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Lenvatinib derivatives, preparation method and application

A compound and selected technology, applied in the field of lenvatinib derivatives and their preparation, can solve the problems of limiting lenvatinib

Active Publication Date: 2019-12-20
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The above side effects limit the clinical application of lenvatinib, so further research on lenvatinib is urgently needed to improve the efficacy and safety, and benefit more patients

Method used

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  • Lenvatinib derivatives, preparation method and application
  • Lenvatinib derivatives, preparation method and application
  • Lenvatinib derivatives, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Isopropyl(2S)-2-[[[4-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6- Carbonyl]carbamoyloxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propionate 2,2,2-trifluoroacetate (compound 1);

[0079] isopropyl

[0080] (2S)-2-[[[4-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino] propanoate 2,2,2-trifluoroacetate.

[0081]

[0082] (1) The first step:

[0083] Isopropyl (2S)-2-[[[4-(hydroxymethyl)phenoxy]-(methoxymethyl)phosphoryl]amino]propionate;

[0084] isopropyl

[0085] (2S)-2-[[[4-(hydroxymethyl)phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate.

[0086] Under nitrogen protection, dichloromethane (90 mL) was added into the reaction flask, methoxymethyl)phosphonic dichloride (8.96 g, 55 mmol) was added with stirring, and cooled to -30°C. Add L-alanine isopropyl ester hydrochloride (9.22g, 55mmol), slowly drop into a mixed solution of triet...

Embodiment 2

[0103] Isopropyl(2S)-2-[[[5-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6- Carbonyl]carbamoyloxymethyl]-2-methoxy-phenoxy]-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphine Acyl]amino]propionate (compound 2);

[0104] isopropyl

[0105] (2S)-2-[[[5-[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]-2-methoxy-phenoxy]-[[ (1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate;

[0106]

[0107] (1) The first step:

[0108] Isopropyl(2S)-2-[[(5-formyl-2-methoxy-phenoxy)-[[(1S)-2-isopropoxy-1-methyl-2-oxo- Ethyl]amino]phosphoryl]amino]propionate;

[0109] isopropyl

[0110] (2S)-2-[[(5-formyl-2-methoxy-phenoxy)-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate;

[0111] 2A (5g, 32.86mmol) was dissolved in 200mL of dichloromethane, phosphorus oxychloride (5g, 32.86mmol) was added at -78 degrees Celsius, and triethylamine (3.4g, 33.60mmol) was ...

Embodiment 3

[0136] Isopropyl(2S)-2[[[5-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl ]carbamoyloxymethyl]-2-methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propionate (compound 3)

[0137] isopropyl

[0138] (2S)-2-[[[5-[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]-2-methoxy-phenoxy]-(methoxymethyl ) phosphoryl] amino] propanoate.

[0139]

[0140] (1) The first step:

[0141] Under nitrogen protection, dichloromethane (90 mL) was added into the reaction flask, methoxymethyl)phosphonic dichloride (8.96 g, 55 mmol) was added with stirring, and cooled to -30°C. Add L-alanine isopropyl hydrochloride (9.22g, 55mmol), slowly drop into a mixed solution of triethylamine (11.11g, 110mmol) and dichloromethane (5mL), and react at -30°C for 30min after the addition is complete . Then 3A (7.50g, 50mmol) and triethylamine (5.05g, 50mmol) were added successively, and then raised to room temperature a...

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Abstract

The present invention relates to a compound shown in a general formula (I) and stereoisomers or pharmacologically acceptable salts thereof, as well as to application to preparation of drugs for resisting tumors. The structure of the compound of the general formula (I) is Q-L-R1, and the definition of groups in the general formula (I) is consistent with the definition in the specification.

Description

technical field [0001] The invention relates to a lenvatinib derivative, a preparation method thereof, and an application in the preparation of antitumor drugs. Background technique [0002] Lenvatinib (Lenvatinib) is an oral multi-target tyrosine kinase inhibitor (TKI) developed by Japan's Eisai Company, which was approved by the FDA in February 2015. It is suitable for patients with local recurrence or metastasis, progressive , Treatment of patients with radioiodine-refractory differentiated thyroid cancer. [0003] However, lenvatinib has serious side effects, including heart failure, thrombosis (arterial thromboembolic event), kidney injury (kidney failure and injury), perforation of the gastrointestinal tract or abnormal connections between the stomach or intestines, changes in the activity of the electrocardiogram ( QT interval prolongation), hypocalcemia, concomitant headache, seizures and visual changes (reversible leukoencephalopathy syndrome), severe bleeding (hem...

Claims

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Application Information

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IPC IPC(8): C07F9/60A61K31/675A61P35/00A61P35/02
CPCC07F9/60A61P35/00A61P35/02
Inventor 张晨钱国飞王建民唐平明李瑶严庞科郑伟
Owner SICHUAN HAISCO PHARMA CO LTD
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