Tyrosine kinase inhibitor indolinone derivative

A technology of amino and compound, applied in the field of tyrosine kinase inhibitor indolinone derivatives

Active Publication Date: 2013-05-15
KBP BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] 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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  • Tyrosine kinase inhibitor indolinone derivative
  • Tyrosine kinase inhibitor indolinone derivative
  • Tyrosine kinase inhibitor indolinone derivative

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0157] The preparation of step 1 intermediate 1

[0158] 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.

[0159] Step 2 Preparation of Intermediate 2

[0160] Dissolve intermediate 1 and organic base in DCM, add raw material 3 dropwise, react at room temperature for 12 h, extract with DCM, dry the organic layer with anhydrous sodium sulfate, and evaporate to dryness to obtain intermediate 2.

[0161] Step 3 Preparation of Intermediate 3

[0162] 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 purification.

[0163] Pr...

Embodiment 1

[0223] Example 1 (Z)-3-((4-(N-methyl-2-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)acetamido)anilino ) (phenyl) sub Preparation of methyl)-2-oxoindoline-6-carboxylate (compound 1)

[0224]

[0225] (1) 6-(2-(methyl(4-nitrophenyl)amino)-2-oxoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert Preparation of butyl ester

[0226]

[0227] Dissolve 2-chloro-Nmethyl-N-(4-nitrophenyl)acetamide (2.28g, 10mmol) and sodium bicarbonate (8.4g, 100mmol) in 60mL THF, add bis(2, 6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl) oxalate (2.43g, 5mmol), the reaction solution was heated to 65°C for 24h. The reaction solution was added with water, extracted with dichloromethane, dried, concentrated and separated by silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain 1.2 g of the product with a yield of 30.7%.

[0228] (2) Preparation of N-methyl-N-(4-nitrophenyl)-2-(2,6-diazaspiro[3.3]heptane-2 base)acetamide

[0229]

[0230] tert-butyl 6-(2-(methyl(4-nitrop...

Embodiment 2

[0242] Example 2 (Z)-3-((4-(N-methyl-2-(3-azabicyclo[3.1.0]hexane-6-yl)acetamido)anilino)(phenyl)phenylene First base)-2-oxoindoline-6-carboxylate methyl ester (compound 2)

[0243]

[0244] (1) Preparation of N-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-6-yl)-N-(4-nitrophenyl)acetamide

[0245]

[0246] Dissolve 2-(3-methyl-3-azabicyclo[3.1.0]hexan-6-ylacetic acid (1.0 g, 6.4 mmol) in 30 mL of DCM, add thionyl chloride (5 mL, 64 mmol), and heat After refluxing for 5h, pull it dry, redissolve it in 40mL of dichloromethane, add triethylamine (5mL, 32mL) and N-methyl-4nitrobenzene (3g, 20mmol).React overnight at room temperature, evaporate the solvent to dryness, The remaining solid was separated by silica gel column (dichloromethane:methanol=30:1) to obtain 1.5g of the product with a yield of 80.6%.

[0247] (2) Preparation of N-(4-aminophenyl)-N-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexane-6-yl)acetamide

[0248]

[0249] The method is the same as in Example ...

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Abstract

The invention belongs to the technical field of medicine, and in particular relates to a tyrosine kinase inhibitor indolinone derivative as shown in formula (I), as well as a deuterium substituent, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, n and ring A are defined as in the specification. The invention further relates to a preparation method of the compounds, a pharmaceutic preparation containing the compounds as well as an application of the compounds for preparing medicines for preventing or treating fibrotic diseases and hyperplasias, in particular to breast cancer, colorectal cancer, non small cell lung cancer, anti-angiogenesis and/or reducing vascular permeability.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a tyrosine kinase inhibitor indolinone derivative, a deuterated substance thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a preparation method of these compounds, and a compound containing these compounds Pharmaceutical preparations, and the application of these compounds in preventing or treating fibrotic diseases and treating hyperproliferative diseases, especially breast cancer, colorectal cancer, non-small cell lung cancer, anti-angiogenesis and / or reducing vascular permeability. 2. Background technology [0002] Angiogenesis is the generation of new blood vessels in tissues or organs. Under normal physiological conditions, humans and animals only undergo angiogenesis under very specific and limited circumstances. For example, angiogenesis is commonly observed in wound healing, fetal and embryonic development, and formation of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/10C07D209/52C07D487/08C07D403/12C07D471/10C07D401/12C07D209/34C07D403/14C07D401/14C07D491/107A61K31/404A61K31/4995A61K31/407A61K31/438A61K31/435A61K31/439A61K31/4439A61K31/506A61P43/00A61P11/00A61P11/06A61P19/02A61P1/16A61P39/00A61P13/12A61P17/00A61P35/00A61P13/08
Inventor 王爱臣张倩
Owner KBP BIOSCIENCES CO LTD
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