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WO2002036066A2 - Compositions pharmaceutiques comprenant des complexes de vanadium organiques pour le traitement de l'ischemie - Google Patents

Compositions pharmaceutiques comprenant des complexes de vanadium organiques pour le traitement de l'ischemie Download PDF

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Publication number
WO2002036066A2
WO2002036066A2 PCT/IL2001/001004 IL0101004W WO0236066A2 WO 2002036066 A2 WO2002036066 A2 WO 2002036066A2 IL 0101004 W IL0101004 W IL 0101004W WO 0236066 A2 WO0236066 A2 WO 0236066A2
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WO
WIPO (PCT)
Prior art keywords
vanadium
complex
monohydroxamate
vanadate
bis
Prior art date
Application number
PCT/IL2001/001004
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English (en)
Other versions
WO2002036066A3 (fr
Inventor
Yoram Shechter
Matityahu Fridkin
Itzhak Goldwaser
Original Assignee
Yeda Research And Development Co. Ltd.
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
Priority claimed from IL13939900A external-priority patent/IL139399A0/xx
Priority claimed from IL14118201A external-priority patent/IL141182A0/xx
Application filed by Yeda Research And Development Co. Ltd. filed Critical Yeda Research And Development Co. Ltd.
Priority to AU2002214222A priority Critical patent/AU2002214222A1/en
Publication of WO2002036066A2 publication Critical patent/WO2002036066A2/fr
Publication of WO2002036066A3 publication Critical patent/WO2002036066A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol

