1,2,8-oxo azacyclononane-9-thioketone derivative, and synthetic method and applications thereof

Abstract

The invention discloses a 1,2,8-oxo azacyclononane-9-thioketone derivative, and a synthetic method and applications thereof. The structure of the 1,2,8-oxo azacyclononane-9-thioketone derivative is represented by formula I. According to the synthetic method, a compound represented by formula II and a compound represented by formula III are introduced into an organic solvent, in the presence of oxygen, reaction is carried out so as to obtain a target crude product. The synthetic method is simple and convenient to control; the period is short; no waterless anoxic conditions are required; the formula I, II, and III are disclosed in the invention, wherein R1 is used for representing phenyl, R2 is used for representing phenyl, R3 and R4 are used for representing structures disclosed in the invention, R5 is used for representing hydrogen atom, R6 is used for representing 4-trifluoromethyl benzyl, and X is used for representing sulfur atom.

Description

[0001] This application is a divisional application of "1-oxo-2,8-diazacyclononane derivatives and their synthesis method". The filing date of the original application is: September 18, 2016, and the application number is: 201610826407.9. The title of the invention is: 1-oxo-2,8-diazacyclononane derivative and its synthesis method. technical field

[0002] The invention relates to the technical field of medicine, in particular to a 1-oxo-2,8-diazacyclononane derivative and a synthesis method thereof. Background technique

[0003] The diazacyclononane skeleton is an important core skeleton in natural products and drug molecules, and is an important physiologically active unit, which has important applications in anti-tumor and anti-cancer. Since the diaza nine-membered ring skeleton has always been a difficulty and challenge in organic synthesis, the application of such compounds has been greatly limited. The current strategy for synthesizing this nine-membered heterocyclic ...

Examples

Embodiment 1

[0052] The 1-oxo-2,8-diazacyclononane derivatives of the present invention were synthesized according to the following synthetic route.

[0053]

[0054] in,

[0055] R 1 stands for hydrogen, C 1～4 Alkyl, C 1～4 Alkoxyl, C 1～4 perfluoroalkyl or halogen atom, or unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or Unsubstituted naphthyl; where the substituent is C 1～4 Alkoxyl, C 1～4 Perfluoroalkyl, C 1～4 Alkyl, cyano or halogen atoms;

[0056] R 2 stands for hydrogen, C 1～4 Alkyl, C 1～4 Alkoxyl, C 1～4 perfluoroalkyl or halogen atom, or unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or Unsubstituted naphthyl; where the substituent is C 1～4 Alkoxyl, C 1～4 Perfluoroalkyl, C 1～4 Alkyl, cyano or halogen atoms;

[0057] R 3 stands for hydrogen, C 1～...

Embodiment 2

[0098] The 1-oxo-2,8-diazacyclononane derivatives of the present invention were synthesized according to the following synthetic route.

[0099]

[0100] in,

[0101] R 1 stands for hydrogen, C 1～4 Alkyl, C 1～4 Alkoxyl, C 1～4 perfluoroalkyl or halogen atom, or unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or Unsubstituted naphthyl; where the substituent is C 1～4 Alkoxyl, C 1～4 Perfluoroalkyl, C 1～4 Alkyl, cyano or halogen atoms;

[0102] R 2 stands for hydrogen, C 1～4 Alkyl, C 1～4 Alkoxyl, C 1～4 perfluoroalkyl or halogen atom, or unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or Unsubstituted naphthyl; where the substituent is C 1～4 Alkoxyl, C 1～4 Perfluoroalkyl, C 1～4 Alkyl, cyano or halogen atoms;

[0103] R 3 stands for hydrogen, C 1～...

experiment example 1

[0118] Experimental example 1: In vitro inhibitory activity test of the 1-oxo-2,8-diazacyclononane derivatives of the present invention on various human tumor strains:

[0119] (1) Cell culture: culture T24, HepG2, NCI-H460, 7702 cells in DMEM medium containing 10% (volume ratio) fetal bovine serum and 1% (volume ratio) double antibody (containing penicillin and streptomycin) , at a temperature of 37°C, 5% CO 2and 95% air incubator, and change the medium every other day. After the cells were confluent, they were passaged and frozen.

