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4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML)

The technology of quinoline nitrile and quinoline is applied in the field of 4-anilino-3-quinoline nitrile for the treatment of chronic myeloid leukemia (CML), and can solve the problems of weak patient response and the like

Inactive Publication Date: 2006-12-06
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the selective Abl kinase inhibitor STI-571 is potent and well tolerated by most patients in the chronic phase of CML, patients in the accelerated and flare-up phases of disease tend to respond less

Method used

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  • 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML)
  • 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML)
  • 4-anilino-3-quinolinecarbonitriles for the treatment of chronic myelogenous leukemia (CML)

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0061] The preparation of formula I compound is in literature [Boschelli, D.H., et al., J.Med.Chem., 44,3965 (2001), Boschelli, D.H., et al., J Med.Chem., 44,822 (2001), Boschelli , D.H., et al., Bioorg.Med.Chem.Lett., 13, 3797 (2003), Boschelli, D.H., et al., J.Med.Chem., 47, 1599 (2004) and Ye, F. et al., 221th National Meeting of the American Chemical Society, San Diego, CA (April 2001)].

[0062] The present invention will be more fully described in conjunction with the following specific examples, which should not be construed as limiting the scope of the invention.

[0063] Materials and methods:

[0064] Src kinase assay, homogeneous solution based assay (Lance format)

[0065] Kinase buffer:

[0066] 50mM Hepes pH7.5

[0067] 10mM MgCl 2

[0068] 20 μg / ml BSA

[0069] 0.001% Brij-35

[0070] (For convenience, prepare 2× Kinase Buffer:

[0071] 100mM Hepes, 20mM MgCl 2 , add fresh 40 μg / ml BSA and 0.002% Brij)

[0072] Stop buffer (1:1 continuous addition to ...

example 1

[0120] Example 1 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy ]-3-quinolinenitrile

[0121] mp 116-120°C; MS (ES) m / z 530.2, 532.2 (M+1);

example 2

[0122] Example 2 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[3-(4-ethyl-1-piperazinyl)propoxy]-6-methoxy yl-3-quinolinecarbonitrile

[0123] mp 102-104°C; MS (ES) m / z 544.3, 546.4 (M+1);

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Abstract

Compounds of formula (I) wherein n is an integer from 1-3; X is N, CH, provided that when X is N, n is 2 or 3; R is alkyl of 1 to 3 carbon atoms; R<1> is 2,4-diCI, 5-OMe; 2,4-diCI; 3,4,5-triOMe; 3-CI, 5-OMe; 2-Me, 5-OMe; 2,4-di-Me; 2,4-diMe-5-OMe, 2,4-diCI, 5-OEt; R<2> is alkyl of 1 to 2 carbon atoms, and pharmaceutically acceptable salts thereof are useful for the treatment of chronic myelogenous leukemia (CML).

Description

technical field [0001] none Background technique [0002] The constitutive tyrosine kinase activity of Bcr-Abl promotes proliferation and survival of chronic myelogenous leukemia (CML) cells. Inhibition of Bcr-Abl tyrosine kinase activity or signaling proteins activated by Bcr-Abl in CML cells blocks proliferation and leads to apoptotic cell death. The selective Abl kinase inhibitor STI-571 (marketed as Gleevec) is toxic to CML cells in culture, causes regression of CML tumors in nude mice and is currently used to treat CML patients. [0003] Expression of Bcr-Abl in hematopoietic stem cells promotes transformation and plays an early role in leukemogenesis. Inhibition of this kinase with STI-571 is effective in controlling CML in the chronic phase of the disease, but more advanced patients frequently worsen under STI-571 therapy. These observations suggest that other molecular alterations unaffected by STI-571 play a role in advanced disease. In vitro models of STI-571 r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4709A61K31/496A61P35/00A61K31/4706C07D215/38
CPCA61K31/4706A61K31/4709A61K31/496A61P35/00A61P35/02A61P43/00
Inventor 弗兰克·查尔斯·博舍立珍妮弗·米谢勒·格拉斯金·蒂莫西·阿恩特
Owner WYETH LLC
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