US 6,162,931 AGranted

Fluorinated xanthene derivatives

AssigneeMolecular Probes, Inc.

InventorsKyle R. Gee, Martin Poot, Dieter H. Klaubert, Wei-Chuan Sun, Richard P. Haugland, Fei Mao

Life of this patent

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Abstract

The family of dyes of the invention are fluoresceins and rhodols that are directly substituted on one or more aromatic carbons by fluorine. These fluorine-substituted fluorescent dyes possess greater photostability and have lower sensitivity to pH changes in the physiological range of 6-8 than do non-fluorinated dyes, exhibit less quenching when conjugated to a substance, and possess additional advantages. The dyes of the invention are useful as detectable tracers and for preparing conjugates of organic and inorganic substances.

Claims107

Dependent claims

A compound having the formula ##STR10## or the formula ##STR11## wherein R.sup.1 and R.sup.6 are independently H, F, Cl, Br, I, C.sub.1 -C.sub.18 alkyl or C.sub.1 -C.sub.18 alkoxy;

R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently H, F, Cl, Br, I, CN;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy or C.sub.1 -C.sub.18 alkylthio, where each alkyl, alkoxy or alkylthio is optionally further substituted by F, Cl, Br, I, sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 where R.sup.18 is a C.sub.1 -C.sub.4 alkyl;
or amino, alkylamino, dialkylamino, or alkoxy, the alkyl portions of which independently have 1-6 carbons;
or one or both of R.sup.3 and R.sup.4 are --CH.sub.2 N(CH.sub.2 COOR.sup.17).sub.2, where R.sup.17 is H, a biologically compatible counterion, a linear or branched alkyl having 1-6 carbons, or --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
A is OR.sup.7 or NR.sup.8 R.sup.9,
where each R.sup.7 is independently H, C.sub.1 -C.sub.18 alkyl, a C.sub.1 -C.sub.18 acyl wherein each alkyl group independently has 1-6 carbons and is optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or a trialkylsilyl wherein each alkyl group independently has 1-6 carbons;
R.sup.8 and R.sup.9 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 carboxyalkyl, C.sub.1 -C.sub.6 sulfoalkyl, a salt of C.sub.1 -C.sub.6 carboxyalkyl, a salt of C.sub.1 -C.sub.6 sulfoalkyl, or C.sub.1 -C.sub.18 acyl wherein the alkyl portions are optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.8 in combination with R.sup.2, or R.sup.9 in combination with R.sup.3, or both, form a saturated 5- or 6-membered ring that is optionally substituted by one or more methyls;
or R.sup.8 in combination with R.sup.9 forms a saturated 5- or 6-membered heterocycle that is a piperidine, a morpholine, a pyrrolidine or a piperazine, each of which is optionally substituted by methyl, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
R.sup.10 is F, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.10 is C.sub.1 -C.sub.18 alkyl, alkenyl or alkynyl that is optionally substituted one or more times by F, Cl, Br, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, or dialkylamino, the alkyl groups of which have 1-6 carbons;
or R.sup.10 has the formula ##STR12## where R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently H, F, Cl, Br, I;
or sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, CN, nitro, hydroxy, azido, amino, hydrazino;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy, C.sub.1 -C.sub.18 alkylthio, C.sub.1 -C.sub.18 alkylamino, C.sub.1 -C.sub.18 alkylester, C.sub.1 -C.sub.18 alkylamido or C.sub.1 -C.sub.18 arylamido, the alkyl or aryl portions of which are optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, dialkylamino or alkoxy, the alkyl portions of each having 1-6 carbons;
or one pair of adjacent substituents R.sup.13 and R.sup.14, R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, when taken in combination, form a fused 6-membered aromatic ring that is optionally further substituted by carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
and
R.sup.11 is H, hydroxy, CN or a C.sub.1 -C.sub.6 alkoxy;
or R.sup.10 in combination with R.sup.11 forms a 5-membered spirolactone ring or a 5-membered spirosultone ring;
or R.sup.11 in combination with R.sup.12 forms a 5- or 6-membered spirolactone ring or a 5- or 6-membered spirosultone ring that is optionally and independently substituted by H, F or CH.sub.3 ;
or R.sup.10 when taken in combination with R.sup.11 is a carbonyl oxygen;
provided that at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.10 is F, or at least three of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are F.

