Compounds with chelation affinity selectivity for first transition series elements: use in medical therapy and diagnosis

A method for treating conditions dependent on the bioavailability of first transition series elements in a patient, comprising administering to said patient an effective amount of a complexing agent having the formula ##STR218## wherein, t, u, and v are each independently 2 or 3;

• w is an integer of from 1 to 4;
• R.sup.12 and R.sup.13 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by one or more oxa, alkenyl interrupted by one or more oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, and halogen-substituted versions thereof;
• R.sup.11 is a member selected from the group consisting of R.sup.12, R.sup.13, and radicals of the formula:
• ##STR219## wherein, R.sup.41, R.sup.42, and R.sup.43 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by oxa, alkenyl interrupted by oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, and halogen-substituted versions thereof;
• R.sup.44 is a member selected from the group consisting of H, hydroxy, amino, alkyl interrupted by oxa, alkoxy, aryl, aryloxyalkyl, alkoxyaryl, and halogen-substituted versions thereof;
• n is zero or 1;
• and
• X is a member selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by one or more oxa, alkenyl interrupted by one or more oxa, alkyl interrupted by one or more thia, alkenyl interrupted by one or more thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, halogen-substituted versions thereof, and radicals selected form the group consisting of:
• ##STR220## wherein, R.sup.41, R.sup.42, R.sup.43 and R.sup.44 are each independently as described above;
• R.sup.46 and R.sup.47 are each independently selected from the group consisting of H, alkyl and aryl, or taken together form a divalent linking group between the atoms to which they are attached, thereby forming a ring structure;
• R.sup.48 and R.sup.49 are each independently selected from the group consisting of H, alkyl, aryl, alkoxy, alkyl interrupted by oxa, aryloxyalkyl, alkoxyaryl, and halogen-substituted versions thereof;
• R.sup.50, R.sup.51 and R.sup.52 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenyloxy, allkenylthio, aryloxy, arylthio, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylakyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, and hydroxyarylalkyl;
• and
• m is an integer of from 1 to 3,
• and wherein, optionally, any two R.sup.11 groups are combined to form a ring structure;
• and dimers thereof, said dimers being formed by the covalent attachment of two complexing agents of formula II through a linking group having from 1 to 6 carbon atoms;
• and physiological salts thereof, with the proviso that the molecular weight of said complexing agent does not exceed 2000.

A method for treating conditions dependent on elevated levels of first transition series elements in a patient, comprising administering to said patient an effective amount of a complexing agent having the formula ##STR221## wherein, t, u, and v are each independently 2 or 3;

• w is an integer of from 1 to 4;
• R.sup.12 and R.sup.13 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by one or more oxa, alkenyl interrupted by one or more oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, and halogen-substituted versions thereof;
• R.sup.11 is a member selected from the group consisting of R.sup.12, R.sup.13, and radicals of the formula:
• ##STR222## wherein, R.sup.41, R.sup.42, and R.sup.43 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by oxa, alkenyl interrupted by oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, and halogen-substituted versions thereof;
• R.sup.44 is a member selected from the group consisting of H, hydroxy, amino, alkyl interrupted by oxa, alkoxy, aryl, aryloxyalkyl, alkoxyaryl, and halogen-substituted versions thereof;
• n is zero or 1;
• and
• X is a member selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by one or more oxa, alkenyl interrupted by one or more oxa, alkyl interrupted by one or more thia, alkenyl interrupted by one or more thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, halogen-substituted versions thereof, and radicals selected form the group consisting of:
• ##STR223## wherein, R.sup.41, R.sup.42, R.sup.43 and R.sup.44 are each independently as described above;
• R.sup.46 and R.sup.47 are each independently selected from the group consisting of H, alkyl and aryl, or taken together form a divalent linking group between the atoms to which they are attached, thereby forming a ring structure;
• R.sup.48 and R.sup.49 are each independently selected from the group consisting of H, alkyl, aryl, alkoxy, alkyl interrupted by oxa, aryloxyalkyl, alkoxyaryl, and halogen-substituted versions thereof;
• R.sup.50, R.sup.51 and R.sup.52 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenyloxy, allkenylthio, aryloxy, arylthio, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylakyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, and hydroxyarylalkyl;
• and
• m is an integer of from 1 to 3,
• and wherein, optionally, any two R.sup.11 groups are combined to form a ring structure;
• and dimers thereof, said dimers being formed by the covalent attachment of two complexing agents of formula II through a linking group having from 1 to 6 carbon atoms;
• and physiological salts thereof;
• with the proviso that the molecular weight of said complexing agent does not exceed 2000.

A method for nuclear medical imaging or enhancing contrast in magnetic resonance imaging in a patient, said method comprising;

• administering to said patient a pharmaceutical composition comprising a radioisotopic or paramagnetic first transition series element which is in chelated form with a compound of formula:
• ##STR224## wherein, t, u and v are each independently 2 or 3;
• w is an integer of from 1 to 4;
• R.sup.12 and R.sup.13 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by one or more oxa, alkenyl interrupted by one or more oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, halogen substituted versions thereof;
• R.sup.11 is a member selected from the group consisting of R.sup.12, R.sup.13 and radicals of formula:
• ##STR225## wherein, R.sup.41, R.sup.42 and R.sup.43 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl interrupted by oxa, alkenyl interrupted by oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, and halogen substituted versions thereof;
• R.sup.44 is a member selected from the group consisting of H, hydroxy, amino, alkyl, alkyl interrupted by oxa, alkoxy, aryl, aryloxyalkyl, alkoxyaryl, and halogen substituted versions thereof;
• n is zero or 1;
• and
• X is a member selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, aryloxy, arylthio, alkyl interrupted by one or more oxa, alkenyl interrupted by one or more oxa, alkyl interrupted by one or more thia, alkenyl interrupted by one or more thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl hydroxyarylalkyl, halogen substituted versions of each of the above, and radicals selected from the group consisting of:
• ##STR226## wherein R.sup.41, R.sup.42, R.sup.43 and R.sup.44 are each independently as described above;
• R.sup.46 and R.sup.47 are each independently selected from the group consisting of H, alkyl and aryl, or taken together form a divalent linking group between the atoms to which they are attached, thereby forming a ring structure;
• R.sup.48 and R.sup.49 are each independently selected from the group consisting of H, alkyl, aryl, alkoxy, alkyl interrupted by oxa, aryloxyalkyl, alkoxyaryl, and halogen substituted versions thereof;
• R.sup.50 R.sup.51 and R.sup.52 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkyloxy, alkylthio, alkenyloxy, alkenylthio, aryloxy, arylthio, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, and hydroxyarylalkyl;
• and
• m is an integer of from 1 to 3;
• and wherein, optionally, any two of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are combined to form a ring structure;
• and dimers thereof, said dimers being formed by the covalent attachment of two compounds of formula (I) through a linking group having from 1 to 6 carbon atoms;
• with the proviso that the molecular weight of said compound does not exceed 2000;
• and
• detecting said radioisotopic or paramagnetic first transition series element.