Bicycloaniline derivative

A technology of derivatives and compounds, applied in the field of Wee1 kinase inhibitors, can solve the problems of anticancer agents or reduced radiosensitivity

Inactive Publication Date: 2010-07-21
บันยิว ฟาร์มาซูติคัล โค แอลทีดี
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the function of the G2 checkpoint remains in such cancer cells, and this is considered to be one of the main factors leading to decreased sensitivity to DNA-active anticancer agents or radiation

Method used

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  • Bicycloaniline derivative
  • Bicycloaniline derivative
  • Bicycloaniline derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0328] The compound of Example 1 is administered on Day1, 8, and 15

[0329] The tumor proliferation rate was reduced by administration of gemcitabine, but the tumor proliferation rate was further reduced by the combined administration of the compound of the present invention and gemcitabine, and tumor regression was observed in the high-dose combination group.

[0330] As described above, the compounds of the present invention potentiate the effects of other anticancer agents when used in combination with other anticancer agents.

[0331] Pharmacological test 5 (Method for judging drug effect using cells (radiation (X-ray) increase Sensitivity))

[0332] a) Reagents

[0333] Fetal bovine serum (FBS) was purchased from Morgate Company, RPMI1640 medium and 0.25% trypsin EDTA were purchased from Invitrogen Company, Cycle Test Plus DNA kit was purchased from Becton Dickinson Company, and nylon mesh filter was purchased from Millipore Company.

[0334] b) cells

[0335] Hum...

preparation example 1

[0434] 7-Chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido Preparation of [4,5-d]pyrimidin-2(1H)-one

[0435]

[0436] To a solution of 3.0 g of 4-amino-2-chloropyrimidine-5-carbonitrile in N,N-dimethylformamide (35 mL) was added 1.12 g of sodium hydride, followed by stirring at room temperature for 5 minutes. 4.38 g of 2,6-dichlorophenylisocyanate was added to the reaction liquid, and stirred at room temperature for 1 hour. Ethyl acetate and 1N aqueous hydrochloric acid solution were added to the reaction solution, and the organic layer was separated. After washing with saturated brine, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The precipitated solid was solidified with a methanol-ethyl acetate mixed solvent and collected by filtration to obtain 3.8 g of the title compound as a white solid.

[0437] 1 H-NMR (400MHz, DMSO-d 6 )δ: 9.33 (1H, s), 7.66 (2H, d, J=8.2Hz), 7.53 (1H, t, J=8.2Hz).

[0438] ESI-MS Found: m / z[M+...

preparation example 2

[0440] 7-Chloro-3-(2-chloro-6-methylphenyl)-4-imino-3,4-dihydropyrimidine Preparation of imido[4,5-d]pyrimidin-2(1H)-ones

[0441]

[0442] Except that 298 mg of 2-chloro-6-methylphenyl isocyanate was used instead of 2,6-dichlorophenyl isocyanate used in Preparation Example 1, the same method as Preparation Example 1 was followed to obtain 110 mg of the title compound as a pale yellow solid .

[0443]ESI-MSFound: m / z[M+H]322

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Abstract

Disclosed are: a compound represented by the general formula (I); and others. (I) wherein A1 and A2 independently represent a nitrogen atom or a methine group which may be substituted; the ring B represents a 5- to 7-membered aliphatic ring or a spiro or bicyclo ring formed by the aliphatic ring and a 3- to 7-membered aliphatic ring which is different from the aforementioned aliphatic ring; R1 represents a hydrogen atom, a C1-C6 alkyl group which may be substituted or an aryl, aralkyl or heteroaryl group which may be substituted; R2 represents an aryl, aralkyl or heteroaryl group which may be substituted; and X represents a group represented by the formula =NH or =O. The compound has an excellent cell proliferation inhibition activity relying on a Wee1 kinase inhibition activity and an additive / synergistic effect with other anti-cancer agent, and is therefore useful in the medical field.

Description

technical field [0001] The present invention is useful in the field of medicine. More specifically, the bicyclic aniline derivatives of the present invention are useful as kinase inhibitors, particularly Wee1 kinase inhibitors, in the field of treatment of various cancers. Background technique [0002] Cells have a checkpoint mechanism for repairing DNA by halting the cell cycle when it is damaged [Cell Proliferation, Vol. 33, pp. 261-274]. About half of human cancers have lost the function of the G1 checkpoint due to mutations or defects in the cancer suppressor gene p53. However, the G2 checkpoint function remains in such cancer cells, and this is considered to be one of the main factors leading to decreased sensitivity to DNA-active anticancer agents or radiation. [0003] Wee1 kinase is a tyrosine kinase involved in the G2 checkpoint of the cell cycle. Wee1 inactivates Cdc2 by phosphorylating tyrosine 15 of Cdc2 (Cdk1), which is involved in the transition from the G2 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/522A61K31/5415A61K31/55A61K31/553A61K45/00A61P35/00A61P43/00C07D519/00
CPCC07D519/00C07D487/04A61K31/5415A61K31/522A61K45/06A61K31/55A61P35/00A61P43/00C07D498/04A61K31/553
Inventor 番场诚古山英知新山健治坂本俊浩角南聪高桥启治山本冬树吉住隆
Owner บันยิว ฟาร์มาซูติคัล โค แอลทีดี
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