19 more elements

A compound having the formula ##STR14## or the formula ##STR15## wherein R.sup.1 and R.sup.6 are independently H, F, Cl, Br, I, C.sub.1 -C.sub.18 alkyl or C.sub.1 -C.sub.18 alkoxy;

R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently H, F, Cl, Br, I, CN;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy or C.sub.1 -C.sub.18 alkylthio, where each alkyl, alkoxy or alkylthio is optionally further substituted by F, Cl, Br, I, sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 where R.sup.18 is a C.sub.1 -C.sub.4 alkyl;
or amino, alkylamino, dialkylamino, or alkoxy, the alkyl portions of which independently have 1-6 carbons;
or one or more of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is --L--R.sub.x ;
A is OR.sup.7 or NR.sup.8 R.sup.9,
where each R.sup.7 is independently H, C.sub.1 -C.sub.18 alkyl, a C.sub.1 -C.sub.18 acyl wherein each alkyl group independently has 1-6 carbons and is optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or a trialkylsilyl wherein each alkyl group independently has 1-6 carbons;
or R.sup.7 is an --L--R.sub.x ;
R.sup.8 and R.sup.9 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 carboxyalkyl, C.sub.1 -C.sub.6 sulfoalkyl, a salt of C.sub.1-C.sub.6 carboxyalkyl, a salt of C.sub.1 -C.sub.6 sulfoalkyl, or C.sub.1 -C.sub.18 acyl wherein the alkyl portions are optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.8 in combination with R.sup.2, or R.sup.9 in combination with R.sup.8, or both, form a saturated 5- or 6-membered ring that is optionally substituted by one or more methyls;
or R.sup.8 in combination with R.sup.9 forms a saturated 5- or 6-membered heterocycle that is a piperidine, a morpholine, a pyrrolidine or a piperazine, each of which is optionally substituted by methyl, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one of R.sup.8 and R.sup.9 is --L--R.sub.x ;
and
R.sup.10 is F, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.10 is C.sub.1 -C.sub.18 alkyl, alkenyl or alkynyl that is optionally substituted one or more times by F, Cl, Br, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, or dialkylamino, the alkyl groups of which have 1-6 carbons;
or R.sup.10 is an --L--R.sub.x ;
or R.sup.10 has the formula ##STR16## where R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently H, F, Cl, Br, I;
or sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, CN, nitro, hydroxy, azido, amino, hydrazino;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy, C.sub.1 -C.sub.18 alkylthio, C.sub.1 -C.sub.18 alkylamino, C.sub.1 -C.sub.18 alkylester, C.sub.1 -C.sub.18 alkylamido or C.sub.1 -C.sub.18 arylamido, the alkyl or aryl portions of which are optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, dialkylamino or alkoxy, the alkyl portions of each having 1-6 carbons;
or one pair of adjacent substituents R.sup.13 and R.sup.14, R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, when taken in combination, form a fused 6-membered aromatic ring that is optionally further substituted by carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one or more of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 is --L--R.sub.x ;
R.sup.11 is H, hydroxy, CN or a C.sub.1 -C.sub.6 alkoxy;
or R.sup.10 in combination with R.sup.11 forms a 5-membered spirolactone ring or a 5-membered spirosultone ring;
or R.sup.11 in combination with R.sup.12 forms a 5- or 6-membered spirolactone ring or a 5- or 6-membered spirosultone ring that is optionally and independently substituted by H, F or CH.sub.3 ;
or R.sup.10 when taken in combination with R.sup.11 is a carbonyl oxygen;
provided that at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.10 is F, or at least three of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are F;
and
further provided that at least one of R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 is --L--R.sub.x, where each --L--R.sub.x is optionally the same or different;
wherein
L is a single covalent bond, or L is a covalent linkage having 1-24 nonhydrogen atoms selected from the group consisting of C, N, O and S and is composed of any combination of single, double, triple or aromatic carbon-carbon bonds, carbon-nitrogen bonds, nitrogen-nitrogen bonds, carbon-oxygen bonds and carbon-sulfur bonds;
and
R.sub.x is a reactive site.

