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Amino acid derivatives of indolinone based protein kinase inhibitors

An amino and alkyl technology, applied in the field of protein kinase inhibitors, can solve the problems of weakening, poor water solubility, etc.

Inactive Publication Date: 2009-03-18
THE SCRIPPS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The clinical applications of these compounds are promising but partially limited by poor water solubility and / or other pharmaceutical properties

Method used

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  • Amino acid derivatives of indolinone based protein kinase inhibitors
  • Amino acid derivatives of indolinone based protein kinase inhibitors
  • Amino acid derivatives of indolinone based protein kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-23

[0029] Examples 1-23: General scheme:

[0030]

[0031] Scenario 2

[0032] The synthesis of the starting HATU ester (1-1) is shown in Scheme 1. To prepare the free carboxylic acid 1-2, the unprotected amino acid (1.0 equiv) was added to a solution of 1-1 (1.0 equiv) and DIEA (1.5 equiv) in DMF as shown in Scheme 2. After stirring the solution overnight at 25°C, LC-MS showed complete formation of 1-2 with no starting material remaining. Amides 1-3 were prepared directly from this solution in the next step. Thus, the amine (2 equiv), HATU (1.0 mmol) and DIEA (1 equiv) were added to the solution. After stirring at 25°C for 2 hours, the reaction was found to be complete according to LC-MS analysis. The reaction solution was directly subjected to preparative HPLC to obtain pure amide products 1-3, which were subsequently characterized by LC-MS and NMR spectroscopy.

Embodiment 1

[0033] Example 1. Preparation of 5-[5-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3 -Formic acid (2-dimethylcarbamoyl-propyl)-amide

[0034]

[0035] Preparative HPLC from 52 mg of starting material (active ester 1-1) gave 50 mg of the title compound (96%). LC-MS: singlet at 254nm, MH + Calculate C 22 h 25 FN 4 o 3 : 413, get value: 413.

[0036] 1 H-NMR (DMSO-d 6, 400MHz), δ13.68(s, 1H), 10.89(s, 1H), 7.76(dd, J=2.4Hz, 9.6Hz, 1H), 7.71(s, 1H), 7.68(t, J=5.6Hz , 1H), 6.93(m, 1H), 6.84(dd, J=4.4Hz, 8.4Hz, 1H), 3.31(m, 1H), 3.16(m, 2H), 3.05(s, 3H), 2.84(s , 3H), 2.41(s, 3H), 2.39(s, 3H), 1.03(d, J=6.8Hz, 3H).

Embodiment 25-

[0037] Example 2.5-[5-fluoro-2-oxo-1,2-dihydro-indole-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ( 2-Methyl-3-(morpholin-4-yl)-3-oxo-propyl)-amide

[0038]

[0039] Preparative HPLC from 52 mg of starting material (active ester) gave 56 mg of the title compound (98%). LC-MS: singlet at 254nm, MH + Calculate C 24 h 27 f 2 N 4 o 4 : 455, get value: 455.

[0040] 1 H-NMR (DMSO-d 6 , 400MHz), δ13.68(s, 1H), 10.89(s, 1H), 7.75(dd, J=2.4Hz, 9.2Hz, 1H), 7.71(s, 1H), 7.67(t, J=5.6Hz , 1H), 6.92(m, 1H), 6.83(dd, J=4.8Hz, 8.4Hz, 1H), 3.55(m, 7H), 3.41(m, 1H), 3.35(m, 1H), 3.22(m , 1H), 3.12(m, 1H), 2.42(s, 3H), 2.40(s, 3H), 1.04(d, J=7.2Hz, 3H).

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PUM

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Abstract

Amino acid derivatives of pyrrolyl-indolinones and their amide or ester 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 for the treatment of diseases associated with abnormal protein kinase activity, such as cancer and inflammation. More specifically, the present invention relates to pyrrolyl-indolinone amino acid derivatives and their amide or ester derivatives and pharmaceutically acceptable salts thereof useful as protein kinase inhibitors. Background of the invention [0002] Protein kinases are enzymes that catalyze the hydroxyl phosphorylation of tyrosine, serine and threonine residues of proteins. Many aspects of cellular life, such as cell growth, differentiation, proliferation, cell cycle, and survival, depend on protein kinase activity. Furthermore, aberrant protein kinase activity has been associated with a host of diseases such as cancer and inflammation. Accordingly, considerable work has been directed to identifying ways of modulating protein kinase activity. In particular, many...

Claims

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Application Information

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IPC IPC(8): A61K31/404C07D403/02
CPCC07D403/06A61P9/10A61P27/02A61P35/00A61P43/00A61K31/404C07D403/02
Inventor C·梁Y·冯
Owner THE SCRIPPS RES INST
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