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7-azaindolinyl-2-one compounds and preparation method thereof

A compound and drug technology applied in the field of medicinal chemistry to achieve superior anti-tumor activity, high drug safety, and reduced toxic and side effects

Active Publication Date: 2015-09-02
ZHEJIANG STARRY PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, all these modifications are based on retaining the core structure of sunitinib (indolin-2-one), and modifying the substituents at its 1-position, 3-position and / or 5-position and optimization, but no reports on the modification of the sunitinib core structure itself

Method used

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  • 7-azaindolinyl-2-one compounds and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 (Z)-N-[2-(dimethylamino)ethyl]-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrrole[2,3-b ]pyridin-3-ylmethylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide

[0050] 2,4-Dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid (167mg, 1mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (230mg, 1.2mmol), a mixture of 1-hydroxybenzotriazole (162mg, 1.2mmol) and N,N-dimethylformamide (15mL) was stirred at 0-4°C for 20min, and N,N- Dimethylethylenediamine (0.26mL, 2mmol) was reacted at the same temperature for 30min, then stirred at room temperature for 12h. Dilute with distilled water, adjust the pH to 9 with saturated sodium carbonate solution, extract 15 mL x 3 times with dichloromethane containing 10% methanol, wash once with water and once with saturated brine, and dry over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated under reduced pressure to obtain a red oily liquid (59% yield).

[0051] The above oily liquid and 5-fluoro-7-azai...

Embodiment 2

[0059] Example 2 (Z)-N-{2-[methyl (ethyl) amino] ethyl}-5-(5-fluoro-2-oxo-1,2-dihydro-3H-pyrrole [2 ,3-b]pyridin-3-ylmethylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide

[0060] The same as the preparation method of the compound in Example 1, 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid first undergoes a condensation reaction with N,N-methylethylethylenediamine, and then reacts with 5-Fluoro-7-azaindol-2-one was condensed to give an orange solid (yield: 50%).

[0061] 1H NMR (400MHz, DMSO-d6) δ: 13.50(s, 1H), 11.52(s, 1H), 8.19(dd, J=9.2, 2.7Hz, 1H), 7.98(dd, J=2.7, 1.7Hz, 1H),7.81(s,1H),7.48(t,J=5.6Hz,1H),3.28(q,J=6.4Hz,2H),2.57-2.51(m,4H),2.46(s,3H), 2.43(s,3H),2.20(s,3H),0.97(t,J=7.1Hz,3H).

[0062] MS-ESI(m / z):386.63(M+H) + .

[0063] HRMS-ESI(m / z): Calcd.for C 20 h 24 o 2 N 5 F(M+H)+: 386.20126; Found: 386.20113.

Embodiment 3

[0064] Example 3 (Z)-N-[2-(diethylamino)ethyl]-5-(5-chloro-2-oxo-1,2-dihydro-3H-pyrrole[2,3-b ]pyridin-3-ylmethylene)-2,4-dimethyl-1H-pyrrole-3-carboxamide

[0065] Same as the preparation method of the compound in Example 1, 2,4-dimethyl-5-formyl-1H-pyrrole-3-carboxylic acid is first condensed with N,N-diethylethylenediamine, and then reacted with 5 - Chloro-7-azaindol-2-one was condensed to give a yellow solid (yield: 52%), mp: 225-226°C.

[0066] 1H NMR (400MHz, DMSO-d6) δ: 13.45(s, 1H), 11.61(s, 1H), 8.35(d, J=2.2Hz, 1H), 8.02(d, J=2.2Hz, 1H), 7.84 (s,1H),7.48(t,J=5.2Hz,1H),3.28(q,J=6.2Hz,2H),2.55–2.50(m,6H),2.46(s,3H),2.43(s, 3H), 0.98(t, J=7.1Hz, 6H).

[0067] MS-ESI(m / z):416.31(M+H) + .

[0068] HRMS-ESI(m / z): Calcd.for C 21 h 27 o 2 N 5 Cl(M+H) + :416.18478; Found: 416.18492.

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Abstract

The invention relates to 7-azaindolinyl-2-one compounds disclosed as Formula, a preparation method and medical application thereof, and an antineoplastic drug composition using the compounds as effective components. In the 7-azaindolinyl-2-one compounds, the 5- substituent group at the parent nucleus is halogen, and the 3- substituent group is 2,4-dimethylpyrryl-5-ethylene containing various amino formacyl groups. Compared with the similar antineoplastic drug-sunitinib, the 7-azaindolinyl-2-one compounds have higher antineoplastic activity.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to 7-azaindolin-2-one compounds with antitumor activity, a preparation method thereof, and an antitumor pharmaceutical composition containing them. Specifically, 5-(5-halo-2-oxo-1,2-dihydro-3H-pyrrole[2,3-b]pyridine-3-methylene)-2,4-dimethyl Base-1H-pyrrole-3-carboxamide compound and its preparation method. Background technique [0002] Multi-target tyrosine kinase inhibitors have been a research hotspot in the field of anti-tumor in recent years. At present, several excellent varieties have been approved for marketing, and many candidates are in the clinical or preclinical research stage (J Shenyang Pharm Univ. 2011, 28, 1005 ; Chinese J Org Chem. 2011, 31, 1595). [0003] As the first multi-target tyrosine kinase inhibitor approved by the US FDA, Sunitinib has shown clear anti-tumor activity against various solid tumors (Chin J New Drugs Clin Rem.2007, 26, 474) , whose clinical...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61K31/4545A61K31/496A61P35/00A61P35/02
CPCC07D471/04
Inventor 刘明亮郭慧元王明华夏桂民李林虎王春兰沈伟艺陈仕洪
Owner ZHEJIANG STARRY PHARMA
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