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Aurora kinase modulators and method of use

A solvate, stereoisomeric technology for compounds and compositions that modulate Aurora kinases, control cell proliferation and treat cancer

Active Publication Date: 2009-04-08
AMGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, of the available cancer treatments and therapies to date, very few have been able to provide any degree of success worth considering

Method used

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  • Aurora kinase modulators and method of use
  • Aurora kinase modulators and method of use
  • Aurora kinase modulators and method of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0366]

[0367] Synthesis of 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine

[0368] Preparation of step 1.2-chloro-nicotinamide

[0369] 2-Chloro-3-cyanopyridine (5.0 g, 36 mmol) was dissolved in anhydrous EtOH (100 mL) at 0 °C. HCl was bubbled through the mixture for 3 h, the mixture was sealed and centrifuged (ca. 8° C.) overnight. After concentration, the residue was stirred with ammonium acetate (5.5 g) in 100 mL of IpOH. After 12h, with concentrated NH 4 OH solution, adjust the pH to 9 (from 4), and continue stirring for 2 more days. The mixture was concentrated and subjected to flash chromatography (10:1:0.1 CH 2 Cl 2 / MeOH / NH 4 OH) purification. Trituration in hot tBuOMe / IpOH removed some residual amide by-product to give the product as a white solid.

[0370] Step 2: Amino-(2-chloro-pyridin-3-yl)-methylcyanamide

[0371] 2-Chloro-nicotinamidine was suspended in 10 mL of IpOH with 500 mg of solid cyanamide, and the stirred solid was passed through t...

Embodiment 2

[0375]

[0376] Synthesis of [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-methyl-amino

[0377] To a solution of 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine (10.0 g, 44.0 mmol) in 55 ml of dichloromethane at 0°C was added methylamine (45ml, 88.0mmol) in 2.0M THF. After stirring at room temperature for 18 h, the mixture was diluted with acetone, filtered through a pad of silica gel, and concentrated to give the desired product. MS m / z=222[M+H] + . C 9 h 8 ClN 5 Calculated value: 221.65.

Embodiment 3

[0379]

[0380] Synthesis of 4-(2-chloro-pyridin-3-yl)-pyrimidine

[0381] Step 1. Preparation of 1-(2-chloro-pyridin-3-yl)-3-dimethylamino-propenone

[0382] In a drying tube at 85°C, 1-(2-chloro-pyridin-3-yl)-ethanone (21.7g, 139mmol) was dissolved in 46mL N,N-dimethylformamide dimethylacetal (42g, 350mmol ) for 1.5h, then concentrated. The residue was purified by suction filtration chromatography (using 150 g of silica gel in a Buchner funnel, rapidly collecting fractions with 10:1, then 5:1 CH 2 Cl 2 / IpOH) to give the product as a yellow solid. MS m / z=211[M+H] + . C 10 h 11 ClN 2 O calculated value: 210.66.

[0383] Step 2. Preparation of 4-(2-chloro-pyridin-3-yl)-pyrimidine

[0384] Using a 500mL IpOH bath at room temperature as a cold source, at room temperature, N 2 Next, by intermittently adding small pieces of sodium metal (8.3 g, 360 mmol in total) to 400 mL of anhydrous methanol, sodium methoxide was generated over 1.5 hours. Formamidine acetate ...

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Abstract

The present invention relates to chemical compounds having a general formula (I) wherein A1, A2, C1, C2, D, L1, L2, Z and R<1-8> are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of such kinases. For example, the compounds are capable of modulating Aurora kinase thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.

Description

[0001] This application claims the benefit of US Provisional Application No. 60 / 761,675, filed January 23, 2006, which is hereby incorporated by reference in its entirety. field of invention [0002] The present invention relates to the field of medicine, and more specifically, relates to compounds and compositions for regulating Aurora kinase, as well as uses and methods for controlling cell proliferation and treating cancer. Background of the invention [0003] Cancer is one of the most widespread diseases affecting humans and is a leading cause of human death worldwide. Numerous groups have devoted considerable time, effort and financial resources over the last two decades in an effort to find effective treatments or cures for one or more of the many different types of cancer. However, of the existing cancer treatments and therapies to date, very few have been able to provide any degree of success worth considering. [0004] Cancer is generally characterized by the dereg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14C07D403/12C07D409/14C07D413/14C07D417/14C07D471/04C07D487/04C07D497/04A61K31/502A61P35/00
CPCY02A50/30
Inventor V·J·西H·L·迪克B·杜S·D·格伊恩斯-迈尔B·L·霍多斯H·N·阮P·R·奥利维里V·F·帕特尔K·罗姆罗L·申克尔
Owner AMGEN INC
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