Definitions

  • the present invention relates to pharmaceutical compositions comprising organic vanadium complexes useful for prevention or treatment of cerebral ischemia.
  • Stroke or cerebral ischemia can be initiated by a state of stress (i.e., by cardiac arrest) and ultimately result in neuronal death and brain damage (Myers and Yamaguchi, 1977).
  • the cellular mechanisms and the sequence of events leading to ischemia are still obscure.
  • An extreme case is a normoxic brain condition in which glucose is consumed by brain tissues at a faster rate and in large quantities. Cellular ATP levels are then depleted, leading to the inability of brain tissues to utilize glucose as a source of energy, thus culminating in ischemia.
  • Stroke or cerebral ischemia is the third leading cause of death in the U.S. and other Western countries.
  • a large toll on society estimated at hundreds of billions of dollars are spent annually as a result of this pathological syndrome.
  • preischemic hyperglycemia has been shown to aggravate (rather than reduce) cerebral ischemic damage. This phenomenon has been initially accounted for by excessive production and accumulation of lactic acid and acidosis in brain tissues (Siesjo, 1981).
  • Schurr et al. have refuted this hypothesis by demonstrating that high concentrations of lactic acid not only do not damage but rather protect rat hippocampal slices from hypoxia (Schurr et al., 1988a and b).
  • hippocampal slices utilize lactate aerobically as an energy source (Schurr et al., 1988b) - an absolute essential event under normoxic conditions when the ATP level is depleted and glucose cannot be utilized as a source of energy.
  • Vanadium salts were investigated in the last two decades with respect to their insulin-like effects in vitro, and in relation to their antidiabetic actions in diabetic rodents and in human patients (reviewed in Shechter, 1990 and Brichard and Henquin, 1995). Vanadium salts are particularly effective in reversing the deteriorating actions of chronic hyperglycemia in diabetic rodents.
  • vanadium therapy restores the activity of glucokinase, increases the level of 2,6-bisphosphate by elevating the level of the L-pyruvate kinase gene, and suppresses gluconeogenesis by lowering niRNA and protein levels of phosphoenolpyruvate carboxykinase (Gil et al, 1988).
  • vanadium therapy also restores glycogen synthesis. All of these aberrations are the direct consequence of chronic hyperglycemia in diabetic rodents.
  • HXM amino acid monohydroxamates
  • Glu( ⁇ )HXM glutamic acid ⁇ -monohydroxamate
  • Asp( ⁇ )HXM aspartic acid ⁇ - monohydroxamate
  • organic vanadium complexes in particular vanadium complexes of monohydroxamates, and more particularly the complex of the L-form of glutamic acid ⁇ - monohydroxamate (Glu( ⁇ )HXM) with vanadium (+5) (2:1, herein designated LP- 100), can antagonize the deteriorating actions of preischemic hyperglycemia and those of corticosterone.
  • the present invention relates to pharmaceutical compositions for prevention and/or treatment of cerebral ischemia comprising as active ingredient an organic vanadium complex.
  • Any suitable organic vanadium complex can be used according to the invention such as, but not being limited to, bis(N-octyl cysteine amide) oxovanadium (IV), bis(maltolato)oxovanadium (IV), bis(picolinato) oxovanadium
  • the present invention provides a pharmaceutical composition for prevention and/or treatment of cerebral ischemia comprising as active ingredient an organic vanadium complex of a monohydroxamate of the formula (I):
  • R is a residue selected from:
  • the composition of the invention comprises a vanadium complex of a monohydroxamate of an amino acid as defined in (i) above, most preferably wherein n is 2, namely the ⁇ - monohydroxamate of L-glutamic acid.
  • the 3-pyridyl radical namely the nicotinic acid hydroxamate, the 2- or 3-piperidyl radical and the 3-tetrahydroisoquinolrnyl radical.
  • vanadium salts used to form the vanadium complexes of hydroxamates used in the compositions of the present invention are, without being limited to, VOCl 2 (+4), VOSO 4 (+4), NaVO 3 (+5) and Na 3 VO 4 (+5).
  • HXM vanadium complexes of amino acid hydroxamates
  • various HXM:vanadium salt stoichiometric molar ratios of the complexes are envisaged by the present invention, but 1:1 and 2:1 HXM:vanadium salt molar ratios are preferred.
  • the composition comprises the complex formed between 2 mol of ⁇ -monohydroxamate of L- glutamic acid and 1 mol of NaVO 3 (+5), herein identified as LP-100, of the formula: [H 2 N-CH(COOH)-CH 2 -CH 2 -CO-NHOH] 2 : Na VO 3
  • the vanadium complexes in particular the complexes with monohydroxamates of formula I of the compositions of the invention, are prepared by mixing water solutions of the organic compound, e.g. the monohydroxamate, and the vanadium salt, freezing and lyophilizing the solution, thus obtaining a dry powder that can be stored, for example, at room temperature.
  • compositions of the invention are useful for prevention and/or treatment of cerebral ischemia also known as cerebral infarction or stroke.
  • the dosage to be administered will depend on the conditions of the patient.
  • the allowed amount of vanadium being used in diabetic patients in clinical trials today is about 2-4 mg/kg/day, that corresponds to about 6-12 mg/kg/day of LP- 100. This range could be used for prevention of cerebral ischemia in individuals likely to develop it. However, in case of evolving stroke or acute complete stroke, the dose may be higher since it is an acute treatment.
  • compositions of the invention comprising the organic vanadium complex may be presented in soluble form, such as drops, or in the form of capsules or tablets, and are preferably administered orally. They may be administered alone or in combination with another drug for prevention and/or treatment of cerebral ischemia.
  • the invention relates to the use of an organic vanadium complex, particularly those described above, for the preparation of a pharmaceutical composition for the prevention and/or treatment of cerebral ischemia.
  • the invention relates to a method for prevention and/or treatment of cerebral ischemia in order to diminish the deteriorating effects thereof, which comprises administering to an individual in need thereof an effective amount of an organic vanadium complex, particularly those described above.
