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Indolinone derivatives serving as tyrosine kinase inhibitors

A technology of amino compounds, applied in the field of indolinone derivatives as tyrosine kinase inhibitors

Active Publication Date: 2013-06-05
KBP BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Currently, there are no inhibitors that simultaneously act on FGFR, VEGFR and PDGFR tyrosine kinases on the market for the treatment of tumors and pulmonary fibrosis

Method used

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  • Indolinone derivatives serving as tyrosine kinase inhibitors
  • Indolinone derivatives serving as tyrosine kinase inhibitors
  • Indolinone derivatives serving as tyrosine kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0167] The preparation of step 1 intermediate 1

[0168] Dissolve raw material 1 and organic base in DCM, add raw material 2 dropwise under ice-water bath, raise to room temperature and react for half an hour, add water, extract with DCM, dry, evaporate to dryness, and dry the solid in vacuo to obtain intermediate 1.

[0169] Step 2 Preparation of Intermediate 2

[0170] Dissolve intermediate 1 and organic base in DCM, add raw material 3 dropwise, react at room temperature for 12 h, extract with DCM (dichloromethane), dry the organic layer with anhydrous sodium sulfate, and evaporate to dryness to obtain intermediate 2.

[0171] Step 3 Preparation of Intermediate 3

[0172] Dissolve intermediate 2 in DCM, add TFA, after the reaction at room temperature, concentrate to obtain intermediate 3 or dissolve intermediate 2 in methanol, hydrogenate Pd / C overnight, filter, and concentrate to obtain intermediate 3, the product It was directly used in the next reaction without purifica...

Embodiment 1

[0247] Example 1 (Z)-N-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-6-yl)-N-(4-((2-oxo- 6-(1H-pyrazol-5-yl) Preparation of Indolin-3-ylmethylene)(phenyl)methylamino)phenyl)acetamide

[0248]

[0249] (1) Preparation of 2-chloro-N-methyl-N-(4-nitrophenyl)acetamide

[0250]

[0251] N-Methyl-4-nitroaniline (7.6g, 50mmol) and triethylamine (5.5g, 54mmol) were dissolved in 200mL DCM, and chloroacetyl chloride (11.5g, 50mmol) was added dropwise under ice-water bath, rising to React at room temperature for half an hour, add 30 mL of water, extract DCM, dry, evaporate to dryness, and dry the solid in vacuum to obtain 9.69 g of 2-chloro-N-methyl-N-(4-nitrophenyl)acetamide, with a yield of 85% .

[0252] (2) Preparation of N-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-6-yl)-N-(4-nitrophenyl)acetamide

[0253]

[0254] 2-Chloro-N-methyl-N-(4-nitrophenyl)acetamide (4.56g, 20mmol) and triethylamine (2.42g, 24mmol) were dissolved in 50mL DCM, and 3-methyl -3-Azabicyclo[3....

Embodiment 2

[0286] Example 2 (Z)-N-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-6-yl)-N-(4-((2-oxo- 6-(thiazol-2-yl)indole Preparation of Indoline-3-ylmethylene)(phenyl)methylamino)phenyl)acetamide

[0287]

[0288] (1) (Z)-N-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-6-yl)-N-(4-((2-oxo- 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-3-ylmethylene)(phenyl)methylamino)phenyl)-acetamide

[0289]

[0290] (Z)-N-(4-((6-bromo-2-oxoindolin-3-ylmethylene)(phenyl)methylamino)phenyl)-N-methyl-2 -(3-Methyl-3-azabicyclo[3.1.0]hexan-6-yl)acetamide (11.1g, 20mmol) was dissolved in 120mL of dioxane, and bis-pinacol borate was added (7.38g, 29mmol), potassium acetate (2.45g, 25mmol) and Pd(Ph 3 P) 2 Cl 2 (0.7 g, 0.1 mmol). Heat to 90°C overnight. Add water and extract with ethyl acetate, dry, concentrate and separate through silica gel column to obtain (Z)-N-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-6-yl) -N-(4-((2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-3-ylmethylene)(benzene B...

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Abstract

The invention belongs to the technical field of medicine, and particularly relates to indolinone derivatives of general formula (I), deuterium of the derivatives, pharmaceutically acceptable salts of the derivatives or stereoisomer of the derivatives, wherein the indolinone derivatives serve as tyrosine kinase inhibitors, and R1, R2, R3, R4, R5, R6, R7, R8, R9, n, X and cycle A are defined as in the description. The invention further relates to preparation methods of the compounds, a pharmaceutical preparation comprising the compounds, and applications of the compounds, wherein the applications of the compounds include prevention or treatment of fibrosis diseases, treatment of excessive hyperplasia diseases, especially breast cancer, colorectal cancer and non-small cell lung cancer, anti-angiogenesis and / or reduction of vascular permeability.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to indolinone derivatives as tyrosine kinase inhibitors, deuterated products thereof, pharmaceutically acceptable salts thereof or stereoisomers thereof, and methods for preparing these compounds, including these Pharmaceutical preparations and pharmaceutical compositions of compounds, their deuterated substances, their pharmaceutically acceptable salts or their stereoisomers, and the preparation of these compounds, their deuterated substances, their pharmaceutically acceptable salts or their stereoisomers Use in the prevention or treatment of fibrotic diseases and in the treatment of hyperproliferative diseases, especially breast cancer, colorectal cancer, non-small cell lung cancer, anti-angiogenesis and / or reduction of vascular permeability. . 2. Background technology [0002] Angiogenesis is the generation of new blood vessels in tissues or organs. Under normal ...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D417/14C07D487/10C07D413/14C07D405/14A61K31/4045A61K31/415A61K31/422A61K31/439A61K31/427A61K31/4178A61K45/00A61P11/00A61P19/02A61P1/16A61P13/12A61P17/00A61P17/02A61P35/00A61P13/08
Inventor 王爱臣张倩
Owner KBP BIOSCIENCES CO LTD
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