Reactive derivatives of bapta used to make ion-selective chelators

A fluorescent ion-selective conjugate with a carrier having the formula:

• ##STR9## where at least one of W' and X' contains -POLY that is attached by a covalent linkage that is an ether, a thioether, a carboxamide, a sulfonamide, an alkyl amide, a urea or a thiourea linkage,
• where -POLY is a biologically compatible polymolecular assembly with a molecular weight greater than about 750 Daltons;
• and at least one of X' and Z' contains a fluorophore according to the formula:
• (R.sup.a).sub.n (R.sup.b).sub.n' -FLUOR, wherein n=0 or 1;
• R.sup.a is --OCH.sub.2 R.sup.3 --, --OR.sup.3 --, --SR.sup.3 --, --SR.sup.3' --, --NHCOCH.sub.2 R.sup.3 --, --NHCOR.sup.3' --, --CONHCH.sub.2 R.sup.3 --, --CONHR.sup.3' --, --NHSO.sub.2 R.sup.3 --, --NHSO.sub.2 R.sup.3' --, --NHCONHCH.sub.2 R.sup.3 --, --NHCONHR.sup.3' --, --NHCSNHCH.sub.2 R.sup.3 --, or --NHCSNHR.sup.3' --, where R.sup.3 is (CH.sub.2).sub.m and m=1-6, and R.sup.3' is phenylene (--C.sub.6 H.sub.4 --);
• R.sup.b is --NH--, --NHCO--, --NHCS--, --S--, --O--, --CO--;
• or --CH.sub.2 -- or --COCH.sub.2 --, or succinimidyl, and n'=0 or 1;
• and
• -FLUOR is an aromatic oxygen heterocycle fluorophore, or a 2-indolyl or a carboxy substituted 2-indolyl fluorophore, provided that when -FLUOR is a 2-indolyl or a carboxy substituted 2-indolyl fluorophore, n and n' are 0;
• or Z' taken together with Y' and the aromatic carbons at the 4' and 5' positions form a benzofuran or oxazolyl-substituted or carboxy-oxazolyl substituted benzofuran fluorophore;
• the remainder of substituents W', X', Y', and Z', which may be the same or different, are independently H, CH.sub.3, NO.sub.2, CF.sub.3, F, Cl, Br, I, --OR.sup.5, --CO.sub.2 R.sup.5, or --OCH.sub.2 CO.sub.2 R.sup.5, where R.sup.5 is an alkyl group with 1-5 carbons, a benzyl (C.sub.6 H.sub.5 CH.sub.2 --), an alpha-acyloxyalkyl or a pharmaceutically acceptable esterifying group, or a pharmaceutically acceptable salt;
• (R.sup.a).sub.n (R.sup.b)-POLY, in any of its described variations;
• or (R.sup.a).sub.n (R.sup.b).sub.n' -FLUOR, in any of its described variations;
• or combinations thereof;
• and
• R.sup.6 is an alkyl group with 1-5 carbons, a benzyl, an alpha-acyloxyalkyl or a pharmaceutically acceptable esterifying group, or a pharmaceutically acceptable salt.

A fluorescent ion-selective compound having the formula:

• ##STR10## where at least one of W', X', Y' and Z' contains a fluorophore conjugate -FLUOR' that is attached to the compound by a covalent linkage that is an ether, thioether, sulfonamide, carboxamide, alkyl amine, urea, or thiourea linkage, according to the formula:
• (R.sup.a).sub.n (R.sup.b)-FLUOR', wherein n=0 or 1;
• R.sup.a is --OCH.sub.2 R.sup.3 --, --OR.sup.3' --, --SR.sup.3 --, --SR.sup.3' --, NHCOCH.sub.2 R.sup.3 --, --NHCOR.sup.3' --, --CONHCH.sub.2 R.sup.3 --, --CONHR.sup.3' --, NHSO.sub.2 R.sup.3 --, --NHSO.sub.2 R.sup.3' --, --NHCONHCH.sub.2 R.sup.3 --, --NHCONHR.sup.3' --, --NHCSNHCH.sub.2 R.sup.3 --, or --NHCSNHR.sup.3' --, where R.sup.3 is (CH.sub.2).sub.m and m=1-6, and R.sup.3' is phenylene (--C.sub.6 H.sub.4 --);
• R.sup.b is --NH--, --NHCO--, --NHCS--, --S--, --O--, --CO--;
• or --CH.sub.2 -- or --COCH.sub.2 --, or succinimidyl;
• and -FLUOR' is a fluorescein, rhodamine or coumarin fluorophore;
• and
• the remainder of substituents W', X', Y', and Z', which may be the same or different, are independently H, CH.sub.3, NO.sub.2, CF.sub.3, F, Cl, Br, I, --OR.sup.5, --CO.sub.2 R.sup.5, or --OCH.sub.2 CO.sub.2 R.sup.5, where R.sup.5 is an alkyl group with 1-5 carbons, a benzyl (C.sub.6 H.sub.5 CH.sub.2 --), an alpha-acyloxyalkyl or a pharmaceutically acceptable esterifying group, or a pharmaceutically acceptable salt;
• or contains an additional fluorophore -FLUOR that is attached to the compound by a covalent linkage that is an ether, thioether, sulfonamide, carboxamide, alkylamine, urea, or thiourea linkage or a single covalent bond, according to the formula:
• (R.sup.a).sub.n (R.sup.b).sub.n' -FLUOR, wherein n=0 or 1;
• R.sup.a is --OCH.sub.2 R.sup.3 --, --OR.sup.3' --, --SR.sup.3 --, --SR.sup.3' --, NHCOCH.sub.2 R.sup.3 --, --NHCOR.sup.3' --, --CONHCH.sub.2 R.sup.3 --, --CONHR.sup.3' --, --NHSO.sub.2 R.sup.3 --, --NHSO.sub.2 R.sup.3' --, --NHCONHCH.sub.2 R.sup.3 --, --NHCONHR.sup.3' --, --NHCSNHCH.sub.2 R.sup.3 --, or --NHCSNHR.sup.3' --, where R.sup.3 is (CH.sub.2).sub.m and m=1-6, and R.sup.3' is phenylene (--C.sub.6 H.sub.4 --);
• R.sup.b is --NH--, --NHCO--, --NHCONH--, --NHCS--, --NHCSNH-- , --NHSO.sub.2 --, --S--, --O--, --CO--;
• or --CH.sub.2 -- or --COCH.sub.2 --, or succinimidyl, and n'=0 or 1;
• and
• -FLUOR is a fluorescein rhodamine or coumarin fluorophore, a 2-indolyl or a carboxy substituted 2-indolyl fluorophore, provided that when -FLUOR is a 2-indolyl or a carboxy, substituted 2-indolyl fluorophore, the linkage is a single covalent bond;
• or Z' taken together with Y' and the aromatic carbons at the 4' and 5' positions form a benzofuran or oxazolyl-substituted
• or carboxy-oxazolyl substituted benzofuran fluorophore;
• or combinations thereof;
• and
• R.sup.6 is an alkyl group with 1-5 carbons, a benzyl, an alpha-acyloxyalkyl or a pharmaceutically acceptable esterifying group, or a pharmaceutically acceptable salt.

A non-fluorescent ion-selective conjugate with a carrier having the formula:

• ##STR11## where at least one of W', X', Y', and Z' contains -POLY that is attached by a covalent linkage that is an ether, a thioether, a carboxamide, a sulfonamide, an alkyl amide, a urea or a thiourea linkage,
• where -POLY is a polymolecular assembly with a molecular weight greater than about 750 Daltons;
• the remainder of substituents W', X', Y', and Z', which may be the same or different, are independently H, CH.sub.3, NO.sub.2, CF.sub.3, F, Cl, Br, I, --OR.sup.5, --CO.sub.2 R.sup.5, or --OCH.sub.2 CO.sub.2 R.sup.5, where R.sup.5 is an alkyl group with 1-5 carbons, a benzyl (C.sub.6 H.sub.5 CH.sub.2 --), an alpha-acyloxyalkyl or a pharmaceutically acceptable esterifying group, or a pharmaceutically acceptable salt;
• or (R.sup.a).sub.n (R.sup.b)-POLY, in any of its described variations;
• or combinations thereof;
• and
• R.sup.6 is an alkyl group with 1-5 carbons, a benzyl, an alpha-acyloxyalkyl or a pharmaceutically acceptable esterifying group, or a pharmaceutically acceptable salt.