[0120] (2) Seed plate: Take cells in the logarithmic growth phase, remove the old medium, wash twice with PBS, digest the cells with trypsin, add new medium after the cells become round, stop the digestion of the cells and pipette the suspended cells to prepare into a single cell suspension. Take an appropriate amount of cell suspension, add a certain amount of medium to dilute, inoculate into a 96-well plate, 180 μL per well, and the number o...

[0001] This application is a divisional application of "1-oxo-2,8-diazacyclononane derivatives and their synthesis method". The filing date of the original application is: September 18, 2016, and the application number is: 201610826407.9. The title of the invention is: 1-oxo-2,8-diazacyclononane derivative and its synthesis method. technical field

[0002] The invention relates to the technical field of medicine, in particular to a 1-oxo-2,8-diazacyclononane derivative and a synthesis method thereof. Background technique

[0003] The diazacyclononane skeleton is an important core skeleton in natural products and drug molecules, and is an important physiologically active unit, which has important applications in anti-tumor and anti-cancer. Since the diaza nine-membered ring skeleton has always been a difficulty and challenge in organic synthesis, the application of such compounds has been greatly limited. The current strategy for synthesizing this nine-membered heterocyclic ...

Examples

Embodiment 1

[0052] The 1-oxo-2,8-diazacyclononane derivatives of the present invention were synthesized according to the following synthetic route.

[0053]

[0054] in,

[0055] R 1 stands for hydrogen, C 1～4 Alkyl, C 1～4 Alkoxyl, C 1～4 perfluoroalkyl or halogen atom, or unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or Unsubstituted naphthyl; where the substituent is C 1～4 Alkoxyl, C 1～4 Perfluoroalkyl, C 1～4 Alkyl, cyano or halogen atoms;

[0056] R 2 stands for hydrogen, C 1～4 Alkyl, C 1～4 Alkoxyl, C 1～4 perfluoroalkyl or halogen atom, or unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or Unsubstituted naphthyl; where the substituent is C 1～4 Alkoxyl, C 1～4 Perfluoroalkyl, C 1～4 Alkyl, cyano or halogen atoms;

[0057] R 3 stands for hydrogen, C 1～...

Embodiment 2

[0098] The 1-oxo-2,8-diazacyclononane derivatives of the present invention were synthesized according to the following synthetic route.

[0099]

[0100] in,

[0101] R 1 stands for hydrogen, C 1～4 Alkyl, C 1～4 Alkoxyl, C 1～4 perfluoroalkyl or halogen atom, or unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or Unsubstituted naphthyl; where the substituent is C 1～4 Alkoxyl, C 1～4 Perfluoroalkyl, C 1～4 Alkyl, cyano or halogen atoms;

[0102] R 2 stands for hydrogen, C 1～4 Alkyl, C 1～4 Alkoxyl, C 1～4 perfluoroalkyl or halogen atom, or unsubstituted, monosubstituted, disubstituted, trisubstituted, tetrasubstituted or pentasubstituted phenyl, or unsubstituted furyl, or unsubstituted thienyl, or Unsubstituted naphthyl; where the substituent is C 1～4 Alkoxyl, C 1～4 Perfluoroalkyl, C 1～4 Alkyl, cyano or halogen atoms;

[0103] R 3 stands for hydrogen, C 1～...

experiment example 1

[0118] Experimental example 1: In vitro inhibitory activity test of the 1-oxo-2,8-diazacyclononane derivatives of the present invention on various human tumor strains:

[0119] (1) Cell culture: culture T24, HepG2, NCI-H460, 7702 cells in DMEM medium containing 10% (volume ratio) fetal bovine serum and 1% (volume ratio) double antibody (containing penicillin and streptomycin) , at a temperature of 37°C, 5% CO 2and 95% air incubator, and change the medium every other day. After the cells were confluent, they were passaged and frozen.

[0120] (2) Seed plate: Take cells in the logarithmic growth phase, remove the old medium, wash twice with PBS, digest the cells with trypsin, add new medium after the cells become round, stop the digestion of the cells and pipette the suspended cells to prepare into a single cell suspension. Take an appropriate amount of cell suspension, add a certain amount of medium to dilute, inoculate into a 96-well plate, 180 μL per well, and the number o...

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