  • Figs. 1A-1B show that corticosterone decreases percentage of rat hippocampal slices with normal neuronal function in an in vitro experimental system, following 30 min hypoxia, in a dose-dependent manner (1 A) and vanadate (200 ⁇ M) and LP-100 (20 ⁇ M) antagonize corticosterone-evoked ischemic damage in vitro (IB).
  • the indicated concentrations of vanadate and LP-100 were perfused during the 30 min of ischemic period only. Ischemia was induced by depleting glucose for 30 min and oxygen for 4 min.
  • Fig. 2 shows an in vivo experimental system for analyzing cardiac arrest- evoked cerebral ischemia in hyperglycemic rats and the beneficial effects of vanadate and LP-100.
  • Groups of rats are injected (i.p.) with the indicated concentrations of vanadate or LP-100 administered either 1 h ('early vanadium') or 1 min ('late vanadium') prior to cardiac arrest. Rats are then subjected to glucose- loading and chest compression cardiac arrest. Rats are sacrificed a week later and the extent of neuronal damage in hippocampal slices is evaluated by an electrophysiological procedure. Each group consists of five rats.
  • the present invention relates to the use of organic vanadium complexes such as vanadium complexes of certain monohydroxamates, more particularly the complex of the L-form of glutamic acid ⁇ -monohydroxamate (Glu( ⁇ )HXM) with vanadium (+5) (2:1, herein designated LP-100), for prevention and/or treatment of cerebral ischemia (also known as cerebral infarction or stroke).
  • organic vanadium complexes such as vanadium complexes of certain monohydroxamates, more particularly the complex of the L-form of glutamic acid ⁇ -monohydroxamate (Glu( ⁇ )HXM) with vanadium (+5) (2:1, herein designated LP-100)
  • Vanadium salts and LP-100 antagonize a variety of deteriorating actions originating from hyperglycemia in liver and in muscle tissue of diabetic rodents and, as shown herein, are also effective in reversing corticosterone-evoked cerebral damage in brain slices and in cardiac arrest induced hyperglycemic- ischemic rat model.
  • the level of the 'stress hormone' cortisol (the human analog of rat corticosterone) is, however, elevated under pathological conditions such as ischemia and/or cardiac arrest in an ACTH- dependent fashion.
  • Vanadium salts mimic the effects of insulin in a post-receptor-mediated fashion and ameliorate diabetic deficiencies originating from hyperglycemia.
  • Hyperglycemia has been implicated in aggravating cerebral ischemia by elevating the levels of corticosterone. It is shown herein that vanadium (+5), and more so L- Glu( ⁇ )HXM- vanadium (+5), (2:1, LP-100), have neuroprotective effects on cerebral ischemia. This is demonstrated in vitro using hippocampal slices, and in vivo in cardiac-arrest-induced transient global cerebral ischemia in hyperglycemic rats.
  • aCSF cerebrospinal fluid
  • NaCL 124 NaCL 124
  • KC1 NaH 2 PO 4 , 3
  • CaCl 2 2.5
  • MgSO 4 NaHCO 3
  • D- glucose 10.
  • the pH was 7.3-7.4 (295-300 mOsm).
  • glucose was reduced to 5 mM.
  • Chemicals were of analytical grade and obtained from Sigma Chemical Co. (St. Louis, MO). Corticosterone acetate was dissolved in ethanol for a final CSF concentration of 0.01%.
  • the anesthetized rat is placed supine and a 14-gauge angiocath tube is placed in the trachea for the respiratory assistance during resuscitation following chest compression-induced cardiac arrest.
  • a catheter is placed in the abdominal aorta via the femoral artery for continuous monitoring of blood pressure before and during chest compression, and during cardiopulmonary resuscitation (CPR).
  • Temperature is controlled at 35.5 + 0.5° C during the chest compression- resuscitation period and during 1 h post-TGI.
  • Chest compression is maintained for 5 min by placing a 3-kg weight on a chest bar (Reid et al., 1996). The speed of the weight descent is regulated manually to allow deflation of the lungs as they are compressed.
  • the end point of compression is the complete loss of pulse pressure.
  • Post-compression CPR is initiated at the end of 5-min compression after removing the weight and chest bar.
  • Chest massage is applied to reestablish cardiac circulation.
  • Reoxygenation of the rat is enhanced by ventilation with a humidified mixture of 95%O 2 /5%CO 2 at intervals of 5 s.
  • Systemic circulation usually returns within 1-3 min after compression is terminated. All rats are loaded with glucose (2 g/kg, i.p.) 15 min prior to chest compression.
  • LP-100 is administered 60 min prior to chest compression (several doses, i.p.) while controls are injected with the vehicle.
  • Example 1 Vanadate and LP-100 reverse corticosterone-enhanced ischemic damage in hippocampal slices. Rat hippocampal slices were maintained under an atmosphere of carbogen
  • Fig. 1 A As shown in Fig. 1 A, increasing concentrations of corticosterone, prior to induction of hypoxia, reduced the extent of normal neuronal function in a dose- dependent fashion. Thus, at 0, 5, 10, 15 and 20 ⁇ M corticosterone, the percentage of slices showing normal neuronal function amounted to 57+3, 41+8, 18+2 and 10+1%, respectively (Fig. 1A).
  • vanadate (200 ⁇ M) or LP-100 (50 ⁇ M) were included in the incubation medium, along with corticosterone, prior to the induction of hypoxia, the aggravating effect of the steroid (10+1% neuronal function, Fig. IB) was fully antagonized (59+2% neuronal function).
  • Sprague-Dowley male rats are first brought to a hyperglycemic state by injecting glucose 15 min prior to the cardiac arrest procedure. This specific time point of glucose administration, rather l o than earlier ones, is chosen to obtain maximal elevation of corticosterone (Schurr et al., 1999). Cardiac arrest induces a transient global cerebral ischemia which, if massive enough, by and large extends the duration of the neuronal damage. Treated rats are sacrificed one week after the insult, hippocampal slices are prepared and the degree of neuronal damage is evaluated both by
  • Vanadate treatment markedly increases glucose utilization in muscle of insulin resistant fa/fa rats without modifying glucose transporter expression.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

