Azatriangulenium salts as PET-quenched fluorescent probes

Patent metadata

Field	Value
Publication number	US-10364249-B2
Application number	US-201415028558-A
Country	US
Kind code	B2
Filing date	Oct 24, 2014
Priority date	Oct 24, 2013
Publication date	Jul 30, 2019
Grant date	Jul 30, 2019

Abstract

The present invention relates to a new class of substituted aza-triangulenium fluorescent dyes having a hydroxy group attached to an aryl as quenching group. The new substituted aza-triangulenium fluorescent dyes may be attached to a linker, conjugated to carrier molecule such as e.g. a protein, a nucleic acid, a lipid, or a saccharide, or deposited or immobilized on solid support materials. The substituted aza-triangulenium fluorescent dyes are useful for various purposes, including use in sensors for monitoring or determining the concentration of analytes, such as H+(pH), Na+, K+, Ca2+, O2, CO2, H2O2, ionic strength, redox potentials, metal ions, and metabolites.

First claim

The invention claimed is:

1. A fluorescent dye compound of Formula (I)

wherein
X 1 denotes NR 11 , O, S, or C(R 11 ) 2 , or denotes two individual substituted or unsubstituted C 1 -C 24 -alkoxy groups, which each are linked to the two adjacent carbon atoms,
X 2 denotes NR 12 , O, S, or C(R 12 ) 2 , or denotes two individual substituted or unsubstituted C 1 -C 24 -alkoxy groups, which each are linked to the two adjacent carbon atoms,
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are independently selected from hydrogen, cyano, halogen, hydroxy, nitro, acyl, acylamino, acyloxy, C 1 -C 24 -alkyl, C 2 -C 24 -alkenyl, C 2 -C 24 -alkynyl, aryl, C 1 -C 24 -alkoxy, C 1 -C 24 -alkylsulfonyl, methylsulfonyl, triflouromethyl, amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, sulfonyl, sulfonyloxy, thioacyl, thiol, thiocarbonyl, C 1 -C 24 -alkylthio, heteroaryl, cycloalkyl, phenyl, hydroxyphenyl, aminophenyl, amino-C 1 -C 24 -alkyl, or heterocyclyl selected from a 5- or 6-membered heterocyclyl containing at least one nitrogen or sulphur atom, or two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 may together form a ring system; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 optionally being substituted once, twice, or three times with R 13 substituent(s), or a L-Si(OR 14 ) 3 substituent,
R 13 is independently selected from hydrogen, cyano, halogen, hydroxy, nitro, acyl, acylamino, acyloxy, C 1 -C 24 -alkyl, C 2 -C 24 -alkenyl,
C 2 -C 24 -alkynyl, aryl, C 1 -C 24 -alkoxy, C 1 -C 24 -alkylsulfonyl, methylsulfonyl, triflouromethyl, amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, sulfonyl, sulfonyloxy, thioacyl, thiol, thiocarbonyl, C 1 -C 24 -alkylthio, heteroaryl, or a cycloalkyl, or two R 13 substituents may together form a ring system,
R 14 is independently selected from hydrogen, or straight or branched C 1 -C 6 alkyl, alkenyl, or alkynyl, and
one or more of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 or R 12 is/are
a quenching group independently selected from phenyl substituted with one to five R 13 substituent(s) wherein at least one R 13 substituent is hydroxy, or a group selected from indole, benzoefuran, naphthalene, a 5- or 6-membered heterocyclyl or a C 1 -C 6 alkylene heterocyclyl containing at least one of N, NH, O, or S, said group being substituted one, two, or three times with R 13 substituent(s), wherein at least one R 13 substituent, attached to indole, benzoefuran, naphthalene, the 5- or 6-membered heterocyclyl, or the heterocyclyl moiety of C 1 -C 6 alkylene heterocyclyl is hydroxy, and
optionally together with a counter ion.

2. The compound of Formula (I) according to claim 1 , wherein at least one of the following substituents, R 10 , R 11 and R 12 , is a quenching group independently selected from the group comprising phenol, benzoefuran, indole, pyrrolidine, pyrrole, thiolane, thiophene, imidazolidine, pyrazolidine, imidazole, pyrazole, oxazolidine, isoxazolidine, oxazole, isoxazole, thiazolidine, isothiazolidine, thiazole, isothiazole, dithiolane, triazoles, furazan, oxadiazole, thiadiazole, dithiazole, tetrazole, piperidine, pyridine, thiane, thiopyran, piperazine, diazines, oxazine, thiazine, dithiane, dithiine, triazine, or tetrazine optionally substituted once, twice, three times with R 13 substituent(s).

3. The compound of Formula (I) according to claim 1 , wherein R 10 , R 11 and R 12 is a quenching group independently selected from the group comprising 2-phenol, 3-phenol, 4-phenol, hydroxy-indole, hydroxy-pyrrolidine, hydroxy-pyrrole, hydroxy-thiophene said group optionally being substituted once, two, or three times with R 13 substituent(s).

