Back to results
US 2004/0006055 A1Published application
Neuroprotection and cardioprotection afforded by chelators with high affinity and specificity for cations of first transition series elements
AssigneesCONCAT, LTD. a California Limited Partnership, CHELATOR LLC., a Delaware corporation
InventorHarry S. Winchell
Life of this patent
Estimating the term…
Abstract
Compounds that demonstrate chelation affinity and selectivity for first transition series elements are administered to patients suffering from such conditions as ischemia, prolonged seizures and trauma to provide neuroprotection, cardioprotection, or both. These compounds when administered form complexes with chelatable iron and copper cations and thereby mitigate the ability of these cations to catalyze Haber-Weiss reactions that form toxic hydroxy free radicals that cause tissue injury. These compounds also form complexes with chelatable zinc cations thereby inhibiting the cytotoxicity associated with excess chelatable zinc.
Claims8
A method for providing neuroprotection or cardioprotection in a patient, said method comprising administering to said patient an effective amount of a chelator that forms a complex with a member selected from the group consisting of cations of iron, copper and zinc having a thermodynamic equilibrium dissociation constant of 10−18 or less, and that forms a complex with calcium cations having a thermodynamic equilibrium dissociation constant of 10−11 or greater.
A method for mitigating damage to the central nervous system of a patient suffering an ischemic stroke, seizure or trauma, said method comprising administering to said patient an effective amount of a chelator that forms a complex with a member selected from the group consisting of cations of iron, copper and zinc, said complex having a thermodynamic equilibrium constant of 10−18 or less.
A method for mitigating damage to the heart in a patient suffering a heart attack or arrhythmia, said method comprising administering to said patient an effective amount of a chelator that forms a complex with a member selected from the group consisting of cations of iron, copper and zinc, said complex having a thermodynamic equilibrium constant of 10−18 or less.
A method for providing neuroprotection or cardiac protection in a patient, said method comprising administering to said patient an effective amount of a chelator having the formula
- 213
- wherein,
- p and q are independently integers of from 2 to 3;
- r is an integer of from 1 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 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;
- R1 is a member selected from the group consisting of R2, R3, R4, and radicals of the formula:
- 214
- 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, 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 oxa, alkenyl interrupted by oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, halogen-substituted versions thereof, and radicals selected form the group consisting of:
- 215
- wherein
- R41, R42, R43 and R44 are each independently as defined 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, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylakyl, 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 of Formula I, said dimers being 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 the molecular weight of said complexing agent does not exceed 2000.
22 more elements
A method for providing neuroprotection or cardiac protection in a patient, said method comprising administering to said patient a chelator having the formula
- 216
- wherein,
- t, u and v are each independently 2 or 3;
- w is an integer of from 1 to 4;
- R12 and R13 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;
- R11 is a member selected from the group consisting of R12, R13 and radicals of the formula:
- 217
- 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, 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 oxa, alkenyl interrupted by oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, halogen-substituted versions thereof, and radicals selected form the group consisting of:
- 218
- wherein,
- p41, R42, R43 and R44 are each independently as defined 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, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylakyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, and hydroxyarylalkyl;
- and
- m is an integer of from 1 to 3
- and wherein, optionally, any two of R11, R12, and R13 are combined to form a ring structure;
- and dimers of Formula 11, 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.
22 more elements
A method for providing neuroprotection or cardiac protection in a patient, said method comprising administering to said patient a chelator having the formula
- 219
- wherein,
- R22 and R23 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;
- R21 is a member selected from the group consisting of R22, R23 and radicals of the formula:
- 220
- 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, 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 oxa, alkenyl interrupted by oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, halogen-substituted versions thereof, and radicals selected form the group consisting of:
- 221
- wherein,
- R41, R42, R43 and R44 are each independently as defined 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, alikenylthio, aryloxy, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylakyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, and hydroxyarylalkyl;
- and
- m is an integer of from 1 to 3
- and wherein, optionally, any two of R21, R22, and R23 are combined to form a ring structure;
- and dimers of Formula III, said dimers being formed by the covalent attachment of two complexing agents of Formula III 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.
20 more elements
A method for providing neuroprotection or cardiac protection in a patient, said method comprising administering to said patient a chelator having the formula
- 222
- wherein,
- R32 and R33 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;
- R31 is a member selected from the group consisting of R32, R33 and radicals of the formula:
- 223
- 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, 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 oxa, alkenyl interrupted by oxa, alkyl interrupted by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, halogen-substituted versions thereof, and radicals selected form the group consisting of:
- 224
- wherein,
- R41, R42, R43 and R44 are each independently as defined 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, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylakyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, and hydroxyarylalkyl;
- and
- m is an integer of from 1 to 3
- and wherein, optionally, any two of R31, R32, and R33 are combined to form a ring structure;
- and dimers of Formula IV, said dimers being formed by the covalent attachment of two complexing agents of Formula IV 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.
20 more elements
Dependencies are inferred from the claim text.