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Halogenated pyrrole-substituted 2-indolinone salt and preparation method and application thereof

A technology of indolinone salt and halogenated pyrrole, which is applied in the fields of medical science and chemical synthesis, can solve the problems of low bioavailability, poor solubility, and no obvious anti-tumor effect, and achieve good solubility and good bioavailability , significant antitumor activity

Inactive Publication Date: 2011-04-27
SHANGHAI LANGLAI MEDICINE TECH CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to disclose a halogenated pyrrole-substituted 2-indolinone salt. The antitumor drug prepared with this salt has multi-target specificity and can overcome the poor solubility in vitro, and has no obvious antitumor effect in vitro. The disadvantage of low bioavailability further improves the efficacy and toxicity

Method used

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  • Halogenated pyrrole-substituted 2-indolinone salt and preparation method and application thereof
  • Halogenated pyrrole-substituted 2-indolinone salt and preparation method and application thereof
  • Halogenated pyrrole-substituted 2-indolinone salt and preparation method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Example 1 N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3-ylidene ) Methyl-2-methyl-4-chloro-1H-pyrrole-3-carboxamide hydrochloride

[0027] N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methanol Base-2-methyl-4-chloro-1H-pyrrole-3-carboxamide (1g, 2.4mmol) (formula II), absolute ethanol 10mL, concentrated hydrochloric acid 0.5mL were mixed and refluxed for 2h, and the precipitate was cooled and filtered. Dry in vacuum at 50°C for 2 hours to obtain 0.9 g of N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H- Indol-3-ylidene)methyl-2-methyl-4-chloro-1H-pyrrole-3-carboxamide hydrochloride. LC-MS (m / z): (M+1). mp: 248°C (decomposition).

[0028] 1 H NMR (D 2 O): 6.32-6.69(m, 5H), 3.25-3.53(m, 8H), 1.91(s, 3H) 1.33(t, 6H, J=7.2Hz).

[0029] Please refer to Chinese patent CN101440086A for the synthesis of formula (II) used in the present invention. Amine and 5-fluorooxindole condensation formed. ...

Embodiment 2

[0030] Example 2 N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3-ylidene ) Methyl-2-methyl-4-chloro-1H-pyrrole-3-carboxamide L-tartrate

[0031] N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methanol Base-2-methyl-4-chloro-1H-pyrrole-3-carboxamide (1g, 2.4mmol) (formula II), absolute ethanol 10mL, L-tartaric acid (0.4g, 2.7mmol) were mixed and refluxed for 2h, cooled The precipitate was filtered, and the precipitate was vacuum-dried at 50° C. for 2 hours to obtain 0.95 g of N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2 -dihydro-3H-indol-3-ylidene)methyl-2-methyl-4-chloro-1H-pyrrole-3-carboxamide L-tartrate. LC-MS (m / z): (M+1). mp: 162°C (decomposition).

[0032] 1 H NMR (D 2 O): 6.32-6.58(m, 5H), 4.43(s, 2H), 3.34-3.68(m, 6H), 2.65-2.98(m, 2H), 1.86(s, 3H), 1.34(t, 6H, J=7.2Hz).

Embodiment 3

[0033] Example 3 N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indole-3-ylidene ) Methyl-2-methyl-4-chloro-1H-pyrrole-3-carboxamide L-malate

[0034]N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methanol Base-2-methyl-4-chloro-1H-pyrrole-3-carboxamide (1g, 2.4mmol) (formula II), absolute ethanol 10mL, L-malic acid (0.38g, 2.8mmol) were mixed and refluxed for 2h, The precipitate was cooled and filtered, and the precipitate was vacuum-dried at 50°C for 2 hours to obtain 0.92 g of N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1, 2-Dihydro-3H-indol-3-ylidene)methyl-2-methyl-4-chloro-1H-pyrrole-3-carboxamide L-malate. LC-MS (m / z): (M+1). mp: 203°C (decomposition).

[0035] 1 H NMR (D 2 O): 6.22-6.53(m, 5H), 4.40(s, 1H), 3.25-3.54(m, 8H), 2.62-2.86(m, 2H), 1.81(s, 3H), 1.30(t, 6H, J=7.2Hz).

[0036] One of the applied effects

[0037] 1. The halogenated pyrrole-substituted 2-indolinone malate prepared in Example 3 is su...

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Abstract

The invention relates to halogenated pyrrole-substituted 2-indolinone salt and a preparation method and application thereof. The salt has a structure which is shown in a formula (I). The preparation method comprises the following step that: the halogenated pyrrole-substituted 2-indolinone salt shown in the formula (I) can be obtained by reacting a compound shown in a formula (II) with acid (HX) in a solvent. The salt has high solubility in water and ethanol and high bioavailability in animal bodies, and is suitable for developing the conventional preparations for treating tumor and suitable to be used as a medicament. The salt prepared by the invention is used for preparing the anti-tumor medicament, has multi-target specificity, and can overcome the disadvantages of poor in-vitro solubility, no obvious in-vitro anti-tumor effect and low in-vivo bioavailability so as to further improve curative effect and toxicity.

Description

technical field [0001] The invention relates to a halogenated pyrrole-substituted 2-indolinone salt, further relates to a preparation method and application of the halogenated pyrrole-substituted 2-indolinone salt, and belongs to the technical fields of medical science and chemical synthesis. Background technique [0002] Sunitinib, as a multi-target specific anti-tumor drug, was approved by the US FDA in 2006 as two indications for the treatment of advanced renal cell carcinoma and gastrointestinal stromal cell tumor, and has received extensive attention. Clinical and basic studies have shown its curative effect on non-small cell lung cancer, ovarian cancer, myeloid leukemia, etc., especially when combined with cytotoxic anti-tumor drugs, radiotherapy, and monoclonal antibody drugs, it has achieved significant results. By the attention. However, clinical studies have also shown the shortcomings of Sunitinib, a class of target-specific anti-tumor drugs. First, their anti-tu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06A61K31/404A61P35/00
Inventor 孙洋君
Owner SHANGHAI LANGLAI MEDICINE TECH CENT
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