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Use of inhibitors of the activity or function of PI3K

一种抑制剂、抑制作用的技术，应用在有机活性成分、含有效成分的医用配制品、抵抗媒介传播的疾病等方向，能够解决有毒性、药昂贵等问题

Active Publication Date: 2014-08-20
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The antifungal amphotericin b has been suggested as a second-line agent but is expensive and relatively more toxic

Method used

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  • Use of inhibitors of the activity or function of PI3K
  • Use of inhibitors of the activity or function of PI3K
  • Use of inhibitors of the activity or function of PI3K

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0733] As long as the preparation of the starting materials is not particularly described, the compounds are known or can be prepared by methods known in the art or similarly as described below.

[0734] The following examples illustrate the invention without any limitation.

[0735] abbreviation:

[0736] Ar Aryl

[0737] AcOH acetic acid

[0738] aq containing water

[0739] Ar Aryl

[0740] BOC tert-butyl-carbonate

[0741] BOP Benzotriazol-1-yloxytris(dimethylamino)phosphorus hexafluorophosphate

[0742] br.s. Broad unimodal

[0743] BSA bovine serum albumin

[0744] CDCl 3 Chloroform-d

[0745] CDI 1,1'-Carbonyldiimidazole

[0746] CH 2 Cl 2 Dichloromethane

[0747] CH 3 CN acetonitrile

[0748] Cs 2 CO 3 cesium carbonate

[0749] d doublet

[0750] dd double doublet

[0751] DIPEA N-Ethyldiisopropylamine

[0752] DME 1,4-Dimethoxyethane

[0753] DMF N,N-Dimethylformamide

[0754] DBU 1,8-diaza-7-bicyclo[5.4.0]und...

Embodiment 1

[1029] Example 1: {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3 -d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone

[1030] Synthesis of Example 1 - Method 1a (according to Scheme 8)

[1031] Sodium hydride (60% dispersion in oil, 17.88 mg, 0.447 mmol) was added to a solution of intermediate 3 (75 mg, 0.378 mmol) in 2 mL of dry THF under argon. The suspension was stirred at ambient temperature for 15 min under an atmosphere of argon. Add 4-chloro-6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (100 mg, 0.344 mmol) and stirred at room temperature for another 3 hours. The reaction mixture was washed with H 2 O quenched with CH 2 Cl 2 extraction. The organic layer was washed with brine, washed with Na 2 SO 4 Dry, filter and evaporate to dryness. By silica gel flash chromatography (CH 2 Cl 2 / MeOH95 / 5) to obtain {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7, 8-tetrahydro-pyrido[4,3-...

Embodiment 10

[1090] Example 10: (2,4-Dimethyl- Azol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[ 4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone

[1091] step 1

[1092] 2,4-Dimethyl- A mixture of azole-5-carboxylic acid (36.4 mg, 0.258 mmol), HTBU (98 mg, 0.258 mmol), DIPEA (86 μl, 0.49 mmol) in DMF (5 mL) was stirred at room temperature for 20 min, then 6-(6-methoxy Base-5-methyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d ] Pyrimidine (prepared in Example 1 Method 1b Step 2) (80 mg, 0.23 mmol) and DIPEA (86 μl, 0.49 mmol) in DMF (0.4 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was directly purified by preparative reverse-phase Gilson HPLC followed by PL-HCO 3 MP neutralized the pooled fractions to give (2,4-dimethyl- Azol-5-yl)-{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[ 4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-methanone (91 mg, 84% yie...

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Abstract

The invention relates to new uses of PI3K inhibitors, wherein said inhibitors have an inhibitory action on the PI3K isoform delta for the treatment of immunopathology in a subject suffering from a disease or disorder selected from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and / or neurocysticercosis, via functional inhibition of TLR9 of the infected subject.

Description

field of invention [0001] The present invention relates to the novel application of the inhibitor of the activity or function of phosphoinositide 3'OH kinase family (hereinafter referred to as PI3K inhibitor) and / or its pharmaceutically acceptable salt and / or solvate, wherein said inhibitor is to The PI3K isoform delta is inhibitory. The present invention also relates to novel applications of tetrahydro-pyrido-pyrimidine derivatives as drug candidates in free form or in pharmaceutically acceptable salt form, which possess valuable drug-like properties such as metabolic stability and favorable pharmacokinetics PI3K isoform δ activity or function is inhibited. Background of the invention [0002] Parasitic infections remain one of the most important causes of morbidity and mortality worldwide. Among the parasites that cause disease in humans and animals, the phylum apicomplexa includes a group of vector-borne parasites that cause a wide variety of serious diseases including,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/517A61K31/519A61P33/00
CPCC07D239/74C07D413/14C07D487/08C07D403/04A61K31/551A61K31/517C07D401/04C07D401/14A61K31/519A61K31/5377A61K31/541A61P33/00A61P33/02A61P33/06A61P33/10A61P43/00Y02A50/30
Inventor N·G·库克P·A·费尔南德斯戈麦斯多斯桑托斯P·菲雷C·黑巴赫K·赫根诺伊尔G·霍林沃思C·凯利斯I·刘易斯A·B·史密斯N·索德尔曼F·施陶费尔R·斯特朗F·施托瓦塞尔N·图菲利A·冯马特R·沃尔夫F·泽克里
Owner NOVARTIS AG