Crown ether derivatives

A composition of matter comprising a compound of the formula:

• 112
• P and Q are independently O, S, or NR3, where each R3 is independently H or C1-C6 alkyl;
• Y is O, S, or NR4, where R4 is H;
• or is —L—RX, —L—SC, or —L—DYE;
• or is C1-C18 alkyl or an aryl or heteroaryl ring system, which alkyl or ring system is optionally substituted by halogen, azido, nitro, nitroso, amino, C1-C6 alkylamino, C2-C12 dialkylamino, cyano, —L—RX, —L—SC, or —L—DYE;
• or by C1-C6 alkyl or C1-C6 alkoxy that is itself optionally substituted by halogen, amino, hydroxy, —(SO2)—R15, —(SO2)—O—R15, —(C═O)—R15, —(C═O)—O—R16, or —(C═O)—NR17R18;
• wherein
• R15 is H or C1-C6 alkyl;
• or —L—RX, —L—SC, or —L—DYE;
• R16 is H, a C1-C6 alkyl, a benzyl, a biologically compatible esterifying group, a biologically compatible salt;
• or —L—RX, —L—SC, or —L—DYE;
• R17 and R18 are independently H, C1-C6 alkyl, C1-C6 carboxyalkyl, an alpha-acyloxyalkyl, a t-butyldimethylsilyl, or a biologically compatible salt;
• or —L—RX, —L—SC, or —L—DYE;
• or R17 and R18 taken in combination form a 5- or 6-membered aliphatic ring that optionally incorporates an oxygen atom;
• each L is independently a covalent linkage;
• each RX is independently a reactive functional group;
• each SC is independently a conjugated substance;
• DYE is a chemical moiety with an absorption maximum beyond 320 nm;
• E1, E2, and E3 are independently —(CR52)n—, where n=2-4, and each R5 is independently H or CH3, or two R5 moieties on adjacent carbons of one or more of E1, E2 or E3, when taken in combination, form a 5- or 6-membered aliphatic ring;
• R1 and R2 are independently H;
• or —L—RX, —L—SC, or —L—DYE;
• or C1-C18 alkyl or C7-C18 arylalkyl, each of which is optionally substituted by halogen, azido, nitro, nitroso, amino, hydroxy, cyano, or by an aryl or heteroaryl ring system;
• or by —(SO2)—R15, —(SO2)—O—R15, —(C═O)—R15, —(C═O)—O—R16, —(C═O)—NR17R18;
• or by C1-C6 alkylamino, C2-C12 dialkylamino;
• or by C1-C6 alkyl or C1-C6 alkoxy, each of which is itself optionally substituted by halogen, amino, hydroxy, —(SO2)—R15, —(SO2)—O—R15, —(C═O)—R15, —(C═O)——O—R16, —(C═O)—NR17R18;
• R7-R14 are independently H, halogen, azido, nitro, nitroso, amino, cyano, —L—RX, —L—SC, —L—DYE;
• or C1-C6 alkyl or C1-C6 alkoxy, each of which is itself optionally substituted by halogen, amino, hydroxy, —(SO2)—R15, —(SO2)—O—R15, —(C═O)—R15, —(C═O)—O—R16, or —(C═O)—NR17R18;
• or any two adjacent substituents R7-R14, taken in combination, form a fused six-membered benzo moiety, which is optionally substituted by halogen, azido, nitro, nitroso, amino, cyano, —L—RX, —L—SC, or —L—DYE;
• or C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted by halogen, amino, hydroxy, —(C═O)—R15, —(C═O)—O—R16, or (C═O)—NR17R18;
• or any two adjacent substituents R7-R14, taken in combination with each other, and with the aromatic ring they are bound to, form a fused DYE;
• provided that said compound is substituted by at least one —L—DYE moiety at one or more of R1, R2, R3, and R7-R14;
• or at least two of R7-R14, taken in combination, form a fused DYE.

A compound having the formula:

• 114
• R1 and R2 are C1-C6 alkyl that are substituted one or more times by cyano, an aryl or heteroaryl ring system, or by —(C═O)—O—R16 or —(C═O)—NR17R18, where
• R16 is H, a C1-C6 alkyl, a benzyl, a biologically compatible esterifying group, or a biologically compatible salt;
• R17 and R18 are independently H, C1-C6 alkyl, C1-C6 carboxyalkyl, an alpha-acyloxymethyl, or a biologically compatible salt;
• R7-R10, and R11-R14, where present, are independently H, chloro, bromo, fluoro, nitro, amino, or cyano;
• or C1-C6 alkyl or C1-C6 alkoxy that is itself optionally substituted by halogen, amino, hydroxy, —(SO2)—R15, —(SO2)—O—R15, —(C═O)—R15, —(C═O)—O—R16, or —(C═O)—NR17R18;
• and
• DYE, where present is a polyazaindacene, an oxazine, or a xanthene, which is optionally substituted by halogen, nitro, sulfo, cyano, an aryl or heteroaryl ring system, or benzo, or alkyl, perfluoroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, arylalkyl, or acyl, the alkyl portions of which contain fewer than 20 carbons.

A compound having the formula:

• 115
• wherein
• R8, where present, is independently H or a C1-C6 alkyoxy, which is optionally substituted by —(C═O)—O—R16 or —(C═O)—NR17R18;
• R16 and R26, where present, are independently H, a C1-C6 alkyl, a benzyl, an alpha-acyloxyalkyl, a t-butyldimethylsilyl, or a biologically compatible salt;
• R17 and R18, where present, are independently H, a C1-C6 alkyl, C1-C6 carboxyalkyl, or a biologically compatible salt;
• W and W′, where present, are independently F or Cl;
• R30-R35, where present, are independently H, halogen, nitro, sulfo, cyano, alkyl, perfluoroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, arylalkyl, or acyl, wherein the alkyl portions of each contain fewer than 20 carbons;
• or an aryl or heteroaryl ring system;
• or adjacent substituents R31 and R32, and adjacent substituents R33 and R34, when taken in combination form a fused benzo ring that is optionally substituted by hydrogen, halogen, nitro, sulfo, cyano, alkyl, perfluoroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, alkylthio, alkylamido, amino, monoalkylamino or dialkylamino wherein the alkyl portions of each contain fewer than 20 carbons.

