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Alkoxy indolinone based protein kinase inhibitors

An alkoxy, alkyl technology, applied in the field of protein kinase inhibitors, can solve problems such as doubts, poor water-soluble drug properties, etc.

Inactive Publication Date: 2008-10-08
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The clinical utility of these compounds has been expected, but partially questioned due to their relatively poor water solubility and / or other pharmaceutical properties

Method used

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  • Alkoxy indolinone based protein kinase inhibitors
  • Alkoxy indolinone based protein kinase inhibitors
  • Alkoxy indolinone based protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1-8

[0030] Example 1-8: the synthesis of acid (1-4) and amide (1-5) as figure 1 shown. Variations of this general synthetic procedure can be understood and performed by those skilled in the art, and thus the compounds of the present invention can be synthesized by such skilled artisans.

example 1

[0031] Example 1: 4-({5-[5-fluoro-2-keto-1,2-dihydro-indole-(3Z)-methylenemethyl]-2,4-dimethyl-1H-pyrrole -3-Carbonyl}-amino)-3-methoxy-butanoic acid

[0032]

[0033] To a solution of methyl 4-amino-3-hydroxybutyric acid (1.0 equiv, prepared by refluxing the free amino acid in anhydrous methanol containing 1.2 equiv of HCl) and DIEA (5 equiv) in DCM was added Mmt- CI (1.1 equiv). After stirring overnight, DCM was removed by distillation under reduced pressure. The residue was suspended in ethyl acetate, washed with brine (3x) and washed with anhydrous Na 2 SO 4 dry. Thereafter, ethyl acetate was removed, and the residue was dried overnight in high vacuum, and compound 1-1 was obtained by flash chromatography. To a solution of compound 1-1 in anhydrous DMF was added NaH (1.5 eq.) under argon atmosphere. After stirring at 25°C for 1 hour, MeI (5 equiv) was added to the solution, and the resulting suspension was shaken gently at 25°C overnight. DMF was removed under va...

example 2

[0034] Example 2: 3-ethoxy-4-({5-[5-fluoro-2-keto-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-di Methyl-1H-pyrrole-3-carbonyl}-amino)-butyric acid

[0035]

[0036] The title compound was prepared using a very similar procedure to the compound in Synthesis Example 1, except that ethyl iodide was used instead of methyl iodide to obtain the 3-ethoxy compound (9.7% based on compound 1-3). LC-MS: 254nm singlet, MH + use C 22 h 24 FN 3 o 5 Calculated value: 430, actual obtained value: 430.

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PUM

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Abstract

Alkoxy indolinone based acid and amide derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.

Description

Field of invention: [0001] The present invention relates to protein kinase inhibitors and their use in the treatment of diseases involving aberrant protein kinase activity, such as cancer and inflammation. In particular, the present invention relates to alkoxyindolinone-based derivatives and their pharmaceutically acceptable salts which are useful as protein kinase inhibitors. technical background: [0002] Protein kinases are enzymes that catalyze the phosphorylation of the hydroxyl groups of serine, tyrosine, and threonine protein residues. Many aspects of cellular life (eg, cell growth, differentiation, proliferation, cell cycle, and survival) depend on the activity of protein kinases. Furthermore, abnormal protein kinase activity is implicated in many diseases such as cancer and inflammation. Accordingly, considerable effort has been devoted to finding ways to modulate the activity of protein kinases. In particular, many attempts have been made to identify small molec...

Claims

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Application Information

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IPC IPC(8): C07D403/06
CPCC07D403/06C07D401/14C07D403/14C07D405/14C07D413/14A61P35/00A61P43/00
Inventor 梁丛薪冯扬波
Owner THE SCRIPPS RES INST
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