29 more elements

A compound having the formula ##STR17## or the formula ##STR18## wherein R.sup.1 and R.sup.6 are independently H, F, Cl, Br, I, C.sub.1 -C.sub.18 alkyl or C.sub.1 -C.sub.18 alkoxy;

R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently H, F, Cl, Br, I, CN;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy or C.sub.1 -C.sub.18 alkylthio, where each alkyl, alkoxy or alkylthio is optionally further substituted by F, Cl, Br, I, sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 where R.sup.18 is a C.sub.1 -C.sub.4 alkyl;
or amino, alkylamino, dialkylamino, or alkoxy, the alkyl portions of which independently have 1-6 carbons;
or one or more of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is --L--S.sub.c ;
A is OR.sup.7 or NR.sup.8 R.sup.9,
where each R.sup.7 is independently H, C.sub.1 -C.sub.18 alkyl, a C.sub.1 -C.sub.18 acyl wherein each alkyl group independently has 1-6 carbons and is optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.7 is --L--S.sub.c ;
R.sup.8 and R.sup.9 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 carboxyalkyl, C.sub.1 -C.sub.6 sulfoalkyl, a salt of C.sub.1 -C.sub.6 carboxyalkyl, a salt of C.sub.1 -C.sub.6 sulfoalkyl, or C.sub.1 -C.sub.18 acyl wherein the alkyl portions are optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.8 in combination with R.sup.2, or R.sup.9 in combination with R.sup.3, or both, form a saturated 5- or 6-membered ring that is optionally substituted by one or more methyls;
or R.sup.8 in combination with R.sup.9 forms a saturated 5- or 6-membered heterocycle that is a piperidine, a morpholine, a pyrrolidine or a piperazine, each of which is optionally substituted by methyl, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one of R.sup.8 and R.sup.9 is --L--S.sub.c ;
and
R.sup.10 is F, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.10 is C.sub.1 -C.sub.18 alkyl, alkenyl or alkynyl that is optionally substituted one or more times by F, Cl, Br, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, or dialkylamino, the alkyl groups of which have 1-6 carbons;
or R.sup.10 is --L--S.sub.c ;
or R.sup.10 has the formula ##STR19## where R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently H, F, Cl, Br, I;
or sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, CN, nitro, hydroxy, azido, amino, hydrazino;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy, C.sub.1 -C.sub.18 alkylthio, C.sub.1 -C.sub.18 alkylamino, C.sub.1 -C.sub.18 alkylester, C.sub.1 -C.sub.18 alkylamido or C.sub.1 -C.sub.18 arylamido, the alkyl or aryl portions of which are optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, dialkylamino or alkoxy, the alkyl portions of each having 1-6 carbons;
or one pair of adjacent substituents R.sup.13 and R.sup.14, R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, when taken in combination, form a fused 6-membered aromatic ring that is optionally further substituted by carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one or more of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 is --L--S.sub.c ;
R.sup.11 is H, hydroxy, CN or a C.sub.1 -C.sub.6 alkoxy;
or R.sup.10 in combination with R.sup.11 forms a 5-membered spirolactone ring or a 5-membered spirosultone ring;
or R.sup.11 in combination with R.sup.12 forms a 5- or 6-membered spirolactone ring or a 5- or 6-membered spirosultone ring that is optionally and independently substituted by H, F or CH.sub.3 ;
or R.sup.10 in combination with R.sup.11 is a carbonyl oxygen;
provided that at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.10 is F, or at least three of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are F;
and
further provided that at least one of R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 is an --L--S.sub.c ;
L is a single covalent bond, or L is a covalent linkage having 1-24 nonhydrogen atoms selected from the group consisting of C, N, O and S and is composed of any combination of single, double, triple or aromatic carbon-carbon bonds, carbon-nitrogen bonds, nitrogen-nitrogen bonds, carbon-oxygen bonds and carbon-sulfur bonds;
and
S.sub.c is a conjugated substance.

27 more elements

A compound having the formula ##STR20## or the formula ##STR21## wherein R.sup.1 and R.sup.6 are independently H, F, Cl, Br, I, C.sub.1 -C.sub.18 alkyl or C.sub.1 -C.sub.18 alkoxy;

