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WO1995000140A1 - Complexes au gallium pour le traitement des maladies induites par les radicaux libres - Google Patents

Complexes au gallium pour le traitement des maladies induites par les radicaux libres Download PDF

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Publication number
WO1995000140A1
WO1995000140A1 PCT/US1994/006878 US9406878W WO9500140A1 WO 1995000140 A1 WO1995000140 A1 WO 1995000140A1 US 9406878 W US9406878 W US 9406878W WO 9500140 A1 WO9500140 A1 WO 9500140A1
Authority
WO
WIPO (PCT)
Prior art keywords
complex
treatment
desferrioxamine
penicillamine
gallium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1994/006878
Other languages
English (en)
Inventor
Mordechai Chevion
Eduard Berenshtein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yissum Research Development Co of Hebrew University of Jerusalem
Helfgott & Karas Pc
Original Assignee
Yissum Research Development Co of Hebrew University of Jerusalem
Helfgott & Karas Pc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yissum Research Development Co of Hebrew University of Jerusalem, Helfgott & Karas Pc filed Critical Yissum Research Development Co of Hebrew University of Jerusalem
Priority to AU72093/94A priority Critical patent/AU7209394A/en
Priority to US08/569,116 priority patent/US5618838A/en
Priority to EP94921320A priority patent/EP0706391A4/fr
Publication of WO1995000140A1 publication Critical patent/WO1995000140A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention relates to a pharmaceutical composition containing a gallium complex (Ga) as active ingredient therein, or a combination of Ga complex with zinc (Zn) and/or manganese (Mn) complexes, therein-
  • Ga gallium complex
  • Zn zinc
  • Mn manganese
  • Redox-active iron and copper have been demonstrated to be responsible for tissue damage in ischemia and reperfusion injury, ionizing irradiation, thallesemia, hemochromatosis and Wilson disease. Furthermore, in a wide variety of pathologic states, the causative role of free radicals has been proposed. These metals can readily serve as effective mediators enhancing free radical-induced damage and thus have been incriminated as a major responsible species for tissue injury (M. Chevion, "A Site- Specific Mechanism for Free Radical-Induced Biological Damage: The Essential Role of Redox Active Transition Metals", Free Radicals for Biology and Medicine, Vol. 5, No. 1, pp. 27-37, 1988).
  • the present inventors have shown that the use of desferrioxamine, and better still, the combination of DFO and nitrilotriacetate (NTA) resulted in a dramatic increase in the rate of survivors in paraquat toxicity. While in control group there were no survivors, following treatment with either chelators, 25-30% survivors were monitored. The administration of a combination of these specific chelators led to 60-90% survivors (average 70%) (R. Kohen and M. Chevion, "Paraquat Toxicity Is Enhanced by Iron and Inhibited by DFO in Laboratory Mice", Biochemical Pharmacology, Vol. 34, pp. 1841-1843, 1985).
  • neocuproine a chelator that effectively binds iron and copper and easily penetrates into cells, provides marked protection against ischemic-induced arrhythmias and against loss of cardiac function in the isolated rat heart using the Langendorff configuration (Y.J. Appelbaum, G. Uretzky, and M. Chevion, "The Protective Effect of Neocuproine on Cardiac Injury Induced by Oxygen Active Species in the Presence of Copper Sulfate", Journal of Molecular and Cellular Cardiology, Vol. 19 (Supp. Ill), Abstract No. 8, 1987; J. Kuvin, Y.J. Appelbaum, M. Chevion, J.B. Borman and G.
  • TPEN Another chelator
  • TPEN A Heavy Metal Chelator, Protects the Isolated Perfused Rat Heart from Reperfusion-Induced Arrhythmias
  • the complex Ga-DFO possesses the characteristics which could markedly improve the pharmaceutical efficacy of Desferal R . This will be achieved by markedly enhancing its permeability into cells, and by the consequent significant increase of its capacity to bind intracellular iron and copper.
  • the transition metals are not redox-active and cannot mediate free radical production.
  • "free" Ga is released from its complex with DFO or penicillamine, in a controlled mode that is fully dependent on the level of cell saturation with "free" iron and copper.
  • Ga is approved as a drug in diagnosis of cardiac function and focal inflammation in human patients
  • DFO is an approved drug (patent protection expired)
  • the Ga-DFO complex is permeable, and thus can be administered orally, providing a prominent advantage over the current procedures for administering Desferal R . This is also true for the complex with penicillamine, which is usually given per os.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a Ga complex of DFO or penicillamine, alone or in combination with complexes of Zn and/or Mn as active ingredients therein, in combination with a pharmacologically acceptable carrier.
