CA2365500A1 - Association of no-synthase inhibitor(s) and metabolic antioxidant(s) - Google Patents
Association of no-synthase inhibitor(s) and metabolic antioxidant(s) Download PDFInfo
- Publication number
- CA2365500A1 CA2365500A1 CA002365500A CA2365500A CA2365500A1 CA 2365500 A1 CA2365500 A1 CA 2365500A1 CA 002365500 A CA002365500 A CA 002365500A CA 2365500 A CA2365500 A CA 2365500A CA 2365500 A1 CA2365500 A1 CA 2365500A1
- Authority
- CA
- Canada
- Prior art keywords
- synthase
- nitro
- metabolic
- pharmaceutical composition
- antioxidant
- 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.)
- Abandoned
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- CQFQZOOEUPGOSM-UHFFFAOYSA-N 1-n-methylbenzimidazole-1,2-diamine Chemical compound C1=CC=C2N(NC)C(N)=NC2=C1 CQFQZOOEUPGOSM-UHFFFAOYSA-N 0.000 claims description 3
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000006676 mitochondrial damage Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
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- 238000011809 primate model Methods 0.000 description 1
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Abstract
Description
ASSOCIATION D'INHIBITEUR(S) DE NO SYNTHASE
ET D'ANTIOXYDANT(S) METABOLIQUE(S) L'invention concerne une composition pharmaceutique comprenant, à titre de principe actif, au moins une substance interférant avec la synthèse de monoxyde d' azote par inhibition de NO synthase et au moins un antioxydant métabolique intervenant dans le statut redox des groupements thiols, et éventuellement un support pharmaceutiquement acceptable. L'invention concerne également un produit comprenant au moins une substance inhibitrice de NO synthase et au moins un antioxydant métabolique intervenant dans le statut redox des groupements thiols, en tant que produit de combinaison, sous forme séparée, de ces principes actifs.
Une composition pharmaceutique et un produit selon l'invention sont intéressants dans le traitement de pathologies où le monoxyde d'azote et le métabolisme d'antioxydants (tels que la vitamine E ou le glutathion) ainsi que le statut redox des groupements thiols sont impliqués, et notamment les troubles cardiovasculaires et cérébrovasculaires comprenant, par exemple, la migraine, l'hypertension artérielle, les infarctus cardiaques ou cérébraux d'origine ischémique ou hémorragique, les ischémies et les thromboses ;
. le choc septique, les irradiations radioactives, les radiations solaires, les transplantations d'organes ;
les troubles du système nerveux central ou périphérique comme, par exemple, les maladies neurodégénératives où l'on peut notamment citer, les infarctus cérébraux, les démences séniles, y compris la maladie d'Alzheimer, la chorée de Huntington, la maladie de Parkinson, la maladie de Creutzfeld Jacob, les maladies dues aux prions, la sclérose latérale amyotrophique mais aussi la douleur, les traumatismes cérébraux ou de la moëlle épinière, l'addiction aux opiacés, à l'alcool et aux substances induisant une accoutumance, les troubles de l'érection et de la reproduction, les désordres cognitifs, les encéphalopathies, la dépression, l'anxiété, la schizophrénie, l'épilepsie, les troubles du sommeil, les troubles alimentaires (anorexie, boulimie...) ;
les maladies prolifératives et inflammatoires comme, par exemple, le cancer, l' athérosclérose, l'hypertension pulmonaire, la glomérulonéphrite, l' hypertension portale, la cataracte, le psoriasis, l'arthrose et l'arthrite rhumatoïde, les fibroses, les WO 00/59448 NO SYNTHASE INHIBITOR (S) ASSOCIATION
AND METABOLIC ANTIOXIDANT (S) The invention relates to a pharmaceutical composition comprising, as principle active, at least one substance interfering with the synthesis of monoxide nitrogen by inhibition of NO synthase and at least one metabolic antioxidant involved in the redox status of thiol groups, and possibly a support pharmaceutically acceptable. The invention also relates to a product comprising at least one NO synthase inhibitor and at least one metabolic antioxidant involved in the redox status of thiol groups, as a product of combination, in separate form, of these active ingredients.