R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently H, F, Cl, Br, I, CN;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy or C.sub.1 -C.sub.18 alkylthio, where each alkyl, alkoxy or alkylthio is optionally further substituted by F, Cl, Br, I, sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 where R.sup.18 is a C.sub.1 -C.sub.4 alkyl;
or amino, alkylamino, dialkylamino, or alkoxy, the alkyl portions of which independently have 1-6 carbons;
or one or both of R.sup.3 and R.sup.4 are --CH.sub.2 N(CH.sub.2 COOR.sup.17).sub.2, where R.sup.17 is H, a biologically compatible counterion, a linear or branched alkyl having 1-6 carbons, or --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one or more of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is --L--R.sub.x ;
or one or more of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is --L--S.sub.c ;
A is OR.sup.7 or NR.sup.8 R.sup.9,
where each R.sup.7 is independently a BLOCK, or R.sup.7 is --L--R.sub.x, or R.sup.7 is --L--S.sub.c ;
R.sup.8 and R.sup.9 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 carboxyalkyl, C.sub.1 -C.sub.6 sulfoalkyl, a salt of C.sub.1 -C.sub.6 carboxyalkyl, a salt of C.sub.1 -C.sub.6 sulfoalkyl, or C.sub.1 -C.sub.18 acyl wherein the alkyl portions are optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.8 in combination with R.sup.2, or R.sup.9 in combination with R.sup.3, or both, form a saturated 5- or 6-membered ring that is optionally substituted by one or more methyls;
or R.sup.8 in combination with R.sup.9 forms a saturated 5- or 6-membered heterocycle that is a piperidine, a morpholine, a pyrrolidine or a piperazine, each of which is optionally substituted by methyl, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one of R.sup.8 and R.sup.9 is a BLOCK;
or one of R.sup.8 and R.sup.9 is --L--R.sub.x ;
or one of R.sup.8 and R.sup.9 is --L--S.sub.c ;
and
R.sup.10 is F, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.10 is C.sub.1 -C.sub.18 alkyl, alkenyl or alkynyl that is optionally substituted one or more times by F, Cl, Br, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, or dialkylamino, the alkyl groups of which have 1-6 carbons;
or R.sup.10 is --L--R.sub.x ;
or R.sup.10 is --L--S.sub.c ;
or R.sup.10 has the formula ##STR22## where R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently H, F, Cl, Br, I;
or sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, CN, nitro, hydroxy, azido, amino, hydrazino;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy, C.sub.1 -C.sub.18 alkylthio, C.sub.1 -C.sub.18 alkylamino, C.sub.1 -C.sub.18 alkylester, C.sub.1 -C.sub.18 alkylamido or C.sub.1 -C.sub.18 arylamido, the alkyl or aryl portions of which are optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, dialkylamino or alkoxy, the alkyl portions of each having 1-6 carbons;
or one pair of adjacent substituents R.sup.13 and R.sup.14, R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, when taken in combination, form a fused 6-membered aromatic ring that is optionally further substituted by carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one or more of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 is --L--R.sub.x ;
or one or more of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 is --L--S.sub.c ;
R.sup.11 is H, hydroxy, CN or a C.sub.1 -C.sub.6 alkoxy;
or R.sup.10 in combination with R.sup.11 forms a 5-membered spirolactone ring or a 5-membered spirosultone ring;
or R.sup.11 in combination with R.sup.12 forms a 5- or 6-membered spirolactone ring or a 5- or 6-membered spirosultone ring that is optionally and independently substituted by H, F or CH.sub.3 ;
or R.sup.10 in combination with R.sup.11 is a carbonyl oxygen;
provided that at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.10 is F, or at least three of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are F;
and
further provided at least one of R.sup.7, R.sup.8 or R.sup.9 is a BLOCK;
each L is a single covalent bond, or L is a covalent linkage having 1-24 nonhydrogen atoms selected from the group consisting of C, N, O and S and is composed of any combination of single, double, triple or aromatic carbon-carbon bonds, carbon-nitrogen bonds, nitrogen-nitrogen bonds, carbon-oxygen bonds and carbon-sulfur bonds;
and
R.sub.x is a reactive site;
S.sub.c is a conjugated substance;
and
each BLOCK moiety is independently a monovalent moiety derived by removal of a hydroxy group from phosphate or from sulfate, or a biologically compatible salt thereof;
or a monovalent moiety derived by removal of a hydroxy group from a carboxy group of an aliphatic or aromatic carboxylic acid or of an amino acid, protected amino acid, peptide, or protected peptide;
or a monovalent moiety derived by removal of a hydroxy group from an alcohol or from a mono- or polysaccharide, where said BLOCK is selected to be removable from said compound by action of an enzyme;
or
BLOCK is a photolabile caging group.

