Merocyanine-based compound and biomolecular labeling dye, kit and contrast agent composition comprising same

Patent metadata

Field	Value
Publication number	US-11292798-B2
Application number	US-202016848586-A
Country	US
Kind code	B2
Filing date	Apr 14, 2020
Priority date	Oct 17, 2017
Publication date	Apr 5, 2022
Grant date	Apr 5, 2022

Abstract

The present invention relates to: a novel merocyanine-based compound which exhibits a fluorescence signal at a visible light region of at least 380 nm, and which may be used for detecting biomolecules; and a biomolecular labeling dye, kit and contrast agent composition comprising the same.

First claim

The invention claimed is:

1. A merocyanine-based compound represented by the following Chemical Formula 1:

wherein,
Ar 1 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl,
Y 1 and Y 2 are each independently selected from sulfur, oxygen, selenium, NR 3 , CR 3 R 4 , SiR 3 R 4 , and —CR 3 ═CR 4 —,
Q is sulfur, oxygen, or NR a ,
R 1 is each independently selected from hydrogen, deuterium, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 2 -C 10 alkenyl, a substituted or unsubstituted C 1 -C 10 haloalkyl, a halogen, cyano, a substituted or unsubstituted amino, a substituted or unsubstituted amide, carboxyl, carboxylates, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, ketones (—COR 5 ), aldehydes, esters (—COOR 5 ), a -L-X functional group, and a -L-Z functional group,
R a and R 2 to R 4 are each independently selected from hydrogen, deuterium, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 2 -C 10 heteroalkyl including at least one heteroatom, a substituted or unsubstituted C 2 -C 10 alkenyl, a substituted or unsubstituted C 2 -C 10 alkynyl, a substituted or unsubstituted C 2 -C 10 alkoxy, a substituted or unsubstituted aryloxy, a substituted or unsubstituted C 1 -C 10 haloalkyl, a halogen, cyano, hydroxyl, a substituted or unsubstituted amino, a substituted or unsubstituted amide, carbamates, sulfhydryl, nitro, carboxyl, carboxylates, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, quaternary ammonium, phosphoric acid, phosphates, ketones (—COR 5 ), aldehydes, esters (—COOR 5 ), acyl chloride, sulfonic acid, sulfonates, a -L-X functional group, and a -L-Z functional group,
when R 1 , R 2 , R 3 , or R 4 is a ketone group (—COR 5 ) or an ester group (—COOR 5 ), R 5 is selected from a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 2 -C 10 heteroalkyl including at least one heteroatom, a substituted or unsubstituted C 2 -C 10 alkenyl, a substituted or unsubstituted C 2 -C 10 alkynyl, a substituted or unsubstituted C 2 -C 10 alkoxy, a substituted or unsubstituted C 1 -C 10 haloalkyl, a substituted or unsubstituted heteroaryl, and a substituted or unsubstituted C 1 -C 10 aminoalkyl,
R 9 and R 10 are each independently selected from hydrogen and a substituted or unsubstituted alkyl, or R 9 and R 10 are bonded to each other to form a four-membered, five-membered, or a six-membered hydrocarbon ring,
in the -L-X and -L-Z functional groups,
L is a linker selected from 1-20 atoms selected from carbon, nitrogen, oxygen, and sulfur, —NHCOO—, —CONH—, —CH 2 NH—, —CH 2 NR 6 —, —COO—, —SO 2 NH—, —HN—C(═NH)—NH—, —NR 6 —, —(CH 2 —CH 2 —O—) p —, —CH═CH—, —C≡C—, —Ar—, and —CO—Ar—NR 6 —, R 6 is selected from hydrogen, a substituted or unsubstituted C 1 -C 6 alkyl, a substituted or unsubstituted C 2 -C 10 heteroalkyl including at least one heteroatom, a substituted or unsubstituted C 2 -C 10 alkenyl, a substituted or unsubstituted C 2 -C 10 alkynyl, a substituted or unsubstituted C 2 -C 6 alkoxy, and a substituted or unsubstituted C 1 -C 6 haloalkyl, Ar is an aryl or a heteroaryl, and p is an integer from 1 to 100,
X is a reactive group selected from carboxyl, succinimidyl ester, sulfo-succinimidyl ester, isothiocyanate, maleimide, haloacetamide, hydrazide, vinyl sulphone, dichlorotriazine, phosphoramidite, alkyl halides, acyl halides, carbohydrazide, hydroxylamine, ketones, alkynes, azide, aliphatic and aromatic amines, sulfotetrafluorophenyl ester, sulfodichlorophenyl ester, carbonyl azide, sulfonyl chloride, sulfonyl fluoride, boronic acid, isocyanate, a halogen-substituted triazine, a halogen-substituted pyridine, a halogen-substituted diazine, tetrafluorophenyl ester, imido ester, azidonitrophenyl, glyoxal, and aldehydes,
Z is a fluorophore capable of generating a fluorescence signal,
when R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 is substituted, any carbon or terminal carbon in the functional group is substituted with at least one selected from sulfonic acid, sulfonates, carboxylic acids, carboxylates, phosphoric acid, phosphates, alkyls, heteroaryls, polyalkylene oxides, quaternary ammonium salts, esters, and amides, and
m is an integer from 1 to 3.

