EP2114400A2 - Verwendung von riluzol und derivaten zur herstellung neuer arzneimittel - Google Patents

Verwendung von riluzol und derivaten zur herstellung neuer arzneimittel

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Publication number
EP2114400A2
EP2114400A2 EP07872459A EP07872459A EP2114400A2 EP 2114400 A2 EP2114400 A2 EP 2114400A2 EP 07872459 A EP07872459 A EP 07872459A EP 07872459 A EP07872459 A EP 07872459A EP 2114400 A2 EP2114400 A2 EP 2114400A2
Authority
EP
European Patent Office
Prior art keywords
use according
riluzole
cells
treatment
pathology
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.)
Withdrawn
Application number
EP07872459A
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English (en)
French (fr)
Inventor
Ammar Achour
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.)
Association Pour Le Developpement de la Biotherapie Experimentale Et Appliquee (adbea)
Original Assignee
Association Pour Le Developpement de la Biotherapie Experimentale Et Appliquee (adbea)
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.)
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Publication of EP2114400A2 publication Critical patent/EP2114400A2/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the use of riluzole and its derivatives, to produce new drugs for restoring and regulating disrupted immune functions in patients with pathologies associated with such dysfunctions, such as infectious diseases or cancers.
  • Riluzole or 6- (trifluoromethoxy) -2-aminobenzothiazole) has the formula (A)
  • Therapeutic activities have already been reported for riluzole and salts thereof, for example activities such as anticonvulsants, anoxolytics and hypnotics (EP 050551).
  • the application WO 94/20103 also describes their use for the treatment of neurosida, dementia disorders, cognitive disorders, neuropathies, myopathy, ocular disorders and all the neurological symptoms related to the HIV-1 virus.
  • riluzole as well as derivatives of this product, were capable of restoring immune function in patients suffering from pathologies associated with deregulations of this function.
  • these compounds are capable of inducing the proliferation of lymphocytes and / or ensuring their survival. in patients with such pathologies and to inhibit cell apoptosis induced by infections.
  • Riluzole is also capable of inducing the expression of interferon ⁇ / ⁇ and interleukin 15, to treat a dysfunction related to a pathology of exogenous or endogenous origin. It is more particularly a pathology associated with an aggression of iatrogenic origin, induced by the action of immunosuppressants such as cyclosporine or by the action of corticosteroids.
  • the invention therefore aims to provide a new use of riluzole or its pharmaceutically acceptable salts for the manufacture of drugs to restore immune function for the treatment of infectious diseases or cancers.
  • salts with mineral acids such as hydrochloride, sulfate, nitrate, phosphate or organic acids such as acetate, propionate, succinate, citrate, oxalate, benzoate, fumarate, maleate, methanesulphonate, isethionate, theophylline-acetate, salicylate, phenolphthalate, methylene-bis- ⁇ -oxynaphthoate or substitution derivatives of these acids.
  • mineral acids such as hydrochloride, sulfate, nitrate, phosphate or organic acids such as acetate, propionate, succinate, citrate, oxalate, benzoate, fumarate, maleate, methanesulphonate, isethionate, theophylline-acetate, salicylate, phenolphthalate, methylene-bis- ⁇ -oxynaphthoate or substitution derivatives of these acids.
  • the drugs manufactured according to the invention can be used in vivo, or ex vivo, or, in the context of tests, in vitro.
  • these drugs can be used in the form of tablets, pills, powders (gelatin capsules, cachets) or granules.
  • the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica, under an argon stream.
  • these compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.
  • Liquid form compositions include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may include substances other than thinners, eg wetting agents, sweeteners, thickeners, flavorings or stabilizers.
  • compositions used in the form of drops or nebulisates are used in the form of drops or nebulisates.
  • the sterile compositions for parenteral administration may preferably be aqueous or nonaqueous solutions, suspensions or emulsions.
  • a solvent or vehicle mention may be made of water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents.
  • These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers.
