Heterocyclic compound as protein kinase inhibitor and preparation method and application thereof

A compound and solvate technology, applied in the field of heterocyclic compounds as protein kinase inhibitors and their preparation and application, can solve the problems of uncontrolled cell growth, loss of cell growth, cancer, etc.

Active Publication Date: 2016-03-09
SHANGHAI KECHOW PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In proliferative diseases, genetic mutations or overexpression of growth factor receptors or their downstream protein kinases lead to uncontrolled cell growth, eventually leading to cancer
For example, in some cancers, due to gene mutation, the signal transduction mechanism is continuously activated, which leads to the continuous production of some growth factors, and finally leads to the loss of control of cell growth, thus cancerous

Method used

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  • Heterocyclic compound as protein kinase inhibitor and preparation method and application thereof
  • Heterocyclic compound as protein kinase inhibitor and preparation method and application thereof
  • Heterocyclic compound as protein kinase inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] Example 1.5-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-8-((3-oxomorpholine)methyl)imidazo[1,5-a ] Synthesis of pyridine-6-carboxamide:

[0148]

[0149] Step 1: Synthesis of 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one

[0150]

[0151] The title compound was prepared according to European Journal of Organic Chemistry; nb, 30; (2007); p.4995-4998. l H-NMR (400MHz, DMSO-d 6 )δ2.30(s,3H).

[0152] Step 2: Synthesis of ethyl 2,6-dichloro-5-methylnicotinate

[0153]

[0154] The title compound was prepared according to synthesis; nb, 9; (1991); p.765-768.

[0155] Step 3: Synthesis of ethyl 6-chloro-2-(2-fluoro-4-iodophenylamino)-5-methylnicotinate

[0156]

[0157]The compound 2-fluoro-4-iodoaniline (12.15g, 51.26mmol) was added to the reaction flask, anhydrous THF (50ml) was added, and after cooling to -78°C under a nitrogen atmosphere, LiHMDS was added dropwise to the reaction solution (1M, 128.5ml, 128.5mmol), after reacting at -78°C for 30 minutes,...

Embodiment 2

[0184] Example 2: N-(2,3-hydroxypropoxy)-5-(2-fluoro-4-iodophenylamino)-8-((3-oxomorpholine)methyl)imidazo[1 ,5-a]Synthesis of pyridine-6-carboxamide

[0185]

[0186] Step 1: Ethyl 5-(2-fluoro-4-iodophenylamino)-8-((3-oxomorpholine)methyl)imidazo[1,5-a]pyridine-6-carboxylate synthesis

[0187]

[0188] The compound 5-(2-fluoro-4-iodophenylamino)-8-((4-(methylamino)-4-oxobutoxyamino)methyl)imidazo[1,5-a] Add ethyl pyridine-6-carboxylate (500mg, 0.88mmol) into the reaction flask, add 1,2-dichloroethane (10ml), heat to 60°C and react for 10 hours, after the reaction is completed, cool to room temperature, Concentrate and separate the product by column chromatography. (400mg, yield: 84.6%). [M+H] + =539.3

[0189] Step 2: N-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-5-(2-fluoro-4-iodophenylamino)-8- Synthesis of ((3-oxomorpholine)methyl)imidazo[1,5-a]pyridine-6-carboxamide:

[0190]

[0191]Compound O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (41mg, 0....

Embodiment 3

[0195] Example 3: N-(cyclopropylmethyloxy)-5-(2-fluoro-4-iodophenylamino)-8-((3-oxomorpholine)methyl)imidazo[1,5- a] the synthesis of pyridine-6-carboxamide:

[0196]

[0197] Compound O-(cyclopropylmethyl)hydroxylamine (12mg, 0.14mmol) was added to the reaction flask, anhydrous THF (1ml) was added, and after cooling to -78°C under a nitrogen atmosphere, LiHMDS was added dropwise to the reaction solution (1M, 0.27ml, 0.27mmol), after reacting at -78°C for 30 minutes, add the compound 5-(2-fluoro-4-iodophenylamino)-8-((3-oxomorpholine)methyl) Ethyl imidazo[1,5-a]pyridine-6-carboxylate (50mg, 0.09mmol), after the addition, the dry ice was removed, and the reaction was continued for 3 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the product. (50 mg, yield: 55%). 1 HNMR (400MHz, CD 3 OD) 1 ...

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Abstract

The invention relates to a compound of formulas (I) and (II) and a pharmaceutically acceptable salt, prodrug and solvate thereof, wherein R1, R2, R3, A and X are as defined in the specification. The compound is a protein kinase inhibitor, particularly the protein kinase inhibitor Mek inhibitor, and can be used for treating cancers and inflammation in mammals. The invention further discloses a preparation method of the compound of formulas (I) and (II) and a medicine composition containing the compound.

Description

technical field [0001] The present invention relates to protein kinase (especially protein kinase Mek) inhibitors, more specifically, to imidazopyridine compounds as protein kinase (especially protein kinase Mek) inhibitors and pharmaceutically acceptable salts, prodrugs, Solvates, and compositions comprising these substances, and relate to the preparation method of said imidazopyridine compounds, also relate to said imidazopyridine derivatives and pharmaceutically acceptable salts, prodrugs and solvates thereof as protein kinases ( In particular the use of protein kinase Mek) inhibitors. Background technique [0002] Cellular signal transduction controlled by growth factors and protein kinases plays an important role in cell growth, proliferation and differentiation. In the growth of normal cells, growth factors (such as PDGF or EGF, etc.) activate the MAP (Mitogen-activatingprotein) kinase signal transduction channel through receptor activation (such as ErbB2, EGFR, PDGFR...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/5355A61K31/4545A61K31/437A61P35/00A61P29/00A61P1/00A61P17/00A61P3/10A61P27/02
CPCC07D471/04
Inventor 田红旗黄功超
Owner SHANGHAI KECHOW PHARMA
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