A pharmaceutical composition and a product according to the invention are interesting in the treatment of pathologies where nitric oxide and metabolism antioxidants (such as vitamin E or glutathione) as well as the redox status of groupings thiols are involved, and in particular cardiovascular and cerebrovascular disorders including, for example, the migraine, high blood pressure, heart or brain infarction original ischemic or hemorrhagic, ischemia and thrombosis;
. septic shock, radioactive radiation, solar radiation, the organ transplants;
central or peripheral nervous system disorders such as, for example, the neurodegenerative diseases which include, in particular, infarctions cerebral, senile dementia, including Alzheimer's disease, chorea Huntington, the Parkinson's disease, Creutzfeld Jacob's disease, disease caused by pray, amyotrophic lateral sclerosis but also pain, trauma cerebral or spinal cord, addiction to opiates, alcohol and substances inducing addiction, erection and reproduction disorders, the cognitive disorders, encephalopathies, depression, anxiety, schizophrenia, epilepsy, sleep disorders, eating disorders (anorexia, bulimia ...);
proliferative and inflammatory diseases like, for example, cancer, atherosclerosis, pulmonary hypertension, glomerulonephritis, hypertension portal, cataracts, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, WO 00/59448
- 2 _ PCT/FR00/00812 amyloïdoses, les inflammations du système gastrointestinal (colite, maladie de Crohn) ou du système pulmonaire et des voies aériennes (asthme, sinusites) ainsi que les hypersensibilités de contact ou retardées ;
les maladies autoimmunes et virales telles que le lupus, le sida, les infections parasitaires et virales, le diabète et ses complications incluant les rétinopathies, les néphropathies et les polyneuropathies, la sclérose en plaque, les myopathies ;
les maladies génétiques autosomiques comme la maladie d'Unverricht-Lunborg ;
les pathologies caractérisées par une production ou un dysfonctionnement de monoxyde d'azote et/ou du métabolisme du glutathion et du statut redox des groupement thiols.
Dans l'ensemble de ces pathologies, il existe des évidences expérimentales démontrant l'implication du monoxyde d'azote ou d'un dysfonctionnement du métabolisme du glutathion (Kerwin et al., Nitric oxide : a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995 ; Packer et al., Alpha-lipoic acid as biological antioxidant, Free Radical Biology & Medicine 19, 227-250, 1995). C'est le cas notamment dans la maladie de Parkinson qui illustre l'invention (Beal MF, Excitotoxicity and nitric oxide in Parkison's disease pathogenesis. Ann.
Neurol.
44[Suppl 1], S110-S114, 1998 ; Donato A et al., Gluthathione in Parkinson's disease : a link between oxidative stress and mitochondrial damage. Ann.
Neurol. 32, S 111-S 115, 1992). Dans ce contexte, les médicaments pouvant inhiber la formation du monoxyde d'azote et/ou rétablir la fonctionnalité biologique des groupements thiols ou du glutathion peuvent apporter des effets bénéfiques. Comme cela est exposé
dans la partie expérimentale, l'association d'un inhibiteur de NO synthase et d'un antioxydant métabolique, principes actifs agissant par des mécanismes différents, augmente de façon inattendue l'effet thérapeutique de ces principes actifs.
Cette invention est particulièrement bien illustrée dans un modèle pathologique expérimental de maladie de Parkinson's : l'intoxication au MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine).
L'invention a donc pour objet une composition pharmaceutique comprenant, à
titre de principe actif, une ou plusieurs substances) interférant avec la synthèse de monoxyde d'azote par inhibition de NO synthase et une ou plusieurs substances) antioxydante(s) métaboliques contenant au moins deux groupements thiols et intervenant dans le statut redox des groupements thiols, et éventuellement un support pharmaceutiquement acceptable.
_3_ L'invention a plus particulièrement pour objet une composition pharmaceutique comprenant, à titre de principe actif, une substance interférant avec la synthèse de monoxyde d' azote par inhibition de NO synthase et une substance antioxydante métabolique intervenant dans le statut redox des groupements thiols.
Dans le terme inhibiteur de NO synthase, il faut comprendre tout inhibiteur spécifique ou non spécifique de l'une de ses isoformes, qu'elle soit constitutive (neuronale ou endothéliale) ou inductible (Kerwin et al., Nitric oxide : a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995). Les inhibiteurs de NO synthase selon l'invention peuvent être choisis, par exemple, parmi certains dérivés d'acides aminés tels que les dérivés de la L-arginine, les guanidines, les isothiourées, les nitro-ou cyano-aryles, les amino-pyridines ou amino-pyrimidines, les amidines, les indazoles ou les imidazoles tels que définis ci-après.
Dans le terme substance antioxydante métabolique intervenant dans le statut redox des groupements thiols, il faut comprendre toute substance chimique possédant au moins deux groupement thiols capables de former par oxydation un pont disulfure intra ou intermoléculaire, cette substance pouvant se trouver sous la forme réduite ou oxydée.
De tels composés permettent la chélation des cations divalents, la régénération d' antioxydants comme la vitamine E ou le glutathion, et interviennent dans le statut redox des groupements thiols. Les substances antioxydantes métaboliques selon l'invention peuvent être choisies, par exemple, parmi le dithiothreitol, le pyritinol, l' acide lipoïque (Packer et al., Alpha-lipoic acid as biological antioxidant, Free Radical Biology & Medicine 19, 227-250, 1995) ou ses dérivés tels que définis ci-après, les dérivés dimériques disulfides de penicillamine ou de N-acétylcystéine, ou bien les peptides comportant au moins deux résidus cystéines. Ces substances peuvent être naturelles ou synthétiques.
