Sophoridine derivative with nitrogen mustard as well as preparation method and application of sophoridine derivative

A definition and compound technology, applied in the field of medicinal chemistry, can solve the problems of limited anti-tumor activity of sophoridine, inability to be widely used, and strong water solubility.

Active Publication Date: 2017-09-05
天津市医药科学研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, sophoridine has limited antitumor activity, high polarity and strong water solubility, so it cannot be widely used in clinical practice.

Method used

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  • Sophoridine derivative with nitrogen mustard as well as preparation method and application of sophoridine derivative
  • Sophoridine derivative with nitrogen mustard as well as preparation method and application of sophoridine derivative
  • Sophoridine derivative with nitrogen mustard as well as preparation method and application of sophoridine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: 4-((3aR,3a1S,10aS)-2-toluenesulfonyl dodecahydropyridin[3,2,1-ij][1,6]naphthyridin-1-yl)butylbis(2 Preparation of -chloroethyl)butyl carbamate

[0038]

[0039] Step 1: Preparation of Sophoridine

[0040]

[0041] Weigh 1.0g of sophoridine, place it in 20mL of 5N potassium hydroxide aqueous solution, heat and reflux for 12h, after the reaction is completed, cool to room temperature, add 5N hydrochloric acid solution, control the pH to be less than 6, and precipitate a large amount of white solid, filter, and after the filtrate is concentrated, residual The substance was fully dissolved with methanol, and the inorganic salt was removed by filtration to obtain a methanol solution of sophoridine. After being spin-dried, the crude product of sophoridine was obtained, and then recrystallized with methanol to separate out the pure product of sophoridine. 13 C NMR (101MHz, CDCl 3 )δ 177.13, 67.62, 58.99, 53.08, 48.78, 41.72, 35.94, 34.64, 33.47, 28.38, 26.46...

Embodiment 2

[0055] Example 2: 4-((3aR,3a1S,10aS)-2-((3,4-dimethylphenyl)sulfonyl)dodecahydropyridine[3,2,1-ij][1,6] Preparation of naphthyridin-1-yl)butylbis(2-chloroethyl)butylcarbamate

[0056]

[0057] 13 C NMR (101MHz, CDCl 3 )δ159.28,139.48,136.26,134.69,131.22,131.12,125.91,66.82,66.08,60.86,53.08,48.91,47.01,41.63,40.87,36.03,31.39,29.69,28.30,26.29,24.09,23.33,23.13,20.55,19.62 .HRMS: calcd for C 28 h 43 Cl 2 N 3 O 4 S:587.2153,found:587.2153.

Embodiment 3

[0058] Example 3: 4-((3aR,3a1S,10aS)-2-((4-chlorophenyl)sulfonyl)dodecahydropyridin[3,2,1-ij][1,6]naphthyridine-1 Preparation of -yl)butyl bis(2-chloroethyl)butyl carbamate

[0059]

[0060] 13 C NMR (101MHz, CDCl 3 )δ159.28, 140.36, 139.69, 130.44, 129.52, 66.82, 66.08, 60.86, 53.08, 48.91, 47.01, 41.63, 40.87, 36.03, 31.39, 29.69, 28.30, 26.29, 24.09 for CMS. HR, 23.3 26 h 38 Cl 3 N 3 O 4 S:593.3212,found:593.3212.

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PUM

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Abstract

The invention belongs to the technical field of anti-tumor medicines, and provides a sophoridine derivative with nitrogen mustard as well as a preparation method and application of the sophoridine derivative, and pharmaceutically acceptable salts of the sophoridine derivative, wherein R1, X, Y and n are as shown in the specification. The invention further relates to a preparation method of the compound, and further discloses a medicinal composition of the compound or the pharmaceutically acceptable salts of the compound as active effective components, and application of the components as anti-tumor medicines.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new class of compounds used for tumor or cancer treatment, in particular to a class of sophoridine derivatives of nitrogen-containing mustards with anti-tumor activity and a preparation method thereof, and such compounds Use as a medicament, especially in the treatment of tumors or cancer. [0002] technical background [0003] Sophoridine is a kind of Sophora flavescens alkaloid extracted and isolated from the leguminous plant Sophora sophora. This type of alkaloid has a quinolizidine structure. Since Professor Li Xuemei discovered its effect on the solid tumor sarcoma 180 (S180) in 1977 Sophoridine has experienced many years of pharmacological research since it has stable anti-cancer effects on various transplanted tumors of animals, such as cervical cancer and Lewis lung cancer. Colon adenocarcinoma cells also have a stable inhibitory effect on proliferation. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/16A61K31/4375A61P35/00
CPCC07D471/16
Inventor 李冬冬代霖霖陶遵威张娜
Owner 天津市医药科学研究所
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