  • Sterilization can be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • the drugs will advantageously be in the form of ointments, creams, gels or patches.
  • the above medicaments advantageously contain, as active principle, 25 to 100 mg of riluzole or a pharmaceutically acceptable salt of this derivative, these compounds being used alone or in combination, in a given treatment with other medicaments. .
  • riluzole or its salts makes it possible to have high-value drugs for the treatment of conditions resulting or at the origin of dysfunctions resulting in cell death or associated with such disturbances, as well as for any pathological situation caused by drugs, cancers or radiation, or physiological, such as old age and, in general, all situations in which the survival and function of immune cells are impaired or need to be reestablished.
  • these include the treatment
  • - pathology related to viral aggression including the treatment of viral or retroviral infections and their virological and immune symptoms, induced, for example, by HIV type 1 or 2, including opportunistic infections and lymphocyte function. and the regulation of immune system, or by the viruses of hepatitis A, B, C, or by herpes, or HTLV I or II,
  • parasitic aggression such as leishmaniasis, malaria or bilhariosis
  • tumor origin such as a hematological tumor such as myeloma, or tissue.
  • the drugs of the invention are also of great interest in the case of allogeneic liver transplants.
  • the drugs manufactured according to the invention are capable of inducing the production of ⁇ / ⁇ interferons and of IL-15.
  • the doses used in these treatments depend on the desired effect, the duration of treatment and the route of administration used. They will generally be between 50 and 200 mg per day orally for an adult with unit doses ranging from 25 to 100 mg of active substance.
  • the dosage will be determined according to age, weight and all other factors specific to the subject to be treated.
  • the dosage forms of this composition comprise in practice, per unit dose or multiple unit doses, an amount of active substance or mixture of active substances corresponding to a concentration of active substance or mixture of active substances of approximately 1 to 100 nM for a test. in vitro.
  • the person skilled in the art will adjust these quantities on a case-by-case basis and / or according to the conditions or physiological conditions for which an increase or tendency to the restoration of cell proliferation and functioning is desired.
  • doses may, depending on the route of administration used, the state of the patient and the active substance used, vary over time and be administered in a dosage comprising administration in one or more times per day, per week or per month.
  • a daily dose as mentioned above may itself be replaced by any other chronology and / or dose of administration of the active substance (weekly or monthly administration, in particular) insofar as the galenic of the active principle thus administered provides a pharmacological effect substantially similar to that obtained with daily administration.
  • the active compositions may be administered together with a physiologically acceptable carrier or vector or diluent to thereby form a ready-to-use complete pharmacological composition.
  • This reservoir is formed early in the course of infection, presumably in the initial phase of primary infection, and remains stable during infection.
  • riluzole in AIDS has been demonstrated in the test of the measurement of cell survival, apoptosis, lymphocyte typing and viral production of lymphocytes of AIDS patients cultured in vitro.
  • the drugs defined above are used alone or in combination with other active ingredients for a given treatment.
  • a pathology related to a viral (or retroviral) aggression advantageously will be used an association with one or more compounds with antiviral properties.
  • they may be for example compounds with antiviral properties, such as DDI, DDC, antiproteases, 3TC and AZT, or interferon ⁇ , interferon ⁇ PEG. , ribavirin.
  • the drugs of the invention will advantageously be used alternately with antivirals to allow a pause due to their toxicity, or indeed their presence to eradicate the infection.
  • an antiviral compound such as, for example, acyclovir.
  • an antiviral compound such as, for example, acyclovir.
  • the induction of the expression of interferon ⁇ / ⁇ with immunomodulatory capacity and the ability to inhibit the proliferation of tumor cells will advantageously be exploited.
