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  Methods for the prevention and/or the treatment of glutamate cytotoxicityUSPTO Application #: 20070225236Title: Methods for the prevention and/or the treatment of glutamate cytotoxicity Abstract: The present invention relates to the use of beta-naphthoquinone derivatives, and salts thereof, for the prevention and/or the treatment of glutamate cytotoxicity. It further relates to the use of beta-naphthoquinone derivatives, and salts thereof, for preventing and/or treating glutamate induced neurological disorders. Additionally, it concerns the use of beta-naphthoquinone derivatives, and salts thereof, for making drugs exerting an inhibitory effect on the release of glutamate. (end of abstract) Agent: Buchanan, Ingersoll & Rooney PC - Alexandria, VA, US Inventors: Maurice Israel, Jordi Molgo, Christian Bloy, Cesar Mattei USPTO Applicaton #: 20070225236 - Class: 514027000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Oxygen Of The Saccharide Radical Bonded Directly To A Nonsaccharide Hetero Ring Or A Polycyclo Ring System Which Contains A Nonsaccharide Hetero Ring The Patent Description & Claims data below is from USPTO Patent Application 20070225236. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to the use of beta-naphthoquinone derivatives, and salts thereof, for the prevention and/or the treatment of glutamate cytotoxicity. It further relates to the use of beta-naphthoquinone derivatives, and salts thereof, for preventing and/or treating glutamate induced neurological disorders. Additionally, it concerns the use of beta-naphthoquinone derivatives, and salts thereof, for making drugs exerting an inhibitory effect on the release of glutamate. [0002] A large number of studies have established that cellular communication using excitatory amino acids can be transformed into a mechanism of cell destruction. [0003] Glutamate is the main excitatory neurotransmitter in the nervous system, especially brain and spinal cord, of mammals wherein it is working at a variety of excitatory synapses. [0004] The ubiquitous distribution of glutamate receptors throughout the nervous system proves that glutamate plays a central role in a wide range of physiological as well as pathological events (Watkins J. C., Collingridge G. L., The NMDA receptor, IRL Oxford, 1989). It is for example strongly suggested that it plays a central role in functions such as learning, pattern recognition, and memory (Bliss T. V. P. Collingridge G. L., Nature 361, 31-39, 1993). [0005] Normally extracellular levels of glutamate are elevated only in a brief and spatially localized fashion associated with normal synaptic transmission however, under pathologic circumstances levels may remain dramatically increased. [0006] Additionally, it has also been known for decades that glutamate is toxic to neurons in vitro and in vivo and that the function of glutamate receptor, especially glutamate receptors of the N-methyl-D-aspartate ("NMDA") receptor subtype, is crucial in a number of neuronal damages and injuries (Appel S. H., Trends Neurosci. 16, 3-5, 1993). Many neurological disorders involving epileptic seizures and chronic or acute degenerative processes, such as for example Alzheimer's, Huntington's, Parkinson's diseases, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), retinopathy, stroke and traumatic brain injury, involve neuronal cell death caused by over-stimulation of the glutamate receptors. Similarly, it has been shown that neuronal injury caused by ischemia after occlusion of cerebral arteries could, at least partially, be mediated by excessive activation of glutamate receptors as in the ischemic brain, extracellular glutamate is elevated rapidly after the onset of ischemia and declines following reperfusion (Davalos et al., 1997, Stroke, 28, 708-710). Other pathologic circumstances associated with dramatic increase of extracellular glutamate levels are hypoxia or hypoglycaemia. Finally, Stephans and Yamamoto (1994, Synapse, 17, 203-209) have shown that drug-induced neurotoxicity, for example neurotoxic effects of methamphetamine (METH) on striatal dopaminergic neurons, could actually be mediated by over-stimulation of the glutamate receptors. [0007] These excessive activations of glutamate receptors, referred to as "glutamate cytotoxicity", are actually associated with the elevation of extracellular glutamate levels. The mechanisms of the elevation of extracellular glutamate include enhanced efflux of glutamate and/or the reduction of glutamate uptake by cells. Thus, it would be desirable to provide a means of protecting