Dans une composition pharmaceutique selon l'invention, l'inhibiteur de NO
synthase et la substance antioxydante métabolique peuvent se présenter sous forme séparée ou sous forme combinée en formant un sel. Bien entendu, la formation d'un sel n'est envisagée que si l'un des principes actifs présente un groupement acide et l'autre principe actif un groupement basique. De préférence, le sel est formé à partir d'un dérivé de la substance inhibitrice de NO synthase contenant au moins un groupe basique et d'un dérivé de l' antioxydant métabolique contenant un groupement acide.
Ainsi, l'inhibiteur de NO synthase peut être choisi, par exemple, parmi les composés tels que définis ci-après. L' antioxydant métabolique peut être choisi, par exemple, parmi l'acide lipoïque ou ses dérivés tels que définis ci-après, les dérivés dimériques disulfides de penicillamine ou de N-acétylcystéine.
WO 00/59448 - 4 _ PCT/FR00/00812 L'invention a également pour objet un produit comprenant une ou plusieurs substances) inhibitrices) de NO synthase et une ou plusieurs substances) antioxydante(s) métaboliques) contenant au moins deux groupements thiols et intervenant dans le statut redox des groupements thiols, en tant que produit de combinaison, sous forme séparée, pour une utilisation simultanée ou séquentielle dans le traitement de pathologies dans lesquelles le monoxyde d'azote et le statut redox des groupements thiols sont impliqués telles que les troubles cardiovasculaires et cérébrovasculaires, le choc septique, les irradiations radioactives, les radiations solaires, les transplantations d' organes, les troubles du système nerveux central ou périphérique particulièrement bien représentée par la maladie de Parkison, les maladies prolifératives et inflammatoires, les maladies autoimmunes et virales, le diabète et ses complications, les maladies génétiques autosomiques et toutes les pathologies caractérisées par une production ou un dysfonctionnement de monoxyde d'azote et/ou impliquant le statut redox des groupements thiols.
Dans une composition pharmaceutique ou un produit selon l'invention, l'inhibiteur de NO synthase et l' antioxydant métabolique peuvent se présenter à des doses qui peuvent être identiques ou différentes. Les dosages sont choisis en fonction des composés associés à des diluants ou excipients appropriés.
L'inhibiteur de NO synthase et l'antioxydant métabolique peuvent être administrés de manière simultanée ou séquentielle, par la même voie d'administration ou par des voies différentes, suivant qu'ils se présentent sous forme séparée ou combinée. De préférence, les voies d'administration sont orale, parentérale orf topique.
Parmi les inhibiteurs de NO synthase, on peut définir les composés de type amino-acide, de type non amino-acide et de type amine aromatique. Les inhibiteurs de NO
synthase de type amino-acide peuvent être des composés tels que décrits dans les demandes WO 95/00505, WO 94/12163, WO 96/06076, WO 98/28257, ou bien des dérivés de la L-arginine, de l'ornithine ou de la lysine tels que décrits dans les demandes WO 93/24126, WO 95/01972, WO 95/24382, WO 95/09619 et WO 95/22968 (les acides aminés sont bien évidemment exclus de cette catégorie car sans activité sur la voie de synthèse du NO ; quant à la L-arginine, elle est le substrat naturel de la NO synthase).
Les inhibiteurs de NO synthase de type non amino-acide, peuvent être des composés de la famille des guanidines, des isothiourées, des nitro- ou cyano-aryles, des amino-pyridines ou amino-pyrimidines, des amidines, des indazoles ou des imidazoles ainsi que des hétérocycles substitués ou des pipéridines condensées.
Les guanidines inhibiteurs de NO synthase peuvent être les composés tels que définis dans les demandes WO 95/28377, WO 91/04023, WO 94/21621, WO 96/18607 et WO 96/18608.
Les isothiourées inhibiteurs de NO synthase peuvent être les composés tels que déimis dans les demandes WO 95/09619, WO 96/09286, WO 94/12165, WO 96/14842, WO 96/18607, WO 96/18608, WO 96/09286, EP 717040 et EP 718294.
Les nitro- ou cyano-aryles inhibiteurs de NO synthase peuvent être les composés tels que définis dans la demande WO 94/12163.
Les amino-pyridines ou amino-pyrimidines inhibiteurs de NO synthase peuvent être les composés tels que définis dans les demandes WO 94/14780, WO 96/18616, WO 96/18617, WO 98/45294, WO 98/24766, WO 00/02860, WO 99/62883, WO 99/10339, WO 00/09130, JP 98/001470, JP 98/120654 et JP 98/036351.
Les amidines inhibiteurs de NO synthase peuvent être les composés tels que définis dans les demandes WO 95/11014, WO 96/01817, WO 95/05363, WO 95/11231, WO 96/14844, WO 96/19440, WO 98/42696, WO 98/158934, WO 98/50380, WO 98/50382, JP 98/265450, ou des composés tels que la N-phényl-2-thiophènecarboximidamide.
Les indazoles inhibiteurs de NO synthase peuvent être les composés tels que définis dans la demande WO 98/02442 ou bien des composés de formule générale IA
R
~N
N
H Ip dans laquelle R1 représente un ou plusieurs substituants choisis parmi l'atome d'hydrogène, le radical nitro, halo, alkyle inférieur ou alkoxy inférieur.