A method of detecting a target cationic metal ion in a sample, comprising:

• a) adding to said sample, in an amount sufficient to generate a detectable optical response when said target ion is present, a compound having the formula:
• 116
• wherein
• P and Q are independently O, S, or NR3, where each R3 is independently H or C1-C6 alkyl;
• Y is O, S, or NR4, where R4 is H;
• or is —L—RX, —L—SC, or —L—DYE;
• or is C1-C18 alkyl or an aryl or heteroaryl ring system, which alkyl or ring system is optionally substituted by halogen, azido, nitro, nitroso, amino, C1-C6 alkylamino, C2-C12 dialkylamino, cyano, —L—RX, —L—SC, or —L—DYE;
• or by C1-C6 alkyl or C1-C6 alkoxy that is itself optionally substituted by halogen, amino, hydroxy, —(SO2)—R15, —(SO2)—O—R15, —(C═O)—R15, —(C═O)—O—R16, or —(C═O)—NR17R18;
• wherein
• R15 is H or C1-C6 alkyl;
• or —L—RX, —L—SC, or —L—DYE;
• R16 is H, a C1-C6 alkyl, a benzyl, a biologically compatible esterifying group, a biologically compatible salt;
• or —L—RX, —L—SC, or —L—DYE;
• R17 and R18 are independently H, C1-C6 alkyl, C1-C6 carboxyalkyl, an alpha-acyloxyalkyl, a t-butyldimethylsilyl, or a biologically compatible salt;
• or —L—RX, —L—SC, or —L—DYE;
• or R17 and R18 taken in combination form a 5- or 6-membered aliphatic ring that optionally incorporates an oxygen atom;
• each L is independently a covalent linkage;
• each RX is independently a reactive functional group;
• each SC is independently a conjugated substance;
• DYE is a chemical moiety with an absorption maximum beyond 320 nm;
• E1, E2, and E3 are independently —(CR52)n—, where n=2-4, and each R5 is independently H or CH3, or two R5 moieties on adjacent carbons of one or more of E1, E2 or E3, when taken in combination, form a 5- or 6-membered aliphatic ring;
• R1 and R2 are independently H;
• or —L—RX, —L—SC, or —L—DYE;
• or C1-C18 alkyl or C7-C18 arylalkyl, each of which is optionally substituted by halogen, azido, nitro, nitroso, amino, hydroxy, cyano, or by an aryl or heteroaryl ring system;
• or by —(SO2)—R15, —(SO2)—O—R15, —(C═O)—R15, —(C═O)—O—R16, —(C═O)—NR17R18;
• or by C1-C6 alkylamino, C2-C12 dialkylamino;
• or by C1-C6 alkyl or C1-C6 alkoxy, each of which is itself optionally substituted by halogen, amino, hydroxy, —(SO2)—R15, —(SO2)—O—R15, —(C═O)—R15, —(C═O)——O—R16, —(C═O)—NR17R18;
• R7-R14 are independently H, halogen, azido, nitro, nitroso, amino, cyano, —L—RX, —L—SC, —L—DYE;
• or C1-C6 alkyl or C1-C6 alkoxy, each of which is itself optionally substituted by halogen, amino, hydroxy, —(SO2)—R15, —(SO2)—O—R15, —(C═O)—R15, —(C═O)—O—R16, or —(C═O)—NR17R18;
• or any two adjacent substituents R7-R14, taken in combination, form a fused six-membered benzo moiety, which is optionally substituted by halogen, azido, nitro, nitroso, amino, cyano, —L—RX, —L—SC, or —L—DYE;
• or C1-C6 alkyl or C1-C6 alkoxy, each of which is optionally substituted by halogen, amino, hydroxy, —(C═O)—R15, —(C═O)—O—R16, or —(C═O)—NR17R18;
• or any two adjacent substituents R7-R14, taken in combination with each other, and with the aromatic ring they are bound to, form a fused DYE;
• provided that said compound is substituted by at least one —L—DYE moiety at one or more of R1, R2, R3, and R7-R14;
• or at least two of R7-R14, taken in combination, form a fused DYE;
• b) illuminating said sample to generate said detectable optical response that indicates that said target ion is present.

A kit for the detection or quantification of a target metal ion, comprising a compound having the formula:

• 118
• R8, where present, is independently H or a C1-C6 alkyoxy, which is optionally substituted by —(C═O)—O—R16 or —(C═O)—NR17R18;
• R16 and R26, where present, are independently H, a C1-C6 alkyl, a benzyl, an alpha-acyloxyalkyl, a t-butyldimethylsilyl, or a biologically compatible salt;
• R17 and R18, where present, are independently H, a C1-C6 alkyl, C1-C6 carboxyalkyl, or a biologically compatible salt;
• W and W′, where present, are independently F or Cl;
• R30-R35, where present, are independently H, halogen, nitro, sulfo, cyano, alkyl, perfluoroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, arylalkyl, or acyl, wherein the alkyl portions of each contain fewer than 20 carbons;
• or an aryl or heteroaryl ring system;
• and comprising one or more components selected from the group consisting of:
• a) a calibration standard of a target ion;
• b) an ionophore;
• c) a fluorescence standard;
• d) an aqueous buffer solution;
• and
• e) an organic solvent.