39 more elements

A method of staining a biological sample, comprising the steps of:

a) preparing a dye solution comprising a dye compound of the formula:
##STR23## or the formula ##STR24## wherein R.sup.1 and R.sup.6 are independently H, F, Cl, Br, I, C.sub.1 -C.sub.18 alkyl or C.sub.1 -C.sub.18 alkoxy;
R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently H, F, Cl, Br, I, CN;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy or C.sub.1 -C.sub.18 alkylthio, where each alkyl, alkoxy or alkylthio is optionally further substituted by F, Cl, Br, I, sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 where R.sup.18 is a C.sub.1 -C.sub.4 alkyl;
or amino, alkylamino, dialkylamino, or alkoxy, the alkyl portions of which independently have 1-6 carbons;
or one or both of R.sup.3 and R.sup.4 are --CH.sub.2 N(CH.sub.2 COOR.sup.17).sub.2, where R.sup.17 is H, a biologically compatible counterion, a linear or branched alkyl having 1-6 carbons, or --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one or more of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is --L--R.sub.x ;
or one or more of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is --L--S.sub.c ;
A is OR.sup.7 or NR.sup.8 R.sup.9,
where each R.sup.7 is independently a BLOCK, or R.sup.7 is --L--R.sub.x, or R.sup.7 is --L--S.sub.c ;
R.sup.8 and R.sup.9 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 carboxyalkyl, C.sub.1 -C.sub.6 sulfoalkyl, a salt of C.sub.1 -C.sub.6 carboxyalkyl, a salt of C.sub.1 -C.sub.6 sulfoalkyl, or C.sub.1 -C.sub.18 acyl wherein the alkyl portions are optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.8 in combination with R.sup.2, or R.sup.9 in combination with R.sup.3, or both, form a saturated 5- or 6-membered ring that is optionally substituted by one or more methyls;
or R.sup.8 in combination with R.sup.9 forms a saturated 5- or 6-membered heterocycle that is a piperidine, a morpholine, a pyrrolidine or a piperazine, each of which is optionally substituted by methyl, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one of R.sup.8 and R.sup.9 is a BLOCK;
or one of R.sup.8 and R.sup.9 is --L--R.sub.x ;
or one of R.sup.8 and R.sup.9 is --L--S.sub.c ;
and
R.sup.10 is F, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.10 is C.sub.1 -C.sub.18 alkyl, alkenyl or alkynyl that is optionally substituted one or more times by F, Cl, Br, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, or dialkylamino, the alkyl groups of which have 1-6 carbons;
or R.sup.10 is --L--R.sub.x ;
or R.sup.10 is --L--S.sub.c ;
or R.sup.10 has the formula ##STR25## where R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently H, F, Cl, Br, I;
or sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, CN, nitro, hydroxy, azido, amino, hydrazino;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy, C.sub.1 -C.sub.18 alkylthio, C.sub.1 -C.sub.18 alkylamino, C.sub.1 -C.sub.18 alkylester, C.sub.1 -C.sub.18 alkylamido or C.sub.1 -C.sub.18 arylamido, the alkyl or aryl portions of which are optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, dialkylamino or alkoxy, the alkyl portions of each having 1-6 carbons;
or one pair of adjacent substituents R.sup.13 and R.sup.14, R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, when taken in combination, form a fused 6-membered aromatic ring that is optionally further substituted by carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or one or more of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 is --L--R.sub.x ;
or one or more of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 is --L--S.sub.c ;
R.sup.11 is H, hydroxy, CN or a C.sub.1 -C.sub.6 alkoxy;
or R.sup.10 in combination with R.sup.11 forms a 5-membered spirolactone ring or a 5-membered spirosultone ring;
or R.sup.11 in combination with R.sup.12 forms a 5- or 6-membered spirolactone ring or a 5- or 6-membered spirosultone ring that is optionally and independently substituted by H, F or CH.sub.3 ;
or R.sup.10 in combination with R.sup.11 is a carbonyl oxygen;
provided that at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.10 is F, or at least three of R.sup.12, R.sup.13, R.sup.4, R.sup.15 and R.sup.16 are F;
each L is a single covalent bond, or L is a covalent linkage having 1-24 nonhydrogen atoms selected from the group consisting of C, N, O and S and is composed of any combination of single, double, triple or aromatic carbon-carbon bonds, carbon-nitrogen bonds, nitrogen-nitrogen bonds, carbon-oxygen bonds and carbon-sulfur bonds;
and
R.sub.x is a reactive site;
S.sub.c is a conjugated substance;
and
each BLOCK moiety is independently a monovalent moiety derived by removal of a hydroxy group from phosphate or from sulfate, or a biologically compatible salt thereof;
or a monovalent moiety derived by removal of a hydroxy group from a carboxy group of an aliphatic or aromatic carboxylic acid or of an amino acid, protected amino acid, peptide, or protected peptide;
or a monovalent moiety derived by removal of a hydroxy group from an alcohol or from a mono- or polysaccharide, where said BLOCK is selected to be removable from said compound by action of an enzyme;
or
BLOCK is a photolabile caging group;
in a concentration sufficient to yield a detectable optical response under the desired conditions;
b) combining the sample of interest with the dye solution for a period of time sufficient for the dye compound to yield a detectable optical response upon illumination;
and
c) illuminating said sample at a wavelength selected to elicit said optical response.