  • FIGS. 1 to 9 represent, respectively, the effect of riluzole
  • FIGS. 1A to 1C and FIGS. 2A to 2C on the lymphocytes of patients suffering from AIDS;
  • FIGS. 3A to 3C on the lymphocytes of a patient suffering from AIDS
  • FIGS. 4A and 4B on the lymphocytes of a healthy seronegative individual
  • FIGS. 5A to 5C total apoptosis expressed by all the lymphocytes, CD8 lymphocytes and CD4 lymphocytes
  • FIG. 7 on apoptosis induced by the anti-FAS antibody;
  • Figure 8 on the expression of cytokine genes; and
  • Figure 9 on the proliferation of tumor cells.
  • the dosages of the active ingredient are related to the volume in liters of the patient's blood plasma.
  • capsules are prepared at 50 mg of active product having the following composition:
  • PBMC peripheral blood mononuclear cells
  • lymphocyte cultures are prepared according to the method described by Achour et al., Antimicrob. Agents. Chemother42, 2482-2491 (1998).
  • the PBMCs were isolated from fresh, citrated-treated whole blood from healthy donors infected with HIV-1 by density gradient centrifugation using a device called Ficoll-Hypaque (Eurobio, Les Ullis, France).
  • the harvested cells were resuspended at 10 6 / ml in RPMI 1640 culture medium containing 10% decomplemented human serum AB, non-essential amino acids, 10 U / ml penicillin (Sigma), 100 ⁇ g streptomycin / ml (Sigma), 2mM L-glutamine (Sigma), 1mM sodium pyruvate (Sigma), 10mM HEPES buffer, plus 20 IU / ml interleukin 2 (Boehringer Mannheim, Germany); this medium constitutes the complete culture medium, abbreviated MC.
  • the cells were then seeded at 4x10 6 / well in 6-well culture plates (Nunc, Roskilde, Denmark) and stimulated with 100ng / ml of anti-CD3 monoclonal antibody (Pharmingen, Los Angeles, CA. , USA) plus 100 ng / ml anti-CD28 monoclonal antibody (Pharmingen, Los Angeles, CA, USA) in the absence or presence of different concentrations of riluzole (10 "4/10" 10 M).
  • the cultures were maintained at 37 ° C in humidified air containing CO 2 .
  • the culture media were changed every 4-5 days, the cultures being maintained at a constant density of viable cells of 1x10 6 cells / ml. On each pass, viable cell counts were performed by trypan blue staining, and the supernatants were harvested for storage at -20 ° C.
  • Apoptosis test Apoptotic cells were measured using FITC-labeled propidium iodide and annexin V, which is a phospholipid-binding protein that binds preferentially to phosphatidylserine exposed on the cell surface in the initial phase. apoptosis, using a commercially available kit (Immunotech, Marseille, France). Cells that were negative to iodide Propidium and annexin V-positive were identified as apoptotic cells, while those that were positive for both propidium iodide and annexin V were considered pre-necrotic cells.
  • Apoptosis caused by the anti-FAS monoclonal antibody (CD95 / APO-1) (Immunotech, Marseille, France) was also measured insofar as it is well known that the Fas / Fas ligand apoptosis is amplified in the AIDS disease).
  • T cell counts of CD4 + and CD8 + phenotypes, Ki-67 activation marker, and annexin V were performed by flow cytometric analysis (FACScan, Becton Dickenson, San Jose, CA, USA).
  • FACScan Fluorescence Activated Cell Sorting
  • CD8-PE Becton Dickinson, France
  • Ki-67-FITC Ki-67-FITC
  • Annexine-FITC Immunotech, Marseille, France.
  • Virus production was determined by measuring HIV RNA in cell-free supernatants by an overlap amplification test induced by multiple primers with a detection threshold of 10 copies / ml equivalents (Lu et al., Nat. Med., 1999).
