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Derivative containing salicylic acid harringtonine, production method and uses thereof

A technology containing harringtonine salicylate and harringtonine salicylate, which is applied in the field of derivatives containing harringtonine salicylate, and can solve the problems of fast metabolism, limited application, and low bioavailability

Active Publication Date: 2019-01-01
NANHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Harringtonine has good pharmacological activity, but its clinical application is limited due to its strong side effects, such as gastrointestinal tract reaction, bone marrow suppression, cardiotoxicity, hypotension, hair loss, rash, etc.
In addition, further studies have found that the activity of harringtonine in the body is not high enough, the absorption is low, the metabolism is fast, and the bioavailability is low, which further limits its application.

Method used

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  • Derivative containing salicylic acid harringtonine, production method and uses thereof
  • Derivative containing salicylic acid harringtonine, production method and uses thereof
  • Derivative containing salicylic acid harringtonine, production method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] The synthesis of embodiment 1 compound 01

[0091] (1S,3aR)-2-Methoxy-1,5,6,8,9,14b-octahydro-4H-[1,3]dioxole[4',5':4, 5] Benzo[1,2-d]cyclopentadiene[b]pyrrolo[1,2-a]azepin-1-yl 2-hydroxybenzoate (compound 01)

[0092] React 0.02mol salicylic acid with 4ml of thionyl chloride at 70°C, add 4 drops of catalyst pyridine, and react for 2 hours to remove excess SOCl2 by suction filtration under reduced pressure, dissolve with 10ml of dichloromethane, and stir in an ice bath . 0.01mol harringtonine was dissolved in anhydrous chloroform, and then 0.02mol DDC and 0.002molPP were dissolved in anhydrous chloroform, added to the reaction solution under nitrogen protection, and stirred at room temperature for three days. The target product was obtained by column chromatography with ethyl acetate:petroleum ether=1:3. The relevant data are as follows:

[0093] Compound 01EI-MS m / z:435.4; Anal.Calcd.For C25H25NO6:C,68.95;H,5.79;N,3.22;Found C,68.97;H,5.81;N,3.24

Embodiment 2

[0094] The synthesis of embodiment 2 compound 02

[0095] (1S,3aS)-2-Oxo-1,2,3,5,6,8,9,14b-octahydro-4H-[1,3]dioxole[4',5': 4,5]Benzo[1,2-d]cyclopentadiene[b]pyrrolo[1,2-a]azepin-1-yl 2-hydroxybenzoate (compound 02)

[0096] With 0.01mol(1S,3aS)-1-hydroxyl-1,5,6,8,9,14b-hexahydro-4H-[1,3]dioxole[4',5':4 ,5] Benzo[1,2-d]cyclopentadiene[b]pyrrolo[1,2-a]azepine-2(3H)-one instead of harringtonine can obtain the target according to the operation of Example 1 product. The relevant data are as follows:

[0097] Compound 02EI-MS m / z:421.1; Anal.Calcd.For C24H23NO6:C,68.40;H,5.50;N,3.32;Found C,68.42;H,5.52;N,3.30

Embodiment 3

[0098] The synthesis of embodiment 3 compound 03

[0099] (S)-2-Oxo-2,3,5,6,8,9-hexahydro-4H-[1,3]dioxole[4',5':4,5]benzene And[1,2-d]cyclopentadiene[b]pyrrolo[1,2-a]azepin-1-yl 2-hydroxybenzoate (compound 03)

[0100] With 0.01mol(S)-1-hydroxy-5,6,8,9-tetrahydro-4H-[1,3]dioxole[4',5':4,5]benzo[ 1,2-d]cyclopentadiene[b]pyrrolo[1,2-a]azepin-2(3H)-one instead of harringtonine The target product can be obtained according to the operation of Example 1. The relevant data are as follows:

[0101] Compound 03EI-MS m / z:419.4; Anal.Calcd.For C24H21NO6:C,68.73;H,5.05;N,3.34;Found C,68.71;H,5.07;N,3.36

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Abstract

The invention relates to a compound of a derivative containing salicylic acid harringtonine, wherein the derivative containing salicylic acid harringtonine has the following general formula (I) defined in the specification, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 can be the same or different, and can be hydrogen, carbonyl, hydroxyl or C1-C8 alkyl, alkoxy, acyl alkoxy or C2-C6 alkynyl, alkenyl or C3-C9 cycloalkyl or aralkyl, phenyl, cyano alkyl, nitro alkyl, carboxyl, haloalkyl, monohydroxy or polyhydroxy alkyl, alkylthioalkyl, alkylsulfonylalkyl, acyloxyalkyl, acylalkyl and sulfonic group,and at least one of R1, R2, R3, R4 and R5 is R. According to the present invention, the compound has excellent anticancer pharmacological effects on chronic granulocytic leukemia, acute myeloid leukemia and lupus erythematosus diseases, can meet the requirements of the medical field, and has high treatment effect, and the preparation method is easy, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a class of harringtonine-containing salicylate derivatives, a production method and uses thereof, specifically, a class of water-containing medicines for treating cancer, chronic myelogenous leukemia, acute myeloid leukemia and lupus erythematosus. Cylic acid harringtonine derivatives. Background technique [0002] Herringoline is one of the main active ingredients of Herringotaxus. Herringoline has various pharmacological activities such as anti-cancer, anti-chronic myelogenous leukemia, anti-acute myeloid leukemia, and anti-lupus erythematosus. Harringtonine has good pharmacological activity, but its clinical application is limited due to its strong side effects, such as gastrointestinal tract reaction, bone marrow suppression, cardiotoxicity, hypotension, alopecia, rash and so on. In addition, further studies have found that the activity of harringtonine in the body is not high enough, the absorption is small, the m...

Claims

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Application Information

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IPC IPC(8): C07D491/20A61K31/625A61P35/00A61P35/02A61P37/06
CPCC07D491/20
Inventor 郑兴龙进陈洪飞杨泽华姚旭罗兴蕊杨治芳张银湘
Owner NANHUA UNIV
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