43 more elements

One or more dye compounds of the formula ##STR27## or the formula ##STR28## wherein R.sup.1 and R.sup.6 are independently H, F, Cl, Br, I, C.sub.1 -C.sub.18 alkyl or C.sub.1 -C.sub.18 alkoxy;

R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently H, F, Cl, Br, I, CN;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy or C.sub.1 -C.sub.18 alkylthio, where each alkyl, alkoxy or alkylthio is optionally further substituted by F, Cl, Br, I, sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 where R.sup.18 is a C.sub.1 -C.sub.4 alkyl;
or amino, alkylamino, dialkylamino, or alkoxy, the alkyl portions of which independently have 1-6 carbons;
A is OR.sup.7 or NR.sup.8 R.sup.9,
where each R.sup.7 is independently H, C.sub.1 -C.sub.18 alkyl, a C.sub.1 -C.sub.18 acyl wherein each alkyl group independently has 1-6 carbons and is optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
R.sup.8 and R.sup.9 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 carboxyalkyl, C.sub.1 -C.sub.6 sulfoalkyl, a salt of C.sub.1 -C.sub.6 carboxyalkyl, a salt of C.sub.1 -C.sub.6 sulfoalkyl, or C.sub.1 -C.sub.18 acyl wherein the alkyl portions are optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.8 in combination with R.sup.2, or R.sup.9 in combination with R.sup.3, or both, form a saturated 5- or 6-membered ring that is optionally substituted by one or more methyls;
or R.sup.8 in combination with R.sup.9 forms a saturated 5- or 6-membered heterocycle that is a piperidine, a morpholine, a pyrrolidine or a piperazine, each of which is optionally substituted by methyl, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
R.sup.10 is F, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sub.10 is C.sub.1 -C.sub.18 alkyl, alkenyl or alkynyl that is optionally substituted one or more times by F, Cl, Br, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, or dialkylamino, the alkyl groups of which have 1-6 carbons;
or R.sup.10 is --L--;
or R.sup.10 has the formula ##STR29## where R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently H, F, Cl, Br, I;
or sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, CN, nitro, hydroxy, azido, amino, hydrazino;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy, C.sub.1 -C.sub.18 alkylthio, C.sub.1 -C.sub.18 alkylamino, C.sub.1 -C.sub.18 alkylester, C.sub.1 -C.sub.18 alkylamido or C.sub.1 -C.sub.18 arylamido, the alkyl or aryl portions of which are optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, dialkylamino or alkoxy, the alkyl portions of each having 1-6 carbons;
or one pair of adjacent substituents R.sup.13 and R.sup.14, R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, when taken in combination, form a fused 6-membered aromatic ring that is optionally further substituted by carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
R.sup.11 is H, hydroxy, CN or a C.sub.1 -C.sub.6 alkoxy;
or R.sup.10 in combination with R.sup.11 forms a 5-membered spirolactone ring or a 5-membered spirosultone ring;
or R.sup.11 in combination with R.sup.12 forms a 5- or 6-membered spirolactone ring or a 5- or 6-membered spirosultone ring that is optionally and independently substituted by H, F or CH.sub.3 ;
or R.sup.10 in combination with R.sup.11 is a carbonyl oxygen;
provided that at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.10 is F, or at least three of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are F;
and
further provided that one of R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15 or R.sup.16 on each dye is --L--;
where each L is a single covalent bond, or L is a covalent linkage having 1-24 nonhydrogen atoms selected from the group consisting of C, N, O and S and is composed of any combination of single, double, triple or aromatic carbon-carbon bonds, carbon-nitrogen bonds, nitrogen-nitrogen bonds, carbon-oxygen bonds and carbon-sulfur bonds;
and
each --L-- is bound to a S.sub.c that is a conjugated substance.

