Benzazolylcoumarin-based ion indicators
First Claim
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1. A compound of the formula:
- ##STR8## wherein m is either 2 or 3;
A is either of the formula ##STR9## or A is of the formula ##STR10## wherein R1 is H, an alkyl group having 1-5 carbons, a benzyl, an alpha-acyloxyalkyl or a pharmaceutically acceptable esterifying group, a t-butyldimethylsilyl ester, or a pharmaceutically acceptable salt;
R2, R3, R4 and R5 are independently H or methyl;
R6 and R7 are independently H, CN, CH3, CF3 or CONH2 ;
X and X'"'"' are independently O, S, or C(CH3)2 ;
Y and Y'"'"' are independently H, an alkyl having 1-18 carbons, --NO2, --NH2, --NH(C═
O)(CH2)n CH3, --CF3, F, Cl, Br, I, --OR8, --CO2 R9, or --OCH2 CO2 R9, where n=0-16;
R8 is H, an alkyl group having 1-18 carbons, a benzyl (C6 H5 CH2 --), an alpha-acyloxyalkyl, acetate, or a t-butyldimethylsilyl ether; and
R9 is H, an alkyl group having 1-17 carbons, a benzyl (C6 H5 CH2 --) an alpha-acyloxyalkyl or other pharmaceutically acceptable esterifying group, a t-butyldimethylsilyl ester, or a pharmaceutically acceptable salt;
or one of Y and Y'"'"' is a covalently attached conjugant; and
Z is one of H, an alkyl having 1-18 carbons, --NH2, --NH(C═
O)(CH2)n CH3, --CF3, F, Cl, Br, I, --OR8, --CO2 R9, or --OCH2 CO2 R9 ;
or Z is a covalently attached conjugant.
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Abstract
The indicator compounds of the present invention are substituted or unsubstituted BAPTA-type chelators that contain a benzazolyl-coumarin substructure, and the pharmaceutically acceptable non-toxic salts and esters thereof. These compounds are useful for the detection and quantification of polycationic metal ions, particularly Ca2+.
The compounds of the invention have the core structure ##STR1## or the structure ##STR2## where m=2 or 3 and X can be S, O, or C(CH3)2. The above core structures are optionally substituted by substituents that alter the binding affinity of the indicator, shift the spectral properties of the indicator, or act as a reactive site for the preparation of a variety of conjugates.
160 Citations
21 Claims
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1. A compound of the formula:
- ##STR8## wherein m is either 2 or 3;
A is either of the formula ##STR9## or A is of the formula ##STR10## wherein R1 is H, an alkyl group having 1-5 carbons, a benzyl, an alpha-acyloxyalkyl or a pharmaceutically acceptable esterifying group, a t-butyldimethylsilyl ester, or a pharmaceutically acceptable salt; R2, R3, R4 and R5 are independently H or methyl; R6 and R7 are independently H, CN, CH3, CF3 or CONH2 ; X and X'"'"' are independently O, S, or C(CH3)2 ; Y and Y'"'"' are independently H, an alkyl having 1-18 carbons, --NO2, --NH2, --NH(C═
O)(CH2)n CH3, --CF3, F, Cl, Br, I, --OR8, --CO2 R9, or --OCH2 CO2 R9, where n=0-16;
R8 is H, an alkyl group having 1-18 carbons, a benzyl (C6 H5 CH2 --), an alpha-acyloxyalkyl, acetate, or a t-butyldimethylsilyl ether; and
R9 is H, an alkyl group having 1-17 carbons, a benzyl (C6 H5 CH2 --) an alpha-acyloxyalkyl or other pharmaceutically acceptable esterifying group, a t-butyldimethylsilyl ester, or a pharmaceutically acceptable salt;
or one of Y and Y'"'"' is a covalently attached conjugant; andZ is one of H, an alkyl having 1-18 carbons, --NH2, --NH(C═
O)(CH2)n CH3, --CF3, F, Cl, Br, I, --OR8, --CO2 R9, or --OCH2 CO2 R9 ;
or Z is a covalently attached conjugant. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
- ##STR8## wherein m is either 2 or 3;
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16. A method of measuring the concentration of a polycationic metal ion in a sample, comprising:
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a) adding to said sample, in an amount sufficient to generate a detectable fluorescent response to said metal ion, a compound according to the formula ##STR13## wherein m is either 2 or 3; A is either of the formula ##STR14## or A is of the formula ##STR15## wherein R1 is H, an alkyl group having 1-5 carbons, a benzyl, an alpha-acyloxyalkyl or a pharmaceutically acceptable esterifying group, a t-butyldimethylsilyl ester, or a pharmaceutically acceptable salt; R2, R3, R4 and R5 are independently H or methyl; R6 and R7 are independently H, CN, CH3, CF3 or CONH2 ; X and X'"'"' are independently O, S, or C(CH3)2 ; Y and Y'"'"' are independently H, an alkyl having 1-18 carbons, --NO2, --NH2, --NH(C═
O)(CH2)n CH3, --CF3, F, Cl, Br, I, --OR8, --CO2 R9, or --OCH2 CO2 R9, where n=0-16;
R9 is H, an alkyl group having 1-18 carbons, a benzyl (C6 H5 CH2 --), an alpha-acyloxyalkyl, acetate, or a t-butyldimethylsilyl ether; and
R9 is H, an alkyl group having 1-17 carbons, a benzyl (C6 H5 CH2 --) an alpha-acyloxyalkyl or other pharmaceutically acceptable esterifying group, a t-butyldimethylsilyl ester, or a pharmaceutically acceptable salt;
or one of Y and Y'"'"' is a covalently attached conjugant; andZ is one of H, an alkyl having 1-18 carbons, --NH2, --NH(C═
O)(CH2)n CH3, --CF3, F, Cl, Br, I, --OR8, --CO2 R9, or --OCH2 CO2 R9 ;
or Z is a covalently attached conjugant;b) illuminating said sample to generate an absorbance or fluorescence response; and c) observing said absorbance or fluorescence response. - View Dependent Claims (17, 18, 19, 20, 21)
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Current AssigneeMolecular Probes Incorporated (Thermo Fisher Scientific Incorporated)
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Original AssigneeMolecular Probes Incorporated (Thermo Fisher Scientific Incorporated)
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InventorsIatridou, Helene, Foukaraki, Evangelia, Malekzadeh, Mohammad N., Katerinopoulos, Haralambos E., Haugland, Richard P., Kuhn, Michael A.
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Primary Examiner(s)Housel, James C.
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Assistant Examiner(s)Soderquist, Arlen
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Application NumberUS08/247,013Time in Patent Office676 DaysField of Search436/73, 436/74, 436/79, 436/172, 436/63, 548/159, 548/215, 548/463US Class Current436/74CPC Class CodesC07D 417/04 directly linked by a ring-m...C07D 417/14 containing three or more he...C09K 11/06 containing organic luminesc...G01N 31/22 using chemical indicators G...G01N 33/1813 specific cations in water, ...
