Two-photon absorbing compound with methods of synthesis and use

Patent metadata

Field	Value
Publication number	US-9353399-B2
Application number	US-201314345137-A
Country	US
Kind code	B2
Filing date	Mar 21, 2013
Priority date	May 17, 2012
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

Disclosed is a compound which is a two-photon absorbing fluorescent substance, a production method for the compound, a fluorescence sensor and molecular probe able to sense various substrates or enzyme activity or the like using the same, and a method of sensing enzyme activity or the like using the same. The disclosed compound can be used as a fluorescence sensor, and can be used in the study and treatment of diseases in which MAO enzymes are involved such as mood disorders using MAO enzyme activity and inhibitor screening.

First claim

The invention claimed is:

1. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

wherein, R is selected from the group consisting of vinyl, propargyl, 4-boronato-benzyl, t-butyldimethylsilyl, homoallyl and phosphate.

2. The compound of claim 1 , comprising Chemical Formula 5 or a pharmaceutically acceptable salt thereof,

wherein, R is selected from the group consisting of vinyl, propargyl, 4-boronato-benzyl, t-butyldimethylsilyl, homoallyl, and phosphate.

3. The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound of Chemical Formula 1 is an one-photon or a two-photon absorbing fluorescent substance.

4. A method for preparing the compound of Chemical Formula 2 of claim 1 , comprising:
1) synthesizing 7-(dimethylamino)naphthalene-2-ol by adding sodium metabisuifite and an aqueous solution of dimethylamine to 2,7-dihydroxy naphthalene;
2) synthesizing 7-(methoxymethoxy)-N,N-dimethylnaphthalene-2-amine by adding sodium hydride and chloromethyl methyl ether to the 7-(dimethylamino)naphthalene-2-ol obtained from step (1);
3) synthesizing 6-(dimethylamino)-3-(methoxymethoxy)-2-naphthaldehyde by adding ethyl ether, and tertiary butyllithium, and N,N-dimethylformamide to the 7-(methoxymethoxy)-N,N-dimethylnaphthalene-2-amine obtained from step (2); and
4) adding isopropyl alcohol and HCl to the 6-(dimethylamino)-3-(methoxymethoxy)-2-naphthaldehyde obtained from step (3) to obtain the compound of Chemical Formula 2.

5. A method for preparing the compound of Chemical Formula 1 of claim 1 comprising adding malononitrile and piperidine to the compound of Chemical Formula 2 of claim 1 to obtain the compound of Chemical Formula 1.

6. A method for preparing the compound of Chemical Formula 3 of claim 1 , comprising:
1) synthesizing 6-dimethylamino-3-{3-[N,N-bis(tert-butyloxycarbonyl)amino]propyloxy}naphthalene-2-carbaldehyde by adding N-ter-butyloxycarbonyl-3-(chloropropyi)carbamic acid tert-butyl ester and potassium carbonate to the compound of Chemical Formula 2 of claim 1 ;
2) synthesizing 2-{3-[N,N-bis(tert-butyloxycarbonyl)amino]propyloxy }-3-(2,2,-dicyano)vinyl-7-(dimethylamino)naphthalene by adding malononitrile and piperidine to the 6-dimethylamino-3-{3-[N,N-bis(tert-butyloxycarbonyl)amino]propyloxy }naphthalene-2-carbaldehyde obtained from step (1); and
3) adding triisopropylsilane to the 2-{3-[N,N-bis(tert-butyloxycarbonyl)amino]propyloxy }-3-(2,2,-dicyano)vinyl-7-(dimethylamino)naphthalene obtained from step (2) to obtain the compound of Chemical Formula 3.

7. A method for preparing the compound of Chemical Formula 4 of claim 1 , comprising:
1) synthesizing 6-dimethylamino-3-{3-[N-methly-N-(tert-butyloxycarbonyl)amino]propyloxy}naphthalene-2-carbaldehyde by adding [3-chloropropyl-N-(methyl)carbamic acid tert-butyl ester]and potassium carbonate to the compound of the Chemical Formula 2 of claim 1 ;
2) synthesizing [2-{3-[N-methyl-N-(tert-butyloxycarbonyl)amino]propyloxy}-3-(2,2-dicyano)vinyl-7-(dimethylamino)naphthalene] by adding malononitrile and piperidine to the 6-dimethylamino-3-{3-[N-methly-N-(tert-butyloxycarbonyl)amino]propyloxy }naphthalene-2-carbaldehyde obtained from step (1); and
3) adding triisopropylsilane to the [2-{3-N-methyl-N-(tert-butyloxycarbonyl)amino]propyloxy}-3-(2,2-dicyano)vinyl-7-(dimethylamino)naphthalene]
obtained from step (2) to obtain the compound of Chemical Formula 4.