affected cells, especially neurons, from glutamate-induced cytotoxicity, and more specifically to provide means of regulating glutamate release and/or uptake by glutamate producing cells. [0008] To this end, it has already been proposed to target the glutamate receptors, mostly the N-methyl-D-aspartate ("NMDA") receptor, present on the targeted cells by inhibiting them by the use of agonist or antagonist specific molecules. Examples of such molecules are anthranilic acid derivatives (see U.S. Pat. No. 5,789,444), Basilen Blue D-3G (Reactive Blue 2) and Cibacron Blue 3GA and 5-adenylylimidodiphosphate (AMPPNP) (see U.S. Pat. No. 6,326,370), NMDA specific antagonists such as ketamine, dextromophan, or 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (Kristensen et al., 1992, Pain, 51:249-253; Eide et al., 1995, Pain, 61, 221-228), or the 2-methyl-6-(phenylethynyl)pyridine (MPEP) which is an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) (Ossowska et al., 2001, Neuropharmacology,41, 413-420). [0009] However, widespread use of these compounds is precluded by their undesirable side effects (e.g. psychotomimetic effects, headache, hallucinations, dysphoria or disturbances of cognitive and motor functions). Thus, the available treatment methods are not satisfactory in terms of safety or efficiency for their wide implementation. [0010] Therefore, there is still a need in the provision of improved methods and means for protecting affected cells, and more preferably neurons, from glutamate-induced cytotoxicity. [0011] The investigation by the inventors has now surprisingly shown that certain beta-naphthoquinone derivative compounds, previously used as vasoprotective drugs, have preventing and/or treating effects on glutamate-induced cytotoxicity. More specifically, said compounds have been shown to control, and preferably inhibit, the spontaneous and/or the evoked (i.e. the glutamate release by cells in response to depolarization) release of glutamate. [0012] Thus the present invention provides a new class of compounds which represents a pharmacological alternative to previously described compounds, such as competitive and non-competitive glutamate antagonists or agonists, gangliosides and growth factors, for the treatment or prevention of acute and chronic glutamate-related diseases or conditions, particularly neurological diseases. In preferred embodiments, the present invention provides a new class of compounds which can be used as pharmacological tools for the modulation of glutamate cellular release and cytotoxicity, preferably neurotoxicity, and which allows the possible treatment and/or prevention of many neurological disorders involving epileptic seizures and acute and chronic neurodegenerative diseases, as well as neuronal injury caused by ischemia or glutamate-related diseases or conditions, wherein said disorders are, at least partially, associated with excessive activation of glutamate receptors and/or with excessive extracellular glutamate levels. [0013] The invention is therefore first directed to a novel use of beta-naphthoquinone derivatives for making drugs with an inhibitory effect on the extracellular glutamate release, wherein said derivatives are selected among the group consisting of: [0014] (i) compounds having the formula (I) [0015] wherein R represents --NH--CO--NH.sub.2, --NH--CO--CH.sub.3, or --OH group, [0016] (ii) glucuronide derivatives thereof having the formula (II): wherein R is as above indicated, and [0017] (iii) addition salts thereof. [0018] According to preferred embodiments, said derivatives are selected among the group consisting of the 1,2-naphthoquinone, 2-semicarbazone, also called naftazone according to its international common name, and its corresponding glucuronidated derivative, i.e. the 1-(1-hydroxy,2-naphthyl)semicarbazide-1-.beta.-O-gluco-pyranosiduronic acid, respectively of formula (III) and formula (IV): [0019] In special embodiment, the derivatives of the invention are further substituted with, one to four, identical or different, heteroatoms and/or hetero groups. Examples of said heteroatoms and/or hetero groups are O, H, alkyl groups C.sub.nH.sub.n+1, with n=1 to 5, OCH.sub.3, N, halogens (for example F or Br), S or any labeling element allowing to visualize said derivatives. These substituting atoms or groups, and their uses, are widely known in the art. [0020] The addition salts of the derivatives of the invention comprise conventional salt formed from inorganic or organic acids or bases, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, ethylenediamine ; formic, benzoic, maleic, tartaric, citric, oxalic, aspartic acid, and alkane-sulfonic acids is even mentioned. [0021] The preparation of compounds used according to the invention has been widely described in the literature, for example, in BSM 924 M or Patent FR 2103 504. [0022] The newly identified inhibitory properties of these compounds, reported in the examples hereafter, make them particularly suitable for treating and/or preventing diseases, conditions and attacks related to deleterious effects of glutamate released in exess, and preferably neurological ones. [0023] Thus the present invention further relates to a method for treating and/or preventing glutamate-evoked cytotoxicity in a patient in need thereof comprising administering to said patient a composition containing a therapeutically effective amount of at least one beta-naphthoquinone derivative and a pharmaceutically acceptable carrier, wherein said derivative is selected among the group consisting of : [0024] (i) compounds having the formula (I): wherein R represents --NH--CO--NH.sub.2, --NH--CO--CH.sub.3, or --OH group, and [0025] (ii) glucuronide derivatives thereof having the formula (II): wherein R is as above indicated, and [0026] (iii) addition salts thereof. [0027] In preferred embodiments, the derivatives administered according to the method of the invention are selected among the group consisting of the 1,2-naphthoquinone, 2-semicarbazone, also called naftazone, and its corresponding glucuronidated derivative, i.e. the 1-(1-hydroxy,2-naphthyl)semicarbazide-1-.beta.-O-gluco-pyranosiduronic acid (see formula (III) and (IV) respectively). Similarly, these derivatives might be substituted with, one to four, identical or different, heteroatoms and/or hetero groups as defined above. [0028] The term "glutamate-evoked cytotoxicity" within the present invention is intended to designate cell toxicity associated with excessive activations of glutamate receptors. These terms are well known by the one skilled in the art. More specifically, the "glutamate-evoked cytotoxicity" concerns all affected cells expressing glutamate receptors. According to preferred embodiments, these affected cells are nervous cells (i.e. neuro-cells), preferably neurons. These affected nervous cells are, for example, present in brain, spinal cord, retina, at the neuro-muscular junction, etc . . . "Cytotoxicity" means that the cell functions and/or properties are affected, leading to cell malfunctioning, and finally to cell death. [0029] In a particularly preferred embodiment, the method of the invention is intended for treating and/or preventing glutamate-evoked neurotoxicity, and even more preferably for treating and/or preventing neurodegeneration (i.e. degeneration of nervous cells). [0030] The present invention further relates to a method for modulating the release of glutamate in a patient comprising administering to said patient a composition containing a therapeutically effective amount of at least one beta-naphthoquinone derivative and a pharmaceutically acceptable carrier, wherein said derivative is selected among the group consisting of derivatives of Formula I to IV, and addition salts thereof. These derivatives are detailed above. "Modulating the release of glutamate" means that the levels of released glutamate in non treated patient is different from the one observed after his treatment with the derivatives of the invention. According to preferred embodiment, treatment of the patient with the derivatives of the invention leads to a negative modulation, preferably to the inhibition, of the glutamate release by the producing cells, and thus to a decreased glutamate level in the treated patient compared to the glutamate level observed before said treatment. [0031] The present invention further relates to a method for treating and/or preventing disease and/or condition associated with the excessive release of glutamate in a patient comprising administration to said patient of a composition containing a therapeutically effective amount of at least one beta-naphtoquinone derivative and a pharmaceutically acceptable carrier, wherein said derivative is selected among the group consisting of derivatives of Formula I to IV, and addition salts thereof. These derivatives are detailed above. Continue reading... Full patent description for Methods for the prevention and/or the treatment of glutamate cytotoxicity Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods for the prevention and/or the treatment of glutamate cytotoxicity patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. 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