Les imidazoles inhibiteurs de NO synthase peuvent être les composés de formule générale IIp R3 N"R
s I
R
4 IIp dans laquelle R2 et R3 représentent, indépendamment l'atome d'hydrogène, le radical halo, hydroxy, amino, alkyle ou alkoxy, ou R2 et R3 sont liés ensembles et forment le radical phényle condensé avec le cycle imidazole, le radical phényle étant éventuellement substitué par un ou plusieurs substituants choisis parmi les radicaux hydroxy, trifluorométhyle, halo, carboxy, alkyle inférieur, alkoxy inférieur ou alkényle inférieur ; R4 représente un atome d'hydrogène,un radical alkyle inférieur, amino, alkyle inférieur amino ou phényle, le radical phényle étant éventuellement substitué par un ou plusieurs substituants choisis parmi les radicaux hydroxy, trifluorométhyle, halo, carboxy, alkyle inférieur, alkoxy inférieur ou alkényle inférieur ; RS représente l'atome d'hydrogène, un radical alkyle inférieur, amino, alkyle inférieur amino.
Tel qu'il est utilisé ici, le terme inférieur en référence aux groupes alkyle et alkoxy désigne des groupes hydrocarbonés aliphatiques saturés, linéaires, ou ramifiés, comportant de 1 à 6 atomes de carbone comme, par exemple, méthyle, éthyle, propyle, isopropyle, butyle, t-butyle, méthoxy et éthoxy. En référence aux groupes alkényle, le terme inférieur désigne des groupes comportant de 2 à 6 atomes de carbone et une ou plusieurs doubles ou triples liaisons comme, par exemple, les groupes vinyle, allyle, propènyle, isopropènyle, pentènyle, butènyle, hexanyle, propènyle et butadiényle. Le terme halo signifie chloro, bromo, iodo ou fluoro.
Les piperidines condensés peuvent être les composés tels que définis dans la demande EP 870763.
Les hétérocycles substitués peuvent être les composés tels que définis dans les demandes WO 98/50372, WO 98/42667, WO 98/46611, WO 99/05131, WO 99/01455, JP 98/182618.
De préférence, l'inhibiteur de NO synthase est un composé de type amino-acide et plus particulièrement un dérivé de la L-arginine, de l'ornithine ou de la lysine, ou un composé de la famille des guanidines, des isothiourées, des nitro- ou cyano-aryles, des amino-pyridines ou amino-pyrimidines, des amidines, des indazoles ou des imidazoles.
L' antioxydant métabolique peut être choisi parmi le dithiothreitol, le pyritinol, les composés tels que définis dans la demande EP 381 439, l'acide lipoïque (sous forme racémique ou d'énantiomères) et ses dérivés, les composés dimériques disulfides de penicillamine ou de N-acétylcystéine, et les peptides comportant au moins deux résidus cystéine. De préférence, les dérivés de l'acide lipoïque sont les composés tels que définis dans les demandes EP 855396, EP 236929, EP 869126, FR 2707983, WO 99/45922 et JP 94227979.
L'invention a plus particulièrement pour objet une composition ou un produit tel que défini ci-dessus, caractérisé en ce que l'inhibiteur de NO synthase est choisi parmi la L-nitro-arginine (LNA), l'ester méthylique de la L-nitro-arginine (LNAME), la L-N-monométhylarginine (LNMMA), l'aminoguanidine, l'agmatine, la 2-amino-1-(méthylamino)benzimidazole, le 5-nitro-indazole, 6-nitro-indazole, le 7-nitro-indazole, le 1,2-(trifluorométhylphényl) imidazole (TRIM), la 2-amino-4-méthyl-6-(2-aminoéthyl)pyridine, la 2-iminopipéridine, la 2-iminohomopipéridine, la 2-imino-5,6-dihydro-1,3-thiazine, la 2-imino-5,6-dihydro-1,3-oxazine, la N-phényl-2-thiophènecarboximidamide, la 2-iminotétrahydropyrimidine, la S-éthylisothiourée, la S-méthyl-L-thiocitrulline ou la S-éthyl-L-thiocitrulline.
L'invention a plus particulièrement pour objet une composition ou un produit tel que défini ci-dessus, caractérisé en ce que l'antioxydant métabolique est l'acide lipoïque, sous forme racémique ou d' énantiomère.
De manière préférentielle, l'invention a également pour objet une composition ou un produit tels que définis ci-dessus, caractérisés en ce que l'inhibiteur de NO
synthase est un inhibiteur de NO synthase neuronale edou inductible.
Les composés inhibiteurs de NO synthase et les antioxydants métaboliques sont commerciaux ou peuvent être préparés par les méthodes connues de l'homme de l'art (ou par analogie à ces dernières) (P. Hamley et al., Bioorganic and medicinal chemistry letters, vol. 5 (15), 1573-1576 (1995) ; W. M. Moore et al., J. Med.