22 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound having the formula ##STR10## or the formula ##STR11## wherein R.sup.1 and R.sup.6 are independently H, F, Cl, Br, I, C.sub.1 -C.sub.18 alkyl or C.sub.1 -C.sub.18 alkoxy;

R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are independently H, F, Cl, Br, I, CN;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy or C.sub.1 -C.sub.18 alkylthio, where each alkyl, alkoxy or alkylthio is optionally further substituted by F, Cl, Br, I, sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 where R.sup.18 is a C.sub.1 -C.sub.4 alkyl;
or amino, alkylamino, dialkylamino, or alkoxy, the alkyl portions of which independently have 1-6 carbons;
or one or both of R.sup.3 and R.sup.4 are --CH.sub.2 N(CH.sub.2 COOR.sup.17).sub.2, where R.sup.17 is H, a biologically compatible counterion, a linear or branched alkyl having 1-6 carbons, or --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
A is OR.sup.7 or NR.sup.8 R.sup.9,
where each R.sup.7 is independently H, C.sub.1 -C.sub.18 alkyl, a C.sub.1 -C.sub.18 acyl wherein each alkyl group independently has 1-6 carbons and is optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or a trialkylsilyl wherein each alkyl group independently has 1-6 carbons;
R.sup.8 and R.sup.9 are independently H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 carboxyalkyl, C.sub.1 -C.sub.6 sulfoalkyl, a salt of C.sub.1 -C.sub.6 carboxyalkyl, a salt of C.sub.1 -C.sub.6 sulfoalkyl, or C.sub.1 -C.sub.18 acyl wherein the alkyl portions are optionally substituted by amino, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.8 in combination with R.sup.2, or R.sup.9 in combination with R.sup.3, or both, form a saturated 5- or 6-membered ring that is optionally substituted by one or more methyls;
or R.sup.8 in combination with R.sup.9 forms a saturated 5- or 6-membered heterocycle that is a piperidine, a morpholine, a pyrrolidine or a piperazine, each of which is optionally substituted by methyl, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
R.sup.10 is F, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, or a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
or R.sup.10 is C.sub.1 -C.sub.18 alkyl, alkenyl or alkynyl that is optionally substituted one or more times by F, Cl, Br, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, or dialkylamino, the alkyl groups of which have 1-6 carbons;
or R.sup.10 has the formula ##STR12## where R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are independently H, F, Cl, Br, I;
or sulfonic acid, salt of sulfonic acid, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, CN, nitro, hydroxy, azido, amino, hydrazino;
or C.sub.1 -C.sub.18 alkyl, C.sub.1 -C.sub.18 alkoxy, C.sub.1 -C.sub.18 alkylthio, C.sub.1 -C.sub.18 alkylamino, C.sub.1 -C.sub.18 alkylester, C.sub.1 -C.sub.18 alkylamido or C.sub.1 -C.sub.18 arylamido, the alkyl or aryl portions of which are optionally substituted one or more times by F, Cl, Br, I, hydroxy, carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18, sulfonic acid, salt of sulfonic acid, amino, alkylamino, dialkylamino or alkoxy, the alkyl portions of each having 1-6 carbons;
or one pair of adjacent substituents R.sup.13 and R.sup.14, R.sup.14 and R.sup.15 or R.sup.15 and R.sup.16, when taken in combination, form a fused 6-membered aromatic ring that is optionally further substituted by carboxylic acid, a salt of carboxylic acid, a carboxylic acid ester of a C.sub.1 -C.sub.6 alkyl, a carboxylic acid ester of --CH.sub.2 --O--(C.dbd.O)--R.sup.18 ;
and
R.sup.11 is H, hydroxy, CN or a C.sub.1 -C.sub.6 alkoxy;
or R.sup.10 in combination with R.sup.11 forms a 5-membered spirolactone ring or a 5-membered spirosultone ring;
or R.sup.11 in combination with R.sup.12 forms a 5- or 6-membered spirolactone ring or a 5- or 6-membered spirosultone ring that is optionally and independently substituted by H, F or CH.sub.3 ;
or R.sup.10 when taken in combination with R.sup.11 is a carbonyl oxygen;
provided that at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.10 is F, or at least three of R.sup.12, R.sup.13, R.sup.14, R.sup.15 and R.sup.16 are F.

19 more elements