  • the primers used are the following;
  • F1 / R1 (F1, nucleotides sense 1, 359-1, 387 of HIV-1 accession HXB2 sequence
  • SEQ ID NO: 1 5 J--GTGGGGGGACATCAA GCAGCCATGCAAAT-3 'antisense nucleotides 1, 630-1, 659 of HXB2,
  • SEQ ID NO: 2 ⁇ 'CCTTTGGTCCTTGTCTTATGTCCAG-AATGC-S '
  • RNA was extracted from 100 ⁇ l of the culture supernatants using a commercial solution of RNA isolation (RNAzol; WAK-Chemie Medical, Bad
  • the optical density was measured at 405/450 nm using a microplate reader (Dynatech MRX). The optical density of the samples is directly correlated to the number of specifically amplified HIV-1 sequences in the sample. The viral load is thus calculated using the standard calibration curve following a log-log regression mode.
  • Proviral DNA was determined by a modified Muprovama test.
  • 2x10 5 cells were used for cell DNA purification with a commercial kit (QIAmp® DNA minikit, Quiagen GmbH, Hilden, Germany).
  • QIAmp® DNA minikit Quiagen GmbH, Hilden, Germany.
  • Four standard dilutions (10, 100, 1000 and 10,000 copies) in equivalent of 10 5 HIV negative donor PBMC DNA cells, plasmid HIV-1 DNA (pBH10-R3) were used as an external standard in each experiment.
  • RNA is first retro-transcribed using a kit (Hight capacity cDNA Archive kit PN: 4322171, Applied Bipsystems, Foster City, CA) using random primers. and the MultiScribe RT enzyme (5U / ⁇ l) for 2 hours at 37 ° C.
  • the labeling method with SYBR Green, a fluorescent molecule that is inserted in the small groove of the double helix was used.
  • the reaction is carried out by means of a thermocycler (ABI prism 7900 HT, Applied Boisystems, Foster City, CA).
  • Glyceraldehyde phosphate dehydrogenase has been used as an endogenous control gene.
  • sequences of the primers used are the following (Proligo LLC, Boulder, CO, USA) (forward-reverse): SEQ ID No. 3 and SEQ ID No. 15: GAPDH (5'-AACAGCCTCAAGATCAGCAA-3 ') - (5' -CAGTCTGGGTGGCAGTGAT-3 ') SEQ ID No. 4 and SEQ ID No. 16:
  • TLR-2 (5'-CTCTCGGTGTCGGAATGTC-3 ') - (5'-AGGGGGGATTGAAGTTCTC-3') SEQ ID NO: 5 and SEQ ID NO: 17:
  • TLR-3 (5'-ACGAGACCCATACCAACATCC-3 ') - (5'-TTCCCAGACCCAATCCTTATC-3') SEQ ID NO: 6 and SEQ ID NO: 18: TLR-7 (5'-GACCTCAGCCACAACCAAC-3 1 ) - (5 "-TAACCCACCAGACAAACCAC-3 ')
  • TLR-9 (5'-CTACAACCGCATCGTCAAAC-3 ') - (5'-CATTCAGCCAGGAGAGAGAAC-3')
  • SEQ ID NO: 8 and SEQ ID NO: 20 IFN- ⁇ (5'-ACT ⁇ GGAT ⁇ CCCCAGGA-3 ') - (5'-CAGGCACAAGGGCTGTATT-3')
  • IFN- ⁇ (5'-ATCTAGCACTGGCTGGAATGAG-3 ') - (5 1 -TTCGGAGGTAACCTGTAAGTCTG-3 1 )
  • IFN- ⁇ (5'-GGGTTCTCTTGGCTGTTACTG-3 ') - (5'-GCATCTGACTCCTTTTTCGC-3') SEQ ID NO: 11 and SEQ ID NO: 23:
  • IL-10 (5'-GCTGGAGGACTTTAAGGGTTACCT-3 ') - (5'CTTGATGTCTGGGTCTTGGTTCT-3')
  • IL-12p40 (5 l -TGGAGTGCCAGGAGGACAGT-3 ') - (5'-TCTTGGGTGGGTCAGGTTTG-3')
  • IL-18 (5'-GACGCATGCCCTCAATCC-3 ') - (5'-CTAGAGCGCAATGGTGCAATC-3')
  • VSV vesicular stomatitis virus
  • IL-15 in the supernatant of the cells conditioned by riluzole is estimated by the enzyme immunoassay ELISA (R & D, Quantikine, U. K).