Chem., 39, 669-672 (1996) ; E. P. Garvey et al., The Journal of Biological Chemistry, vol. 269(43), 26669-26676 (1994)).
Tous les termes techniques et scientifiques utilisés dans le présent texte ont la signification connue de l'homme de l'art. Par ailleurs, tous les brevets (ou demandes de brevet) ainsi que les autres références bibliographiques sont incorporés par référence.
Les exemples suivants sont présentés pour illustrer les procédures ci-dessus et ne doivent en aucun cas être considérés comme une limite à la portée de l'invention.
_g_ PARTIE EXPÉRIMENTALE
Etude pharmacologiaue des produits de l'invention L' activité des composés de l'invention a été évaluée in vivo sur un modèle de neurotoxicité au MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
L'administration de MPTP produit un syndrome similaire à la maladie de Parkinson résultant d'une dégénération des neurones nigrostriataux dopaminergiques. Ceci à été
observé chez l'homme, le primate et la souris [Langston JW et Ballard PA, Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, N. Engl. J. Med. 309, 310 (1983) ; Burns RS et al., A primate model of parkinsonism : selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Proc. Natl. Acad. Sci. U.S.A. 80, 4546-4550 (1983), Heikkila, RE. et al., Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice, Science, 224, 1451-1453 (1984)].
On injecte trois fois à 2 heures d'intervalle 15-20 mg/kg de MPTP par voie intrapéritoneale à des souris (C57BL6) pesant 15-25 g. Les produits sont injectés par voie orale 90 minutes avant chaque injection de MPTP et 90 min après la dernière et 24 h après la première injection de MPTP. Les souris sont sacrifiées 24 heures après la dernière injection de MPTP. Le striatum est prélevé et son taux de dopamine est mesuré par chromatographie liquide haute performance couplée à une détection électrochimique. Le coefficient d'efficacité des composés est catici~lé par le rapport au taux de dopamine du groupe produit + MPTP / taux de dopamine du groupe MPTP
seul. Un produit dont le coefficient d'efficacité est à 1,5 est considéré
comme bénéfique.
Soit A l'inhibiteur de NO synthase et B l'antioxydant métabolique.
Exemple 1 Composé AB, combinaison des principes actifs A et B. Composé A : le N-phényl-2-thiophènecarboximidamine, inhibiteur puissant des NO synthases. Composé B :
la forme réduite de l'acide lipoïque, antioxydant métabolique.
Composé de l'exemple 1 : 4 groupes d'animaux sont constitués Groupe 1 : traité avec le MPTP.
Groupe 2 : traité avec A (3 mg/kg) + MPTP.
Groupe 3 : traité avec B ( 10 mg/kg) + MPTP.
Groupe 4 : traité avec AB + MPTP.
Taux de dopamine N° du groupe Coefficient d'efficacité
ng/mg de tissu 1 3,24 -2 3,77 1,16 - 2 _ PCT / FR00 / 00812 amyloidosis, inflammation of the gastrointestinal system (colitis, disease of Crohn's) or the pulmonary and airways (asthma, sinusitis) so than contact or delayed hypersensitivities;
autoimmune and viral diseases such as lupus, AIDS, infections parasitic and viral, diabetes and its complications including retinopathies, nephropathies and polyneuropathies, multiple sclerosis, myopathies;
autosomal genetic diseases such as Unverricht-Lunborg disease;
pathologies characterized by the production or dysfunction of nitric oxide and / or glutathione metabolism and the redox status of thiol group.
In all of these pathologies, there is experimental evidence demonstrating the involvement of nitric oxide or a dysfunction in the metabolism of glutathione (Kerwin et al., Nitric oxide: a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995; Packer et al., Alpha-lipoic acid as biological antioxidant, Free Radical Biology & Medicine 19, 227-250, 1995). It's the case especially in Parkinson's disease which illustrates the invention (Beal MF, Excitotoxicity and nitric oxide in Parkison's disease pathogenesis. Ann.
Neurol.
44 [Suppl 1], S110-S114, 1998; Donato A et al., Gluthathione in Parkinson's disease: a link between oxidative stress and mitochondrial damage. Ann.
Neurol. 32, S 111-S 115, 1992). In this context, drugs that can inhibit the training nitric oxide and / or restore the biological functionality of thiol groups or glutathione can provide beneficial effects. As exposed in the experimental part, the association of an inhibitor of NO synthase and a metabolic antioxidant, active ingredients acting by mechanisms different, unexpectedly increases the therapeutic effect of these active ingredients.
This invention is particularly well illustrated in a pathological model experimental Parkinson's disease: intoxication with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine).
The subject of the invention is therefore a pharmaceutical composition comprising, title of active ingredient, one or more substances) interfering with the synthesis of monoxide nitrogen by inhibition of NO synthase and one or more substances) antioxidant (s) metabolic groups containing at least two thiol groups and involved in the status redox of thiol groups, and optionally a pharmaceutical carrier acceptable.
