Ferrocene derivative and preparation method and application thereof

A technology of ferrocene derivatives and drugs, applied in chemical instruments and methods, metallocenes, drug combinations, etc., can solve the problems of poor overall clinical treatment effect and difficult cancer treatment

Inactive Publication Date: 2017-03-22
XIAMEN INST OF RARE EARTH MATERIALS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, most cancers are found in the middle to late stages, and the overall effect of clinical treatment is poor, especially the continuous emergence of multidrug resistance, which makes cancer treatment difficult.

Method used

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  • Ferrocene derivative and preparation method and application thereof
  • Ferrocene derivative and preparation method and application thereof
  • Ferrocene derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Synthesis of Example 1 Intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole (II-A) or intermediate 3-substituted phenyl-5-aminomethyl-isoxazole (II-B) :

[0086] Using substituted benzaldehyde as raw material, it is prepared by synthesis of oxime, 1,3-dipolar cycloaddition reaction, methylsulfonyl esterification reaction, azidation, and reduction reaction (R and n are as above), see the following process for details :

[0087]

[0088] The specific synthetic process of intermediate 3-substituted phenyl-5-hydroxymethyl-isoxazole (II-A) or intermediate 3-substituted phenyl-5-aminomethyl-isoxazole (II-B) is detailed See the preparation process in the applicant's previous application with publication numbers CN103360382A, CN103664991A and CN103601762A, the full text of which is incorporated herein as a reference.

Embodiment 2

[0089] Synthesis of ferrocene derivatives (Z is O) shown in embodiment 2 formula (IA)

[0090] The reaction of 1,1'-ferrocenedicarboxylic acid and 3-phenyl-5-hydroxymethyl-isoxazole is used as an example to illustrate:

[0091] Synthesis of ferrocene dicarboxylate derivatives (YJP-1):

[0092]

[0093] Add 0.274g (1mmol) 1,1'-ferrocenedicarboxylic acid and 0.412g (2mmol) DCC into a 50mL round-bottomed flask, add 10mL dry THF, and stir in an ice bath for 30min to dissolve 0.35g (2mmol) 5-Hydroxymethyl-3-phenyl-isoxazole and 0.244g (2mmol) DMAP in 10mL THF solution were slowly added dropwise to the reaction system, stirred in an ice bath for 30min, and then naturally rose to room temperature for reaction. After the TLC detection reaction was completed, the reaction solution was concentrated in vacuo, and the residue was directly separated by column (V (石油醚) :V (乙酸乙酯) =5:1~2:1) to obtain the target compound ferrocene dicarboxylate derivative (YJP-1).

[0094] The remaining...

Embodiment 3

[0095] Synthesis of ferrocene derivatives (Z is NH) shown in embodiment 3 formula (IA)

[0096] The reaction of 1,1'-ferrocenedicarboxylic acid and 3-phenyl-5-aminomethyl-isoxazole is used as an example to illustrate:

[0097] Synthesis of ferrocenedicarboxamide derivatives (YJP-20):

[0098]

[0099] Add 0.274g (1mmol) 1,1'-ferrocenedicarboxylic acid, 0.412g (2mmol) DCC and 0.270g (2mmol) HOBt into a 50mL round bottom flask, add 10mL of dry THF, and stir in an ice bath for 30min. A solution of 0.348g (2mmol) 5-aminomethyl-3-phenyl-isoxazole and 0.244g (2mmol) DMAP in 10mL THF was slowly added dropwise to the reaction system, stirred in an ice bath for 30min, and then naturally rose to room temperature for reaction. After the TLC detection reaction was completed, the reaction solution was concentrated in vacuo, and the residue was directly separated by column (V (石油醚) :V (乙酸乙酯) =5:1~2:1) to obtain the target compound ferrocenedicarboxamide derivative (YJP-20).

[0100] ...

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Abstract

The invention relates to a ferrocene derivative shown as a formula (IA) or a formula (IB) or a pharmaceutically-acceptable salt or a solvate and a medicinal composition thereof. In the formula, R is independently selected from hydrogen, halogen, a cyano-group, a nitro-group, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, hydroxyl-alkyl with 1 to 6 carbon atoms, halogenated alkyl with 1 to 6 carbon atoms, halogenated alkoxy with 1 to 6 carbon atoms, or alkoxy with 1 to 6 carbon atoms; Z is selected from O, S or NR1; R1 is hydrogen or alkyl with 1 to 6 carbon atoms independently; n is an integer of 0 to 5. The invention further provides a preparation method and medical application of the compound shown as the formula (IA) or the formula (IB) or the pharmaceutically-acceptable salt thereof. The compound has very high restraining activity specific to a lung cancer cell line A549, a colorectal carcinoma cell line HCT116 and / or a breast cancer cell line MCT-7, has broad-spectrum anti-cancer activity, and can be taken as a candidate compound or a lead compound for treating tumor diseases or cancer diseases. The derivative is shown in the description.

Description

technical field [0001] The invention belongs to the field of medicine, relates to a class of A and B type ferrocene derivatives with novel structure, and specifically relates to the preparation of the type of ferrocene derivatives, the pharmaceutical composition containing the type of compounds and the use thereof. [0002] The ferrocene derivatives have strong inhibitory activity on human lung cancer cell line A549, colorectal cancer cell line HCT116 and breast cancer cell line MCF-7. The compounds have broad-spectrum anticancer activities and can be used as candidate drugs or lead compounds for treating diseases such as tumors and cancers. Background technique [0003] Cancer has become the most important fatal disease in the world, and the mortality rate of cancer patients in developed countries is also high. Cancer can occur in various organs and tissues at any age. The main types of cancer that cause death are: lung cancer, stomach cancer, liver cancer, colon cancer an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F17/02A61K31/555A61P35/00
CPCC07F17/02
Inventor 雍建平卢灿忠
Owner XIAMEN INST OF RARE EARTH MATERIALS
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