  • the line TG 180 (Crocker sarcoma tumor) is cultured in the presence of different concentrations of Rliluzole. After 5 days the proliferation of cells is estimated by the incorporation of tritiated thymidine ( 3 H).
  • Other tumor lines were used, namely the H9 line (IvmphomeT), the line NB4 (line derived from leukemia acute promvelocyte) and the Jurkat line (Ivmphoblastial T cell line from IvmphomeT).
  • the percentage of cell survival at the day of passage of cultures is estimated as follows:
  • the PE patient had no therapy and had the following parameters (T4: 467 / mm 3 , T8: 1662 / mm 3 , viral load: 60824 copies / ml of plasma).
  • T4 467 / mm 3
  • T8 1662 / mm 3
  • viral load 60824 copies / ml of plasma.
  • the survival of the cells at day 13 of the culture was increased by 216% relative to the control cells at the dose of 10 -6 M, and by 378% at the dose of 10 -7 M (FIG. 1A).
  • the patient PR followed a triple therapy and had the following parameters (T4: 880 / mm 3 , T8: 1280 / mm 3 , viral load: 250 copies / ml of plasma).
  • Cell survival at day 13 of culture was increased by 169% over control cells at the dose of 10 -6 M, and 202% at the dose of 10 -7 M ( Figure 2A).
  • the dose effect of riluzole was then studied on the lymphocytes of a patient
  • AIDS AR following no therapy and having the following parameters CD4: 291 / mm 3 (17%), CD8: 872 / mm 3 (51%), Virus: 43576 copies / ml of plasma).
  • the survival of the cells at day 13 of the culture was increased by 670% compared with the control cells at the dose of 10 -8 M, 407% at the dose of 10 -7 M and 230% at the dose. 10 "6 M ( Figure 3A).
  • the effect dose of riluzole was also examined on lymphocytes from an HIV-negative healthy individual.
  • the cell survival at day 13 of culture was increased by 271 % relative to the control cells at the dose of 10 -8 M, 228 at the dose of 10 -7 M and 157 at the dose of 10 -6 M ( Figure 4A).
  • riluzole in the culture medium thus protects mononuclear cells from HIV-1-induced cell death and allows proliferation of lymphocytes.
  • Negative regulation of apoptosis and Ki-67 expression of lymphocytes by riluzole T cell apoptosis and expression of ki-67 were also regulated after 13 days in the presence of riluzole. Indeed, in the window of concentration of the drug (10 '7 -10 "8 M) riluzole inhibits 66% of total apoptosis expressed by all lymphocytes, 70% of CD8 lymphocyte apoptosis and 80% CD4 lymphocytes ( Figure 5A, 5B, 5C), whereas apoptosis that is weakly expressed by lymphocytes from a healthy donor is not changed by riluzole treatment ( Figure 4C).
  • Ki-67 antigen expression which is a proliferation-competent T cell marker
  • Ki-67 antigen expression shows that it is downregulated. This effect is characterized by an inhibition of the order of 33% by all lymphocytes, 37% by CD8 lymphocytes and 50% by CD4 lymphocytes ( Figure 6A, 6B, 6C). These results reflect the recovery of T cells after completion of their cell proliferation cycle.
  • HIV-1 RNA concentrations in supernatants collected from patient T cell cultures were different in the presence or absence of the compound.
  • the RNA of HIV-1 in the supernatant of cultures from non EP patient treated and having a high viral load, packed with riluzole (10 "7 M) was increased on day 13 of culture by 100%.
  • the load virus is strong from the start, and the peak of virus release for control is on day 6.
  • TT (-) Patient without triple therapy
  • TT (+) Patient under triple therapy * Number of copies per ml of blood. Proviral HIV DNA log (copies [cp] / 10 6 cells).