2. The merocyanine-based compound of claim 1 , wherein when Ar 1 is substituted, any carbon in the functional group is substituted with at least one selected from deuterium, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 2 -C 10 heteroalkyl including at least one heteroatom, a substituted or unsubstituted C 2 -C 10 alkenyl, a substituted or unsubstituted C 2 -C 10 alkynyl, a substituted or unsubstituted C 2 -C 10 alkoxy, a substituted or unsubstituted aryloxy, a substituted or unsubstituted C 1 -C 10 haloalkyl, a halogen, cyano, hydroxyl, a substituted or unsubstituted amino, a substituted or unsubstituted amide, carbamates, nitro, a substituted or unsubstituted sulfonamide, polyalkylene oxides, carboxyl, carboxylates, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, quaternary ammonium, phosphoric acid, phosphates, ester (—COOR 5 ), acyl chloride, sulfonic acid, sulfonates, a -L-X functional group, and a -L-Z functional group.

3. The merocyanine-based compound of claim 1 , wherein Z is a fluorophore selected from structures displayed by coumarins, cyanine, BODIPY, fluoresceins, rhodamines, pyrenes, carbopyronin, oxazines, xanthenes, thioxanthene, acridines, and Chemical Formula 1.

4. The merocyanine-based compound of claim 1 , wherein the merocyanine-based compound is at least one selected from compounds represented by the following Chemical Formulae:

wherein,
R 7 and R 8 are each independently selected from hydrogen, deuterium, a substituted or unsubstituted C 1 -C 10 alkyl, a substituted or unsubstituted C 2 -C 10 heteroalkyl including at least one heteroatom, a substituted or unsubstituted C 2 -C 10 alkenyl, a substituted or unsubstituted C 2 -C 10 alkynyl, a substituted or unsubstituted C 2 -C 10 alkoxy, a substituted or unsubstituted aryloxy, a substituted or unsubstituted C 1 -C 10 haloalkyl, a halogen, cyano, hydroxyl, a substituted or unsubstituted amino, a substituted or unsubstituted amide, carbamates, nitro, a substituted or unsubstituted sulfonamide, polyalkylene oxides, carboxyl, carboxylates, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, quaternary ammonium, phosphoric acid, phosphates, ester (—COOR 5 ), acyl chloride, sulfonic acid, sulfonates, a -L-X functional group, and a -L-Z functional group, and
Y 3 is sulfur, oxygen, selenium, NR 3 , CR 3 R 4 , SiR 3 R 4 , or —CR 3 ═CR 4 —.

5. A biomolecular labeling dye comprising the merocyanine-based compound according to claim 1 .

6. The biomolecular labeling dye of claim 5 , wherein the biomolecular labeling dye is used to label at least one selected from antibodies, lipids, proteins, peptides, carbohydrates, and nucleic acids.

7. A biomolecular labeling kit comprising the biomolecular labeling dye according to claim 6 .

8. A contrast agent composition comprising the merocyanine-based compound according to claim 1 .

Assignees

• Sfc Co Ltd

Inventors

• Shin Bong-Ki
• Je Jong-Tae

Classifications

• C09B57/00

  Other synthetic dyes of known constitution · CPC title

• A61K49/006

  Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery · CPC title

• A61K49/0019

  characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules · CPC title

• C07D517/16

  Peri-condensed systems · CPC title

• C09B23/0091 Primary

  having only one heterocyclic ring at one end of the methine chain, e.g. hemicyamines, hemioxonol (styryl dyes see C09B23/14) · CPC title