Des complexes de vanadium organiques peuvent être utilisés dans la prévention et/ou le traitement de l'ischémie cérébrale. Le complexe de vanadium peut être du bis(N-octyl cystéine amide) oxovanadium (IV), bis(maltolato)oxovanadium (IV), bis(picolinato) oxovanadium (IV) ou un complexe de vanadium d'un hydroxamate, de préférence un monohydroxamate, et est de préférence également un complexe de vanadium d'un monohydroxamate de formule R-CO-NHOH.X, où R représente un radical sélectionné parmi: (i) H2N-CH(COY)-(CH2)n-; (ii) H2N-CH(COOH)-CH2-S-CH2-; et (iii) pyridyle, pipéridyle ou tétrahydro-isoquinolinyle, où n représente 1, 2 ou 3, et Y représente OH ou NH2; et X est un composé de vanadium sélectionné parmi un sel de vanadyle (VO2+), de métavanadate (VO¿3?-) ou de vanadate (VO¿4?3-).
PCT/IL2001/001004 2000-11-01 2001-10-30 Compositions pharmaceutiques comprenant des complexes de vanadium organiques pour le traitement de l'ischemie WO2002036066A2 (fr)

Priority Applications (1)

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AU2002214222A AU2002214222A1 (en) 2000-11-01 2001-10-30 Pharmaceutical compositions comprising organic vanadium complexes for treatment of ischemia

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IL139399 2000-11-01
IL13939900A IL139399A0 (en) 2000-11-01 2000-11-01 Pharmaceutical compositions comprising vanadium complexes of hydroxamates
IL141182 2001-01-30
IL14118201A IL141182A0 (en) 2001-01-30 2001-01-30 Pharmaceutical compositions comprising organic vanadium complexes

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10112915B2 (en) 2015-02-02 2018-10-30 Forma Therapeutics, Inc. 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10183934B2 (en) 2015-02-02 2019-01-22 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
NL2019605B1 (en) * 2017-09-22 2019-03-28 Cfm Pharma Holding B V Vanadyl and vanadate for use in reducing stress-induced metabolic derangement
US10555935B2 (en) 2016-06-17 2020-02-11 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996039385A1 (fr) * 1995-06-06 1996-12-12 Pfizer Inc. (indole-2-carbonyl-)-amides substitues en n et leurs derives, servant d'inhibiteurs de la glycogene phosphorylase
IL121748A0 (en) * 1997-09-11 1998-02-22 Yeda Res & Dev Vanadium complexes of hydroxamates and pharmaceutical compositions comprising them

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US10183934B2 (en) 2015-02-02 2019-01-22 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10214500B2 (en) 2015-02-02 2019-02-26 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10214501B2 (en) 2015-02-02 2019-02-26 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10239845B2 (en) 2015-02-02 2019-03-26 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US12304904B2 (en) 2015-02-02 2025-05-20 Valo Health, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US12264137B2 (en) 2015-02-02 2025-04-01 Valo Health, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US10407418B2 (en) 2015-02-02 2019-09-10 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10414738B2 (en) 2015-02-02 2019-09-17 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US10450283B2 (en) 2015-02-02 2019-10-22 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10457652B2 (en) 2015-02-02 2019-10-29 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10464910B2 (en) 2015-02-02 2019-11-05 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US10112915B2 (en) 2015-02-02 2018-10-30 Forma Therapeutics, Inc. 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US10513501B2 (en) 2015-02-02 2019-12-24 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US10822316B2 (en) 2015-02-02 2020-11-03 Valo Early Discovery, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US10829462B2 (en) 2015-02-02 2020-11-10 Valo Early Discovery, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10870645B2 (en) 2015-02-02 2020-12-22 Valo Early Discovery, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US11702412B2 (en) 2015-02-02 2023-07-18 Valo Health, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10988450B2 (en) 2015-02-02 2021-04-27 Valo Early Discovery, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11274084B2 (en) 2015-02-02 2022-03-15 Valo Health, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US11279681B2 (en) 2015-02-02 2022-03-22 Valo Health, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10874649B2 (en) 2016-06-17 2020-12-29 Valo Early Discovery, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US11730721B2 (en) 2016-06-17 2023-08-22 Valo Health, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US10555935B2 (en) 2016-06-17 2020-02-11 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US12213969B2 (en) 2016-06-17 2025-02-04 Valo Health, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
WO2019059770A1 (fr) * 2017-09-22 2019-03-28 Cfm Pharma Holding B.V. Vanadyle et vanadate destinés à être utilisés pour réduire un trouble métabolique induit par le stress
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