  • Effect of riluzole on the expression of cytokine genes To associate the described effects of riluzole with the expression of cytokines, the inventors measured by real-time PCR the expression of cytokine genes. The results obtained showed that riluzole is capable of inducing the expression of the genes of NL-15, interferon ⁇ and interferon ⁇ , and ToII receptor 3 (FIG. 8). Effect of riluzole on the production of interferon and IL-15: The activation of the interferon and IL-15 genes is associated with the production of these two cytokines in the supernatant of the cells treated with riluzole.
  • the cells When the cells are conditioned by riluzole at a concentration of 10 -8 M, they become capable of producing interferon ⁇ / ⁇ capable of inhibiting the cytolytic capacity of VSV.
  • the quantity thus produced is estimated at 32,000 International Units (Table 2). ).
  • the AZT 10 ⁇ g / ml which exerts an anti-viral effect, also has a suppressor effect (anti-proliferative) on the control cells.
  • riluzole and AZT make it possible to maintain proliferation and highlights the restorative effect of riluzole compared to the activity of a drug known for its anti-proliferative effect at a dose of 10 ⁇ g / ml. .
  • AZT is used at 1 ⁇ g / ml, the antiviral effect is partial or even equivalent on the control cells.
  • Cell survival is estimated by the rate (number of day 18 cells - number of day 12 cells) X 100 / day 12 cell count.

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EP07872459A 2007-01-03 2007-12-28 Verwendung von riluzol und derivaten zur herstellung neuer arzneimittel Withdrawn EP2114400A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0700018A FR2910811B1 (fr) 2007-01-03 2007-01-03 Utilisation du riluzole et de ses derives pour fabriquer de nouveaux medicaments
PCT/FR2007/002186 WO2008096081A2 (fr) 2007-01-03 2007-12-28 Utilisation du riluzole et de ses dérivés pour fabriquer de nouveaux médicaments

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EP2114400A2 true EP2114400A2 (de) 2009-11-11

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US (1) US20100093655A1 (de)
EP (1) EP2114400A2 (de)
CA (1) CA2674014A1 (de)
FR (1) FR2910811B1 (de)
WO (1) WO2008096081A2 (de)

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WO2018031707A1 (en) * 2016-08-10 2018-02-15 Biohaven Pharmaceutical Holding Company Ltd. Acyl benzo[d]thiazol-2-amine and their methods of use
JP2021525714A (ja) 2018-05-27 2021-09-27 バイオヘイブン・ファーマシューティカル・ホールディング・カンパニー・リミテッドＢｉｏｈａｖｅｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｈｏｌｄｉｎｇ Ｃｏｍｐａｎｙ Ｌｔｄ． 疾患の処置のためのリルゾール口腔内崩壊錠の使用

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FR2702148B1 (fr) * 1993-03-05 1995-04-07 Rhone Poulenc Rorer Sa Application d'anticonvulsivants dans le traitement du neuro-sida.
EP1002535A1 (de) * 1998-10-28 2000-05-24 Hrissanthi Ikonomidou Neue Verwendung von Glutamat-Antagonisten zur Behandlung von Krebs
DE60041365D1 (de) * 1999-06-04 2009-02-26 Vereniging Voor Christelijk Wetenschappelijk Onderwijs Verwendung von Riluzol zur Behandlung Multipler Sklerose
US7479498B2 (en) * 1999-08-23 2009-01-20 Phoenix Biosciences, Inc. Treatments for viral infections
US7105183B2 (en) * 2004-02-03 2006-09-12 The Regents Of The University Of California Chlorite in the treatment of neurodegenerative disease

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Title
See references of WO2008096081A2 *

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FR2910811B1 (fr) 2009-07-10
US20100093655A1 (en) 2010-04-15
FR2910811A1 (fr) 2008-07-04
CA2674014A1 (fr) 2008-08-14
WO2008096081A3 (fr) 2008-11-06
WO2008096081A2 (fr) 2008-08-14

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