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

A method for inhibiting bacterial or fungal growth on a surface or in a solution comprising administering to said surface or solution a complexing agent having the formula:

• wherein,
• p and q are each independently integers of from 2 to 3;
• r is an integer of from 0 to 4;
• all R1 are the same and all R4 are the same;
• R2, R3, and R4 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;
• R1 is a member selected from the group consisting of R2, R3, and R4, and radicals of the formula:
• wherein,
• R41, R42, and R43 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;
• R44 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, 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:
• wherein,
• R41, R42, R43 and R44 are each independently as described above;
• R46 and R47 are each independently selected from the group consisting of H, alkyl and aryl, or taken together form a ring structure;
• R48 and R49 are each independently selected from the group consisting of H, alkyl, aryl, alkoxy, alkyl interrupted by oxa, aryloxyalkyl, alkoxyaryl, and halogen-substituted versions thereof;
• R50, R51 and R52 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenyloxy, allkenylthio, 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 R1, R2, R3 and R4 are combined to form a ring structure;
• and dimers thereof formed by the covalent attachment of two compounds of formula (I) 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 a condition 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:

• wherein,
• p and q are each independently integers of from 2 to 3;
• r is an integer of from 0 to 4;
• all R1 are the same and all R4 are the same;
• R2, R3, and R4 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;
• R1 is a member selected from the group consisting of R2, R3, and R4, and radicals of the formula:
• wherein,
• R41, R42, and R43 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;
• R44 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, 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:
• wherein,
• R41, R42, R43 and R44 are each independently as described above;
• R46 and R47 are each independently selected from the group consisting of H, alkyl and aryl, or taken together form a ring structure;
• R48 and R49 are each independently selected from the group consisting of H, alkyl, aryl, alkoxy, alkyl interrupted by oxa, aryloxyalkyl, alkoxyaryl, and halogen-substituted versions thereof;
• R50, R51 and R52 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenyloxy, allkenylthio, 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 R1, R2, R3 and R4 are combined to form a ring structure;
• and dimers thereof formed by the covalent attachment of two complexing agents of formula (I) through a linking group having from 1 to 6 carbon atoms;
• or
• a physiological salt thereof;
• with the proviso that the molecular weight of said complexing agent does not exceed 2000, said complexing agent present in a pharmaceutically acceptable carrier.

A method for treating a condition associated with 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:

• wherein,
• p and q are each independently integers of from 2 to 3;
• r is an integer of from 0 to 4;
• R2, R3, and R4 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;
• R1 is a member selected from the group consisting of R2, R3, and R4, and radicals of the formula:
• wherein,
• R41, R42, and R43 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;
• R44 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, 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:
• wherein,
• R41, R42, R43 and R44 are each independently as described above;
• R46 and R47 are each independently selected from the group consisting of H, alkyl and aryl, or taken together form a ring structure;
• R48 and R49 are each independently selected from the group consisting of H, alkyl, aryl, alkoxy, alkyl interrupted by oxa, aryloxyalkyl, alkoxyaryl, and halogen-substituted versions thereof,
• R50, R51 and R52 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenyloxy, allkenylthio, 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 R1, R2, R3 and R4 are combined to form a ring structure;
• and dimers thereof formed by the covalent attachment of two complexing agents of formula (I) through a linking group having from 1 to 6 carbon atoms;
• and
• physiological salts thereof, with the proviso that at least one R1 group is other than a radical of formula (V) in which X is carboxylic acid and with the further proviso that the molecular weight of said complexing agent does not exceed 2000, said complexing agent present in a pharmaceutically acceptable carrier.

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:
• wherein,
• p and q are each independently integers of from 2 to 3;
• r is an integer of from 0 to 4;
• R2, R3, and R4 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;
• R1 is a member selected from the group consisting of R2, R3, and R4, and radicals of the formula:
• wherein,
• R41, R42, and R43 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;
• R44 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, 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:
• wherein,
• R41, R42, R43 and R44 are each independently as described above;
• R46 and R47 are each independently selected from the group consisting of H, alkyl and aryl, or taken together form a ring structure;
• R48 and R49 are each independently selected from the group consisting of H, alkyl, aryl, alkoxy, alkyl interrupted by oxa, aryloxyalkyl, alkoxyaryl, and halogen-substituted versions thereof;
• R50, R51 and R52 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenyloxy, allkenylthio, 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 R1, R2, R3 and R4 are combined to form a ring structure;
• and dimers thereof formed by the covalent attachment of two complexing agents of formula (I) through a linking group having from 1 to 6 carbon atoms;
• and
• with the proviso that the molecular weight of said compound does not exceed 2000;
• and detecting said radioisotopic or paramagnetic first transition series element.

A method for inhibiting bacterial or fungal growth on a surface or in a solution comprising administering to said surface or solution a complexing agent having the formula:

• wherein,
• p and q are each independently integers of from 2 to 3;
• r is an integer of from 1 to 4;
• R2 and R3 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;
• all R1 are the same and all R4 are the same;
• R1 and R4 are independently selected from the group consisting of R2, R3, and radicals of the formula:
• wherein,
• R41, R42, and R43 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;
• R44 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, 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:
• wherein,
• R41, R42, R43 and R44 are each independently as described above;
• R46 and R47 are each independently selected from the group consisting of H, alkyl and aryl, or taken together form a ring structure;
• R48 and R49 are each independently selected from the group consisting of H, alkyl, aryl, alkoxy, alkyl interrupted by oxa, aryloxyalkyl, alkoxyaryl, and halogen-substituted versions thereof;
• R50, R51 and R52 are each independently selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenyloxy, allkenylthio, 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 R1, R2, R3 and R4 are combined to form a ring structure;
• and dimers thereof formed by the covalent attachment of two complexing agents of formula (I) through a linking group having from 1 to 6 carbon atoms;
• or a salt thereof.