4. The compound of Formula (I) according to claim 1 selected from the group consisting of
9-(2,6-dimethoxyphenyl)-10-(3-hydroxyphenyl)-1,8-dimethoxy-acridinium (1c),
9-(2,6-dimethoxyphenyl)-10-(4-hydroxyphenyl)-1,8-dimethoxy-acridinium (1d),
9-(2,6-dimethoxyphenyl)-10-(2-hydroxy-5-(methylsulfonyl)phenyl)-1,8-dimethoxy-acridinium (1g),
5-(dodecyl)-9-(3-hydroxyphenyl)-1, 1 3-dimethoxy-quin[2,3,4-k]acridinium, (2c),
5-(4-aminophenyl)-9-(3-hydroxypropyl)-1, 1 3-dimethoxy-quin[2,3,4-k]acridinium (2e),
5-(dodecyl)-9-(5-fluor-2-hydroxyphenyl)-1, 1 3-dimethoxy-quin[2,3,4-k]acridinium (2f),
5-(dodecyl)-9-(5-methylsulfonyl-2-hydroxyphenyl)-1,13-dimethoxy-quin[2,3,4-k]acridinium (2g),
5-(dodecyl)-9-(5-trifluormethyl-2-hydroxyphenyl)-1,13-dimethoxy-quin[2,3,4-k]acridinium (2h),
1 2-(2-hydroxyphenyl)-4-aza-8, 1 2-dioxa-4, 8,12,12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (3b),
12-(3-hydroxyphenyl)-4-aza-8,12-dioxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (3c),
4-(3-hydroxyphenyl)-azadioxatriangulenium tetrafluoroborat 3d,
4-dodecyl-8-(2-hydroxyphenyl)-4, 8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4b),
4-dodecyl-8-(5-fluoro-2-hydroxyphenyl)-4, 8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4f),
4-dodecyl-8-(2-hydroxy-5-(methylsulfonyl)phenyl)-4,8-diaza-1 2-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4g),
4-dodecyl-8-(2-hydroxy-5-trifluoromethyl-phenyl)-4,8-diaza-1 2-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4h),
4-propyl-8-(2-hydroxyphenyl)-4,8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4i),
4-propyl-8-(3-hydroxyphenyl)-4,8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4j),
4-propyl-8-(4-hydroxyphenyl)-4,8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4k),
4-propyl-8-(5-fluoro-2-hydroxyphenyl)-4,8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4l),
4-propyl-8-(5-trifluoromethyl-2-hydroxyphenyl)-4,8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4m),
4-propyl-8-(2-hydroxy-5-(methylsulfonyl)phenyl)-4,8-diaza-1 2-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4n),
8-(hydroxy-pyridin)-4,8-diaza-12-oxa-4,8,12,12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4o),
8-(hydroxy-1-methyl-1H-pyrrol)-4,8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4p),
8-(hydroxy-thiophen)-4,8-diaza-12-oxa-4,8, 12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4q),
8-(hydroxy-1-methyl-1H-indol)-4,8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4r),
8-(hydroxy-naphthalen)-4,8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4s),
8-(hydroxybenzofuranyl)-4, 8-diaza-12-oxa-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (4u),
4-(2-hydroxy-5-methylsulfonyl-phenyl)-8,12-diphenyl-4,8,12-triaza-4,8,12, 12c-tetrahydro-dibenzo[cd,mn]-pyrenylium (5),
4-(2-hydroxyphenyl)-4-aza-8, 12-dioxatriangulenium hexafluorophophate (MR-68.1-ADOTA),
4-(2-hydroxyphenyl)-8-methyl-4, 8-diaza-1 2-oxatriangulenium hexafluorophosphate (MR-68-DAOTA),
4-(3-hydroxyphenyl)-4-aza-8, 12-dioxatriangulenium hexafluorophophate (MR-73-ADOTA),
4-(3-hydroxyphenyl)-8-methyl-8-aza-8, 12-dioxatriangulenium hexafluorophosphat, (MR-73.1-DAOTA),
4-(4-hydroxyphenyl)-4-aza-8, 11-dioxatriangulenium hexafluorophosphate (MR-93_ADOTA),
4-(4-hydroxyphenyl)-4, 8-diaza-11-oxatriangulenium hexafluorophosphate (MR-93_DAOTA),
4-(2-hydroxy-5-(trifluoromethyl)phenyl)-3-aza-8, 11-dioxatriangulenium hexafluorophosphate (MR-66.1_ADOTA),
4-(2-h

Assignees

• Univ Copenhagen
• Kobenhavns Univ

Inventors

• Laursen Bo V
• Rosenberg Martin
• Sorensen Thomas Just

Classifications

• C09K11/06

  containing organic luminescent materials · CPC title

• C07D491/16 Primary

  Peri-condensed systems · CPC title

• C07D491/14

  Ortho-condensed systems · CPC title

• C09B69/00

  Dyes not provided for by a single group of this subclass · CPC title

• G01N2021/6439

  with indicators, stains, dyes, tags, labels, marks · CPC title