / science.1243292; Lucas et al., Nature Immunology DOI: 10.1038 / ni.2271; Crank et al. , J. Clin. Immunol., DOI 10.1007 / s10875-014-0012-9; and Deau et al., J. Clin. Invest., DOI: 10.1172 / JCI75746). Some genetic variants may cause silent nucleot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/497A61K31/553A61P11/00
CPCA61K31/497A61K31/553A61P11/00A61P31/00A61P43/00C07D231/56C07D413/14A61K31/496A61K31/5377C12Q1/485G01N2333/91215G01N2800/52
Inventor A.阿莫尔J.N.汉布林E.赫塞尔D.米夏洛维奇S.斯里斯坎塔拉雅
Owner GLAXOSMITHKLINE INTPROP
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