_3_ The invention more particularly relates to a pharmaceutical composition comprising, as active ingredient, a substance which interferes with the synthesis of nitrogen monoxide by inhibition of NO synthase and an antioxidant metabolic agent involved in the redox status of thiol groups.
In the term NO synthase inhibitor, we must understand any inhibitor specific or non-specific of one of its isoforms, whether it is constitutive (neuronal or endothelial) or inducible (Kerwin et al., Nitric oxide: a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995). NO synthase inhibitors according to the invention can be chosen, for example, from certain derivatives acids amines such as L-arginine derivatives, guanidines, isothioureas, nitro-or cyano-aryls, amino-pyridines or amino-pyrimidines, amidines, indazoles or imidazoles as defined below.
In the term metabolic antioxidant substance involved in the status redox of thiol groups, it is necessary to understand any chemical substance having at less two thiol groups capable of forming a disulfide bridge by oxidation intra or intermolecular, this substance may be in the reduced form or oxidized.
Such compounds allow the chelation of divalent cations, the regeneration antioxidants like vitamin E or glutathione, and are involved in status redox of thiol groups. Metabolic antioxidants according to the invention can be chosen, for example, from dithiothreitol, pyritinol, lipoic acid (Packer et al., Alpha-lipoic acid as biological antioxidant, Free radical Biology & Medicine 19, 227-250, 1995) or its derivatives as defined above after the dimeric disulfide derivatives of penicillamine or N-acetylcysteine, or else the peptides comprising at least two cysteine residues. These substances can to be natural or synthetic.
In a pharmaceutical composition according to the invention, the NO inhibitor synthase and the metabolic antioxidant can be in the form separate or in combined form by forming a salt. Of course, the formation of a salt is not considered only if one of the active ingredients has an acid group and the other active ingredient a basic grouping. Preferably the salt is formed from of a derived from the NO synthase inhibitor substance containing at least one group basic and a derivative of the metabolic antioxidant containing a group acid.
Thus, the inhibitor of NO synthase can be chosen, for example, from the compounds as defined below. The metabolic antioxidant can be chosen, by example, among lipoic acid or its derivatives as defined below, the derivatives dimeric penicillamine or N-acetylcysteine disulfides.
WO 00/59448 - 4 _ PCT / FR00 / 00812 The subject of the invention is also a product comprising one or more substances) inhibiting) NO synthase and one or more substances) antioxidant (s) metabolic) containing at least two thiol groups and involved in the redox status of thiol groups, as a product of combination, in separate form, for simultaneous use or sequential in the treatment of pathologies in which nitric oxide and the status redox of thiol groups are involved such as cardiovascular disorders and cerebrovascular, septic shock, radioactive radiation, radiation solar, organ transplants, nervous system disorders central or particularly well represented by Parkison's disease, diseases proliferative and inflammatory, autoimmune and viral diseases, diabetes and its complications, autosomal genetic diseases and all pathologies characterized by production or malfunction of nitric oxide and or implying the redox status of thiol groups.
In a pharmaceutical composition or a product according to the invention, the inhibitor NO synthase and the metabolic antioxidant can occur in doses that may be the same or different. The dosages are chosen according to of compounds associated with suitable diluents or excipients.
The NO synthase inhibitor and the metabolic antioxidant may be administered from simultaneously or sequentially, by the same route of administration or by of different routes, depending on whether they come in separate form or combined. Of preferably, the routes of administration are oral, parenteral or topical.
Among the NO synthase inhibitors, the following compounds can be defined:
amino-acid, non-amino acid type and aromatic amine type. Inhibitors NO
amino acid synthase can be compounds as described in the WO 95/00505, WO 94/12163, WO 96/06076, WO 98/28257, or L-arginine, ornithine or lysine derivatives as described in the applications WO 93/24126, WO 95/01972, WO 95/24382, WO 95/09619 and WO 95/22968 (amino acids are obviously excluded from this category because without activity on the NO synthesis pathway; as for L-arginine, it is the substrate NO synthase).
Non-amino acid NO synthase inhibitors can be compounds from the family of guanidines, isothioureas, nitro- or cyano-aryls, amino-pyridines or amino-pyrimidines, amidines, indazoles or imidazoles so than substituted heterocycles or condensed piperidines.
NO synthase inhibitor guanidines can be compounds such as defined in applications WO 95/28377, WO 91/04023, WO 94/21621, WO 96/18607 and WO 96/18608.
The NO synthase inhibitor isothioureas can be compounds such as demeaned in applications WO 95/09619, WO 96/09286, WO 94/12165, WO 96/14842, WO 96/18607, WO 96/18608, WO 96/09286, EP 717040 and EP 718294.
Nitro- or cyano-aryl inhibitors of NO synthase may be the compounds such as defined in application WO 94/12163.
Amino-pyridines or amino-pyrimidines inhibitors of NO synthase can to be the compounds as defined in applications WO 94/14780, WO 96/18616, WO 96/18617, WO 98/45294, WO 98/24766, WO 00/02860, WO 99/62883, WO 99/10339, WO 00/09130, JP 98/001470, JP 98/120654 and JP 98/036351.