8. A method for preparing the compound of Chemical Formula 5 of claim 1 , comprising:
1) synthesizing 3-(2-bromoethoxy)-6-(dimethylamino)-2-naphthaldehyde by adding 1,2-dibromoethane, Bu 4 NOH, and KOH to the compound of Chemical Formula 2;
2) synthesizing 6-(dimethylamino)-3-(vinyloxy)-2-naphthaldehyde by adding t-BuOK to the 3-(2-bromoethoxy)-6-(dimethylamino)-2-naphthaldehyde obtained from step (1); and
3) synthesizing 2-((6-dimethylamino)-3-(vinyloxy)naphthalene-2-yl)methylene)malononitrile by adding malononitrile and piperidine to the 6-(dimethylamino)-3-(vinyloxy)-2-naphthaldehyde obtained from step (2) to obtain the compound of Chemical formula 5, wherein R is vinyl.

9. A method for preparing the compound of Chemical Formula 5 of claim 1 , wherein R is t-butyldimethylsilyl, comprising:
1) synthesizing 3-(tert-butyldimethylsilyl)oxy)-6-(dimethylamino)-2-naphthaldehyde by adding 4-dimethylaminopyridine, Et 3 N, and t-butyldimethylsilyl chloride to the compound of the Chemical Formula 2 of claim 1 ; and
2) synthesizing 2-((3-((tert-butyldimethylsilyl)oxy)-6-(dimethylamino)naphthalen-2-yl)methylene)malononitrile by adding malononitrile and piperidine to the 3-(tert-butyldimethylsilyl)-6(dimethylamino)-2-naphthaldehyde obtained from step (1) to obtain the compound of Chemical Formula 5, wherein R is t-butyldimethylsilyl.

10. A method for screening a test compound for monoamine oxidase inhibitory activity, comprising the steps of:
a) measuring the fluorescence of the compound of Chemical Formula 3 or Chemical Formula 4 of claim 1 in the absence of the test compound;
b) contacting the test compound with monoamine oxidase in the presence of the compound of Chemical Formula 3 or Chemical Formula 4 of claim 1 ; and
(c) detecting fluorescence generated from step (b) wherein decreased fluorescence associated with the contacting step compared to the measured fluorescence corresponding to Chemical Formula 3 or Chemical Formula 4 in step (a) indicates that the test compound is a monoamine oxidase inhibitor.

11. A method for measuring the enzyme activity of a monoamine oxidase in a solution comprising
contacting the solution with the compound of Chemical Formula 3 or Chemical Formula 4 of claim 1 ;
detecting a change in the fluorescence associated with the contacting step; and
correlating the change in fluorescence with monoamine oxidase activity in the solution.

12. A method for imaging a cell comprising contacting a cell with the compound of Chemical Formula 1 of claim 1 , allowing the cell to uptake the compound of Chemical Formula 1 and exposing the contacted cell to light at a frequency known to cause the compound of Chemical Formula 1 to fluoresce, thereby imaging the cell.

13. A probe for detection of a mercury on comprising the compound of Chemical Formula 5 of claim 1 in which R is vinyl.

14. A probe for detection of a palladium on comprising the compound of Chemical Formula 5 of claim 1 in which R is propargyl.

15. A probe for detection of hydrogen peroxide comprising the compound of Chemical Formula 5 of claim 1 in which R is 4-boranato-benzyl.

16. A probe for detection of a fluoride on comprising the compound of Chemical Formula 5 of claim 1 in which R is t-butyldimethylsilyi.

17. A probe for detection of ozone comprising the compound of Chemical Formula 5 of claim 1 in which R is bromoallyl.

18. A probe for detection of a phosphatase comprising the compound of Chemical Formula 5 of claim 1 in which R is phosphate.

19. A probe for the detection of monoamine oxidase (MAO) comprising the compound of Chemical Formula 3 or Chemical Formula 4 of claim 1 .

20. A method for imaging a cell containing MAO comprising contacting a cell with the compound of Chemical formula 3 or Chemical Formula 4 of claim 1 and exposing the contacted cell to light at a wavelength between 350 nm and 550 nm wh

Assignees

• Ahn Kyo Han
• Kim Dokyoung
• Postech Acad Ind Found

Inventors

• Ahn Kyo Han
• Kim Dokyoung

Classifications

• C07D311/58 Primary

  other than with oxygen or sulphur atoms in position 2 or 4 · CPC title

• G01N2333/90638

  with a definite EC number (1.4.3.-) · CPC title

• C12Q1/26 Primary

  involving oxidoreductase · CPC title

• C07C253/30

  by reactions not involving the formation of cyano groups · CPC title

• C07C221/00

  Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton · CPC title