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Metal delivery agents and therapeutic uses of the same

a metal complex and metal technology, applied in the direction of antiparasitic agents, biocides, drug compositions, etc., can solve the problems of affecting the functioning of these enzymes and proteins, affecting the undesirable consequences, etc., to reduce the effect of extracellular amyloid seta, high level of metal uptake, and reduced the effect of metal uptak

Inactive Publication Date: 2012-10-25
MELBOURNE UNIV OF THE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0036]In yet an even further aspect the invention provides a method of reducing or preventing the effects of Abeta on a cell the method including exposing the cell to an effective amount of a metal complex of the formula (I). In one embodiment the cell is a cell in a subject and exposing the cell to the metal complex includes administering the metal complex to the subject.

Problems solved by technology

It is estimated that one-third of all proteins are metalloproteins (proteins containing a tightly bound metal ion) and therefore a number of biologically important processes are impaired if bio-available metal levels are either elevated or suppressed.
A large percentage of newly discovered enzymes and proteins also contain metal ions at their active sites and variations in metal levels can significantly interfere with the functioning of these enzymes and proteins.
Accordingly whenever there is either too high or too low a level of metals present in a biological system either too high a level or too low a level the normal biological processes are interrupted, typically leading to undesirable consequences.
This typically occurs as many of the crucial enzymatic processes that provide protection in the biological system are suppressed or inactivated leading to undesirable consequences.
One consequence of copper deficiency is that the protective enzymes responsible for detoxifying reactive oxygen species (ROS) are inadequately loaded with copper and therefore do not effectively carry out normal enzyme function.
The most common are vitamin E and vitamin C. However, vitamin E was found to be ineffective at decreasing the oxidative stress at the substantia nigra (The Parkinson Study Group, 1993, Offen et al., 1996) since this compound, although capable of crossing the blood brain barrier, is trapped in the cell membrane and therefore does not reach the cytoplasm where its antioxidant properties are needed.
Vitamin C also does not cross the blood brain barrier and therefore, cannot be used effectively for neurodegenerative diseases of central origin.

Method used

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  • Metal delivery agents and therapeutic uses of the same
  • Metal delivery agents and therapeutic uses of the same
  • Metal delivery agents and therapeutic uses of the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of [Zn(ATSEH2)]

[0185]ATSEH2 (0.134 g, 0.46 mmol) and Zn(CH3CO2)2.2H2O (0.102 g, 0.46 mmol) were added to ethanol (5 mL). The mixture was heated at reflux for 2 hours under an atmosphere of nitrogen and then allowed to cool to room temperature. The bright yellow solid that formed was collected by filtration and washed with ethanol, and diethyl ether to give [Zn(ATSE)] as a yellow powder (0.122 g, 0.35 mmol, 76%). 1H NMR (400 MHz): δ 1.08, 6H, t, 3JHH=7 Hz, CH2CH3; 2.18 ppm, 6H, s, 2×CH3; 3.30, 4H, m partially obscured by H-OD peak from solvent, CH2CH3. ES MS (+ve ion): m / z=351=[Zn(C10H18N6S2)+H+]+.

example 2

Synthesis of ChexTSE

[0186]1,2-Cyclohexanedione (0.439 g, 3.92 mmol) was added to ethanol (25 mL) followed by N4-ethyl-3-thiosemicarbazide (0.933 g, 7.83 mmol) and a few drops of H2SO4 (conc). The mixture was heated at reflux under an atmosphere of nitrogen for 3 hours and then allowed to cool to room temperature. A yellow precipitate formed which was collected by filtration and washed with ethanol, and diethyl ether to ChexTSE as a yellow solid (0.945 g, 3.00 mmol, 76%). 1H NMR (400 MHz): δ 1.09, 3H, t, 3JHH=7 Hz, CH2CH3; 1.13, 3H, t, 3JHH=7 Hz, CH2CH3; 1.66, 4H, m, 2×CH2 cyclohexyl; 2.56, 4H, m, 2×CH2 cyclohexyl; 3.54, 4H, m, 2×NHCH2CH3; 8.18, 1H, br s, NH; 8.61, br s, NH; 10.44, 1H, br s, NH; 12.25, 1H, br s, NH. ES MS (+ve ion): m / z=315=[C12H22N6S2+H+]+.

example 3

Synthesis of [Zn(Chextsc)]

[0187]ChexTSE (0.190 g, 0.60 mmol) was added to ethanol (10 mL−) followed by Zn(CH3CO2).2H2O (0.133 g, 0.60 mmol) and the mixture was heated at reflux under an atmosphere of nitrogen for 3 hours. The mixture was allowed to cool to room temperature and a yellow solid precipitated. The solid was collected by filtration and washed with ethanol, and diethyl ether to give [Zn(Chextsc)] as a yellow solid (0.157 g, 0.42 mmol, 70%). 1H NMR (400 MHz): δ 1.07, 6H, t, 3JHH=7 Hz, 2×CH2CH3; 1.64, 4H, m, 2×CH2 cyclohexyl; 2.58, 4H, m, 2×CH2 cyclohexyl; 3.32, 4H, m, obscured by H-OD signal in solvent, 2×NHCH2CH3. ESMS (+ve ion): m / z=378=[Zn(C12H20N6S2+H+]+.

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Abstract

The present invention relates to metal complexes, processes for their preparation and their use as pharmaceutical or veterinary agents, in particular for the treatment of conditions in which metal delivery can prevent, alleviate or ameliorate the condition. There are a number of clinical conditions which are caused by or associated with abnormal levels of metals (typically low metal levels). Conditions in of this type include cancer and conditions characterised by or associated with oxidative damage, more specifically neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease or Huntington's disease. The invention also relates to ligands useful in the preparation of metal complexes of this type.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the use of metal complexes as pharmaceutical or veterinary agents, in particular for the treatment of conditions in which metal delivery can prevent, alleviate or ameliorate the condition. There are a number of clinical conditions which are caused by or associated with abnormal levels of metals (typically low metal levels). Conditions in of this type include cancer and conditions characterised by or associated with oxidative damage, more specifically neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease or Huntington's disease.BACKGROUND OF THE INVENTION[0002]The life span is thought to be biologically fixed for each species, and the length of the human life span is uncertain, but may be up to 120 years. Since life expectancy has risen significantly in this century, the elderly are an increasing segment of our population, and their health care needs will continue to grow for decades.[0003]Bio-availa...

Claims

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Application Information

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IPC IPC(8): A61K31/555A61P25/00A61P35/00A61P25/28A61P9/10A61P27/12A61P25/08A61P27/06A61P25/14A61P1/00A61P27/02A61P33/06A61P25/16A61P25/18C12N5/07A61K31/315A61K31/30A61P9/00
CPCA61K31/145A61K31/28A61K31/555A61K31/315A61K31/30A61P1/00A61P9/00A61P9/10A61P25/00A61P25/08A61P25/14A61P25/16A61P25/18A61P25/28A61P27/02A61P27/06A61P27/12A61P31/00A61P33/06A61P35/00C07F1/08C07F3/06
Inventor BARNHAM, KEVIN JEFFREYDONNELLY, PAUL STEPHENWHITE, ANTHONY ROBERT
Owner MELBOURNE UNIV OF THE
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