NO synthase inhibiting amidines can be compounds such as defined in applications WO 95/11014, WO 96/01817, WO 95/05363, WO 95/11231, WO 96/14844, WO 96/19440, WO 98/42696, WO 98/158934, WO 98/50380, WO 98/50382, JP 98/265450, or compounds such as N-phenyl-2-thiophenecarboximidamide.
Indazoles inhibitors of NO synthase can be compounds such as defined in application WO 98/02442 or else compounds of general formula IA
R
~ N
NOT
H Ip in which R1 represents one or more substituents chosen from the atom hydrogen, nitro, halo, lower alkyl or lower alkoxy.
NO synthase inhibitor imidazoles can be the compounds of formula general IIp R3 N "R
s I
R
4 IIp in which R2 and R3 independently represent the hydrogen atom, the radical halo, hydroxy, amino, alkyl or alkoxy, or R2 and R3 are linked together and form the phenyl radical condensed with the imidazole ring, the phenyl radical being optionally substituted by one or more substituents chosen from radicals hydroxy, trifluoromethyl, halo, carboxy, lower alkyl, lower alkoxy or lower alkenyl; R4 represents a hydrogen atom, an alkyl radical inferior, amino, lower alkyl amino or phenyl, the phenyl radical being eventually substituted by one or more substituents chosen from hydroxy radicals, trifluoromethyl, halo, carboxy, lower alkyl, lower alkoxy or alkenyl inferior ; RS represents the hydrogen atom, a lower alkyl radical, amino, amino lower alkyl.
As used herein, the lower term with reference to alkyl groups and alkoxy denotes saturated, linear, aliphatic hydrocarbon groups, or branched, having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy and ethoxy. With reference to groups alkenyl, the lower term denotes groups having from 2 to 6 atoms of carbon and one or more double or triple bonds like, for example, the vinyl, allyl, propenyl, isopropenyl, pentenyl, butenyl groups, hexanyl, propenyl and butadienyl. The term halo means chloro, bromo, iodo or fluoro.
The condensed piperidines can be the compounds as defined in the request EP 870763.
The substituted heterocycles can be the compounds as defined in the applications WO 98/50372, WO 98/42667, WO 98/46611, WO 99/05131, WO 99/01455, JP 98/182618.
Preferably, the NO synthase inhibitor is an amino acid compound and more particularly a derivative of L-arginine, ornithine or lysine, or one composed of the family of guanidines, isothioureas, nitro- or cyano-aryles, amino-pyridines or amino-pyrimidines, amidines, indazoles or imidazoles.
The metabolic antioxidant can be chosen from dithiothreitol, pyritinol, the compounds as defined in application EP 381,439, lipoic acid (under form racemic or enantiomers) and its derivatives, dimeric compounds disulfides of penicillamine or N-acetylcysteine, and peptides having at least two cysteine residues. Preferably, the lipoic acid derivatives are the compounds such as defined in the applications EP 855396, EP 236929, EP 869126, FR 2707983, WO 99/45922 and JP 94227979.
The subject of the invention is more particularly a composition or a product such as defined above, characterized in that the NO synthase inhibitor is chosen among the L-nitro-arginine (LNA), the methyl ester of L-nitro-arginine (LNAME), the LN-monomethylarginine (LNMMA), aminoguanidine, agmatine, 2-amino-1- (methylamino) benzimidazole, 5-nitro-indazole, 6-nitro-indazole, 7-nitro-indazole, 1,2- (trifluoromethylphenyl) imidazole (TRIM), 2-amino-4-methyl-6- (2-aminoethyl) pyridine, 2-iminopiperidine, 2-iminohomopiperidine, 2-imino-5,6-dihydro-1,3-thiazine, 2-imino-5,6-dihydro-1,3-oxazine, N-phenyl-2-thiophenecarboximidamide, 2-iminotetrahydropyrimidine, S-ethylisothiourea, S-methyl-L-thiocitrulline or S-ethyl-L-thiocitrulline.
The subject of the invention is more particularly a composition or a product such as defined above, characterized in that the metabolic antioxidant is acid lipoic, in racemic or enantiomeric form.
Preferably, the invention also relates to a composition or one product as defined above, characterized in that the NO inhibitor synthase is an inducible edou neuronal NO synthase inhibitor.
NO synthase inhibitor compounds and metabolic antioxidants are commercial or can be prepared by methods known to man of art (or by analogy to the latter) (P. Hamley et al., Bioorganic and medicinal chemistry letters, vol. 5 (15), 1573-1576 (1995); WM Moore et al., J. Med.
Chem., 39, 669-672 (1996); EP Garvey et al., The Journal of Biological Chemistry, vol. 269 (43), 26669-26676 (1994)).
All the technical and scientific terms used in this text have the meaning known to those skilled in the art. In addition, all patents (or requests patent) as well as the other bibliographic references are incorporated through reference.
