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N3-substituted imidazopyridine-derivatives as C-KIT inhibitors

A technology of -CO2R3, -NR3R31, applied in PDGFR-, FLT3, such as GIST, N3-substituted imidazopyridine compounds, hematopoietic R-PTK field

Inactive Publication Date: 2006-09-27
OSI PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Gleevec TM Inhibits KIT kinase and PDGF receptor kinase in addition to BCR-ABL kinase, but it is not effective against all mutant isoforms of KIT kinase

Method used

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  • N3-substituted imidazopyridine-derivatives as C-KIT inhibitors
  • N3-substituted imidazopyridine-derivatives as C-KIT inhibitors
  • N3-substituted imidazopyridine-derivatives as C-KIT inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment R1

[0136] 3-{4-[(4-(trifluoromethoxy)benzyl)oxy]phenyl}-N-(2-morpholin-4-ylethyl)-3H-imidazo[4,5-b ]pyridine-6-carboxamide

[0137] a) at N 2 In, 5-bromo-3-nitropyridin-2-ol (30.00 g, 0.137 mmol) and p-toluenesulfonyl chloride (30.03 g, 0.158 mmol) were suspended in CH 2 Cl 2 , the suspension was treated dropwise with triethylamine (38.2 mL, 0.274 mmol) before adding DMAP (3.35 g, 0.027 mmol). After stirring at room temperature for 16 h, CH 2 Cl 2 (500 mL) and then washed with 1M HCl(aq) (2 x 500 mL) and brine (500 mL). use CH 2 Cl 2 (200mL) back-extracted the aqueous layer, and the combined organic layer was washed with Na 2 SO 4Dry and concentrate in vacuo. The crude material thus isolated was chromatographed on silica gel eluting with 50% EtOAc / hexanes and evaporated to give a solid which was crystallized from 50% EtOAc / hexanes to give 5-bromo-3-nitropyridine- 2-yl-4-methylbenzenesulfonate. 1 H NMR (400MHz, CDCl 3 )δ2.51(s, 3H), 7.43(dd, 2H, J=8.4, 0.4Hz), 7.99(dt...

Embodiment R2

[0147] 3-{4-[(4-(trifluoromethoxy)benzyl)oxy]phenyl}-N-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine- 6-carboxamide. MS(ES+): m / z 487 [MH + ].

Embodiment R3

[0149] 3-{3-[(4-(Trifluoromethoxy)benzyl)oxy]phenyl}-N-(pyridin-3-ylmethyl)-3H-imidazo[4,5-b]pyridine- 6-carboxamide. MS(ES+): m / z 520 [MH + ].

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Abstract

Compounds represented by Formula (I): (I) or a pharmaceutically acceptable salt or N-oxide thereof, are useful in the treatment of cancer.

Description

Background of the invention [0001] The present invention relates to N3-substituted imidazopyridine compounds. In particular, the present invention relates to N3-substituted imidazopyridine compounds that are inhibitors of the c-kit proto-oncogene (also known as KIT, CD-117, stem cell factor receptor, mast cell growth factor receptor). [0002] The c-kit proto-oncogene is believed to be important in the pathogenesis of embryogenesis, melanogenesis, hematopoiesis, and mastocytosis, gastrointestinal and other solid tumors, and certain leukemias, including AML. Therefore, it is desirable to develop novel compounds that are c-kit receptor inhibitors. [0003] Many current regimens for the treatment of hyperproliferative diseases (cancer) utilize compounds that inhibit DNA synthesis. The mechanism of action of these compounds is that they are toxic to cells, especially rapidly dividing tumor cells. Therefore, their widespread toxicity is a problem for recipient patients. However...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/435A61P35/00C07D233/00C07D221/00
CPCC07D471/04A61P1/00A61P1/18A61P11/00A61P11/02A61P13/08A61P15/00A61P17/00A61P21/00A61P35/00A61P35/02A61P7/00A61K31/435
Inventor 阿林多·L·卡斯特利亚诺安德鲁·菲利普·克鲁董汉清拉多斯劳·洛费尔李安虎裘力科林·皮特·桑布鲁克史密斯张涛
Owner OSI PHARMA INC