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Aurora kinase modulators and method of use

A technology of alkyl and compounds, used in the field of compounds and compositions for controlling cell proliferation and treating cancer, regulating Aurora kinase

Active Publication Date: 2015-03-25
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] Step 1.2-Preparation of Chloro-Nicotinamidine

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

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

[0371] Suspend 2-chloro-nicotinamidine (nicotinamidine) in 10 mL IpOH with 500 mg of solid cyanamide, and add 5% NaHCO to the stirred solid....

Embodiment 2

[0375]

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

[0377] Add methylamine to a solution of 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine (10.0g, 44.0mmol) in 55ml dichloromethane at 0°C (45ml, 88.0mmol) in 2.0MTHF. After stirring for 18 hours at room temperature, the mixture was diluted with acetone, filtered through a silica gel pad, and concentrated to obtain 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 5-(2-chloro-pyridin-3-yl)-3-dimethylamino-propenone

[0382] In a drying tube at 85°C, mix 1-(2-chloro-pyridin-3-yl)-ethanone (21.7g, 139mmol) in 46mL N,N-dimethylformamide dimethylacetal (42g, 350mmol) ) Is heated for 1.5h, and then concentrated. The residue was purified by suction filtration chromatography (using 150g silica gel in a Buchner funnel, quickly collect the fractions, use 10:1, then use 5:1 CH 2 Cl 2 / IpOH) to obtain a yellow solid product. 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] Use 500mL IpOH bath at room temperature as the cold source, at room temperature, N 2 Next, small pieces of metallic sodium (8.3 g, 360 mmol in total) were added intermittently to 400 mL of anhydrous methanol, and sodium methoxide was generated over 1.5 hours. Formamidine acetate (42.7 g, 410 m...

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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 benefits of U.S. Provisional Application No. 60 / 761,675 filed on January 23, 2006, which is incorporated in its entirety into the present invention by reference. Invention field [0002] The present invention relates to the field of medicine, and more specifically, to compounds and compositions for regulating Aurora kinase, and 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 a major cause of human death worldwide. In trying to find effective treatments or cures for one or more of many different types of cancer, many groups have invested a lot of time, effort and financial resources in the last two decades. However, to date, of the existing cancer treatments and therapies, only a few can provide any level of success worth considering. [0004] Cancer is generally characterized by a disorder of cell proliferation. Disrupt...

Claims

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Application Information

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Patent Type & Authority Patents(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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