  • the invention further provides a gallium desferrioxamine or gallium penicillamine complex for medical use in the treatment of free radical-induced pathological conditions; the treatment of injury resulting from ischemic insult to the heart, brain or kidney; the treatment of thallasemia; the treatment of hemochromatosis; the treatment of Wilson disease; the treatment of paraquat toxicity; or for exchanging gallium for iron.
  • gallium desferrioxamine complex as well as a gallium penicillamine complex.
  • gallium is a trace element to which no natural biological activity has been assigned and there is no known essential requirement for its presence in tissues.
  • Zinc has been known for 20 years as an anti-oxidant metal (M. Chvapil, "New Aspects in the Biological Role of Zinc: A Stabilizer of Macromolecules and Biological Membranes", Life Sciences, Vol. 13, pp. 1041-1049, 1973; P. Korbashi, J. Katzhendler, P. Saltman and M. Chevion, "Zinc Protects E. Coli against Copper-Mediated Paraquat-Induced Damage", Journal of Biological Chemistry, Vol. 264, pp. 8479-8482, 1989; S. Powell, P. Saltman, G. Uretzky and M.
  • gallium is a trivalent ion (Gain).
  • the DFO molecule is made up of six basic units. In this form, when it is not bound to metals, it is a linear molecule that cannot easily penetrate into most cells (R. Laub, Y.J. Schneider, J.N. rete, A. Trouet and R.R. Crichton, "Cellular Pharmacology of Desferri ⁇ oxamine B and Derivatives in Cultured Rat Hepatocytes in Relation to Iron Mobilization", Biochemical Pharmacology, Vol. 34, pp. 1175-1183, 1985).
  • the present preparations should contain the following components:
  • GaCl 3 /Desferal R (molar ratios Ga/DFO between 0.1:1.0 and 1.0:1.0), in isotonic solution
  • capsules, tablets, or drinkable preparation should contain:
  • Ga/Desferal R (molar ratios between 0.6:1.0 and 1.0:1.0)
  • GaCl 3 /penicillamine (molar ratios Ga/penicillamine 0.1:1.0 and 1.0:1.0)
  • Ga/DFO (1:1) for protection of the dystrophied heart and maintaining adequate myocardial function
  • 10 mM solution of GMC-1 is mixed with 1 ml of 10 mM solution of Zn/DFO (1:1) and 1 ml of 10 mM solution Mn/DFO (1:1).
  • the ratio Ga/Zn/Mn/DFO is 1.0:1.0:1.2.
  • D-penicillamine (Aldrich Chemical Co., Inc.) 30 mM in doubly distilled water is mixed with equal volume of 30 mM GaCl 3 .
  • the complex Ga-penicillamine (1.0:1.0) is formed.
  • a solution containing 250 mg of D-penicillamine is dissolved in doubly distilled water, and a solution containing 293.6 mg GaCl 3 in doubly distilled water is added together with 1 gr of glucose, and then lyophilize-dried.
  • the solid is finely pulverized and inserted into commercial gelatin capsules.
  • GMC-1 Protects against Cardiac Damage to the Isolated Rat Heart in the Langendorff Configuration: Global Ischemia
  • Ga-DFO complex (1:1, 0.2 mM) was prepared and its spectrum taken. Small volume aliquots of ferric chloride (FeCl 3 , 100 mM) were added to reach a final concentration of Fe(III) 0.05-0.20 mM. Spectrophotometric examination shows the immediate formation of a stoichiometric complex of ferric-DFO, which has a characteristic absorbance of 425 nm.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant un complexe de desferrioxamine et de gallium ou de pénicillamine et de gallium comme principe actif, en combinaison avec un excipient pharmacologiquement acceptable. Le complexe de desferrioxamine ou de pénicillamine et de gallium est utile dans le traitement des pathologies suivantes: états pathologiques induits par les radicaux libres, lésions résultant d'accidents ischémiques au c÷ur, au cerveau ou au rein, thalassémie, hémochromatose, maladie de Wilson, intoxication au paraquat; et on peut l'utiliser également pour substituer du gallium au fer.
PCT/US1994/006878 1993-06-18 1994-06-17 Complexes au gallium pour le traitement des maladies induites par les radicaux libres Ceased WO1995000140A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU72093/94A AU7209394A (en) 1993-06-18 1994-06-17 Gallium complexes for the treatment of free radical-induced diseases
US08/569,116 US5618838A (en) 1993-06-18 1994-06-17 Gallium complexes for the treatment of free radical-induced diseases
EP94921320A EP0706391A4 (fr) 1993-06-18 1994-06-17 Complexes au gallium pour le traitement des maladies induites par les radicaux libres

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL106,064 1993-06-18
IL106064A IL106064A (en) 1993-06-18 1993-06-18 Gallium complexes for the treatment of free radical-induced diseases

Publications (1)

