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

A technology of compounds and solvates, applied in the field of protein kinase inhibitors, can solve the problems of uncontrolled cell growth, loss of cell growth, cancer, etc.

Inactive Publication Date: 2018-08-03
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 serving as protein kinase inhibitor as well as preparation method and application thereof
  • Heterocyclic compound serving as protein kinase inhibitor as well as preparation method and application thereof
  • Heterocyclic compound serving as protein kinase inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0131] Example 2: 5-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-9-methylfuro[3,2-c]imidazo[1,5- a] pyridine-6-carboxamide

[0132]

[0133] Step 1: Synthesis of ethyl 2-(2-ethoxy-2-oxoethyl)-4-methylfuran-3-carboxylate

[0134]

[0135] The title compound was prepared according to J. Am. Chem. Soc, 1985, 107, 2196-2198... l H-NMR (400MHz, CDCl 3 )δ7.13(s,1H),4.28(q,J=7.2Hz,2H),4.18(q,J=6.8Hz,2H),4.01(s,2H),2.17(s,3H),1.34( t,J=6.8Hz,3H),1.26 (t,J=7.2Hz,3H).

[0136] Step 2: 6-(2-Fluoro-4-iodophenylamino)-3-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridine-7-carboxylic acid ethyl Synthesis of esters

[0137]

[0138] Ethyl 2-(2-ethoxy-2-oxoethyl)-4-methylfuran-3-carboxylate (6.0g, 24.97mmol 1.0eq) in anhydrous THF (50ml ) to the stirred solution was added NaH (1.1 g, 27.47 mmol 1.1 eq..60%) in portions. Then, 2-fluoro-N-(iminomethylene)-4-iodoaniline (7.2 g, 27.47 mmol 1.1 eq.) was added slowly over 1 hour using a dropping funnel, and then the mixture was stirred...

Embodiment 3

[0163] Example 3: 5-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)imidazo[1,5-a]thieno[3,2-c]pyridine-6 -Formamide

[0164]

[0165] Step 1: Synthesis of methyl 2-(2-methoxy-2-oxoethyl)thiophene-3-carboxylate

[0166]

[0167] The title compound was prepared according to WO 2005087779. lH NMR (400MHz, DMSO-D6). δ7.46 (d, J = 5.6Hz, 1H), 7.36 (d, J = 5.6Hz, 1H), 4.21 (s, 2H), 3.73 (s, 3H), 3.61 (s, 3H).

[0168] Step 2: Synthesis of methyl 6-(2-fluoro-4-iodophenylamino)-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxylate

[0169]

[0170] Into a stirred solution of methyl 2-(2-methoxy-2-oxoethyl)thiophene-3-carboxylate (5.0 g, 23.34 mmol 1.0 eq) in anhydrous THF (50 mL) at 0°C NaH (1.03g, 25.67mmol 1.1eq..60%) was added in batches. Then, 2-fluoro-N-(iminomethylene)-4-iodoaniline (6.73 g, 25.67 mmol 1.1 eq.) was added slowly over 1 hour using a dropping funnel, and then the mixture was stirred at room temperature overnight. After adding water and ethyl acetate,...

Embodiment 4

[0195] Example 4: 5-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)imidazo[1,5-a]thiazolo[4,5-c]pyridine-4 -Formamide

[0196]

[0197] Step 1: Synthesis of methyl 5-(2-methoxy-2-oxoethyl)thiazole-4-carboxylate

[0198]

[0199] The title compound was prepared according to Bioorganic & Medicinal Chemistry Letters, 2008, 18(6), 2206-2210... 1H NMR (400MHz, CDC13): δ8.75(s, 1H), 4.38(s, 2H), 3.96(s, 3H), 3.78(s, 3H).

[0200] Step 2: Synthesis of methyl 6-(2-2-fluoro-4-iodophenylamino)-4-oxo-4,5-dihydrothiazolo[4,5-c]pyridine-7-carboxylate

[0201]

[0202] To a stirred solution of methyl 5-(2-methoxy-2-oxoethyl)thiazole-4-carboxylate (5.0 g, 23.23 mmol 1.0 eq) in anhydrous THF (50 mL) at 0°C NaH (1.02 g, 25.55 mmol 1.1 eq..60%) was added in portions. Then, 2-fluoro-N-(iminomethylene)-4-iodoaniline (6.70 g, 25.55 mmol 1.1 eq.) was added slowly over 1 hour using a dropping funnel, and then the mixture was stirred at room temperature overnight. After adding water an...

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Abstract

The invention relates to a compound shown as a formula (I) and a formula (II) and a pharmaceutically-acceptable salt and prodrug thereof. The formula (I) and the formula (II) are shown in the description, wherein R1, R2, R3, R4, R5, R6, X, Y, Z and W are as defined in the description. The compound is a protein kinase inhibitor, particularly a protein kinase inhibitor Mek inhibitor, and can be usedfor treating cancers and inflammation in mammals. The invention further discloses a method for treating diseases such as cancers and inflammation in the mammals by using the compound, and a medicinalcomposition including the compound. The invention relates to a preparation process of a benzo-heterocycle compound. The invention mainly relates to preparation of a compound capable of being made into a medicament, such as a pyridino-heterocyclic derivative. The formula (I) and the formula (II) are shown in the description.

Description

technical field [0001] The present invention relates to protein kinase (especially protein kinase Mek) inhibitors, more specifically, to benzoheterocyclic compounds as protein kinase (especially protein kinase Mek) inhibitors and their prodrugs, solvates, and compounds comprising these Composition of matter, and relates to the preparation method of said benzoheterocyclic compound, and also relates to the use of said benzoheterocyclic derivative as protein kinase (especially protein kinase Mek) inhibitor. 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-activating protein) kinase signal transduction channel through receptor activation (such as ErbB2, EGFR, PDGFR, etc.). The Ras / Raf / Mek / Erk signaling mechanism is one of the most important pathway...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/147C07D495/14C07D498/14C07D513/14C07D471/14A61K31/437A61P1/00A61P35/00A61P17/00A61P3/10A61P27/02A61P29/00A61P25/04A61P9/10A61P19/02A61P17/06
Inventor 田红旗黄功超
Owner SHANGHAI KECHOW PHARMA