Publication Number Publication Date
WO1995000140A1 true WO1995000140A1 (fr) 1995-01-05

Family

ID=11064963

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/006878 Ceased WO1995000140A1 (fr) 1993-06-18 1994-06-17 Complexes au gallium pour le traitement des maladies induites par les radicaux libres

Country Status (4)

Country Link
EP (1) EP0706391A4 (fr)
AU (1) AU7209394A (fr)
IL (1) IL106064A (fr)
WO (1) WO1995000140A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015281A1 (fr) * 1996-10-08 1998-04-16 Hartford Hospital Provocation d'une reaction au stress cellulaire au moyen de sels de metaux lourds
WO2004060490A1 (fr) * 2003-01-07 2004-07-22 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composition comprenant un complexe desferrioxamine-metal, et son utilisation pour le traitement de dommages causes aux tissus consecutivement a une exposition a des agents chimiques de combat
WO2011021203A3 (fr) * 2009-08-19 2011-04-14 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Complexes desferrioxamine-métal pour le traitement de troubles liés à l'immunité
JP2018501312A (ja) * 2014-12-22 2018-01-18 モデハイ シェヴィオンCHEVION, Mordechai ノカルダミンの新規金属錯体および医薬組成物におけるそれらの使用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5075469A (en) * 1989-07-19 1991-12-24 Yissum Research Development Company Of The Hebrew University Of Jerusalem Pharmaceutical compositions containing a zinc complex
US5185368A (en) * 1987-07-23 1993-02-09 Ciba-Geigy Corporation Polyethylene glycol carbamates

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2047149T3 (es) * 1988-01-20 1994-02-16 Ciba Geigy Ag Procedimiento para la obtencion de compuestos complejos.
US5254724A (en) * 1991-10-30 1993-10-19 University Of Florida Research Foundation, Inc. Method for synthesis of desferrioxamine B, analogs and homologs thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5185368A (en) * 1987-07-23 1993-02-09 Ciba-Geigy Corporation Polyethylene glycol carbamates
US5075469A (en) * 1989-07-19 1991-12-24 Yissum Research Development Company Of The Hebrew University Of Jerusalem Pharmaceutical compositions containing a zinc complex

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
INORGANIC CHEMISTRY, Vol. 28, No. 18, issued 06 September 1989, B. BORGIAS et al., "Isomerization and Solution Structures of Desferrioxamine B Complexes of A13 + and Ga3+", pages 3538-3545. *
JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, Vol. 16, No. 1, issued 1979, Second International Symposium on Radiopharmaceutical Chemistry, M.M. GOODMAN et al., "Indium-111 Desferrioxamine Complexes: Preparation and Stabilities Studies", Paper No. 67, pages 138-139. *
See also references of EP0706391A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998015281A1 (fr) * 1996-10-08 1998-04-16 Hartford Hospital Provocation d'une reaction au stress cellulaire au moyen de sels de metaux lourds
US5955111A (en) * 1996-10-08 1999-09-21 Hartford Hospital Methods and compositions for inducing production of stress proteins
WO2004060490A1 (fr) * 2003-01-07 2004-07-22 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composition comprenant un complexe desferrioxamine-metal, et son utilisation pour le traitement de dommages causes aux tissus consecutivement a une exposition a des agents chimiques de combat
WO2011021203A3 (fr) * 2009-08-19 2011-04-14 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Complexes desferrioxamine-métal pour le traitement de troubles liés à l'immunité
US8975294B2 (en) 2009-08-19 2015-03-10 Hadasit Medical Research Services And Development Ltd. Desferrioxamine-metal complexes for the treatment of immune-related disorders
AU2010286054B2 (en) * 2009-08-19 2016-10-27 Mordechai Chevion Desferrioxamine-metal complexes for the treatment of immune-related disorders
US9770430B2 (en) 2009-08-19 2017-09-26 Mordechai Chevion Desferrioxamine-metal complexes for the treatment of immune-related disorders
EP3189836A3 (fr) * 2009-08-19 2017-09-27 Mordechai Chevion Complexes desferrioxamine-métal pour le traitement de troubles liés à l'immunité
AU2016244189B2 (en) * 2009-08-19 2018-06-28 Mordechai Chevion Desferrioxamine-metal complexes for the treatment of immune-related disorders
JP2018501312A (ja) * 2014-12-22 2018-01-18 モデハイ シェヴィオンCHEVION, Mordechai ノカルダミンの新規金属錯体および医薬組成物におけるそれらの使用

Also Published As

Publication number Publication date
EP0706391A1 (fr) 1996-04-17
IL106064A0 (en) 1993-10-20
AU7209394A (en) 1995-01-17
IL106064A (en) 1997-11-20
EP0706391A4 (fr) 1997-07-30

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