The following examples are presented to illustrate the above procedures and not must in no case be considered as a limit to the scope of the invention.
_g_ EXPERIMENTAL PART
Pharmacological study of the products of the invention The activity of the compounds of the invention was evaluated in vivo on a model of neurotoxicity to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
MPTP administration produces a syndrome similar to Parkinson's resulting from a degeneration of nigrostriatal dopaminergic neurons. This has been observed in humans, primates and mice [Langston JW and Ballard PA, Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, N. Engl. J. Med. 309, 310 (1983); Burns RS and al., A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Proc. Natl. Acad. Sci. USA 80, 4546-4550 (1983), Heikkila, RE. et al., Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice, Science, 224, 1451-1453 (1984)].
15-20 mg / kg of MPTP is injected three times at 2 hour intervals intraperitoneally to mice (C57BL6) weighing 15-25 g. The products are injected by orally 90 minutes before each MPTP injection and 90 min after last and 24 hours after the first MPTP injection. Mice are sacrificed 24 hours after the last MPTP injection. The striatum is removed and its dopamine level East measured by high performance liquid chromatography coupled with detection electrochemical. The coefficient of effectiveness of the compounds is catici ~ lé by the compared to dopamine level of the product group + MPTP / dopamine level of the MPTP group alone. A product with an efficiency factor of 1.5 is considered as beneficial.
Let A be the inhibitor of NO synthase and B the metabolic antioxidant.
Example 1 Compound AB, combination of active ingredients A and B. Compound A: N-phenyl-2-thiophenecarboximidamine, a powerful inhibitor of NO synthases. Compound B:
the reduced form of lipoic acid, metabolic antioxidant.
Compound of Example 1: 4 groups of animals are formed Group 1: treated with MPTP.
Group 2: treated with A (3 mg / kg) + MPTP.
Group 3: treated with B (10 mg / kg) + MPTP.
Group 4: treated with AB + MPTP.
Dopamine level Efficiency coefficient group number ng / mg tissue 1 3.24 -2 3.77 1.16
3,g1 1,17 3, g1 1.17
4 5,21 1,60 Les résultats montrent que l'acide lipoïque, sous forme réduite, utilisé comme antioxydant métabolique à la dose de 10 mg/kg est inactif pour protéger l'animal de la chute de dopamine survenant après injection de MPTP. Le N-phényl-2-thiophènecarboximidamine utilisé comme inhibiteur de NO synthase à la dose de 3 mg/kg est également inactif. Par contre, l'association des deux composés se révèle active pour restaurer le taux de dopamine des animaux soumis à la neurotoxicité du MPTP.
Exemple 2 Composé AB, combinaison des principes actifs A et B. Composé A : la NGnitro-arginine, inhibiteur puissant des NO synthases constitutives et inductibles.
Composé B : la forme réduite de l'acide lipoïque, antioxydant métabolique.
Composé de l'exemple 2 : 4 groupes d'animaux sont constitués Groupe 1 : traité avec le MPTP.
Groupe 2 : traité avec A (3 mg/kg) + MPTP.
Groupe 3 : traité avec B ( 10 mg/kg) + MPTP.
Groupe 4 : traité avec AB + MPTP.
Taux de dopamine N° du groupe Coefficient d'efficacité
ng/mg de tissu 1 4,11 -2 6,9g 1,69 3 4,4g 1,09 4 8,65 2,1 La NGnitro-arginine utilisée en tant qu'inhibiteur des NO synthases, active à
la dose de 3 mg/kg, a une efficacité augmentée lorsqu'elle est associée à l'acide lipoïque.
Les résultats expérimentaux des exemples 1 et 2 montrent donc un effet potentialisateur voire une synergie entre les deux types de composés. 4 5.21 1.60 The results show that lipoic acid, in reduced form, used as metabolic antioxidant at a dose of 10 mg / kg is inactive to protect the animal of the drop in dopamine occurring after MPTP injection. N-phenyl-2-thiophenecarboximidamine used as a dose synthase NO inhibitor of 3 mg / kg is also inactive. On the other hand, the association of the two compounds is reveals active to restore the dopamine level of animals subjected to neurotoxicity of MPTP.
Example 2 Compound AB, combination of active ingredients A and B. Compound A: NGnitro-arginine, a powerful inhibitor of constitutive and inducible NO synthases.
Compound B: the reduced form of lipoic acid, a metabolic antioxidant.
Compound of Example 2: 4 groups of animals are formed Group 1: treated with MPTP.
Group 2: treated with A (3 mg / kg) + MPTP.
Group 3: treated with B (10 mg / kg) + MPTP.
Group 4: treated with AB + MPTP.
Dopamine level Efficiency coefficient group number ng / mg tissue 1 4.11 -2 6.9g 1.69 3 4.4g 1.09 4 8.65 2.1 NGnitro-arginine used as a NO synthase inhibitor, active at the dose of 3 mg / kg, has increased efficacy when combined with acid lipoic.
The experimental results of examples 1 and 2 therefore show an effect potentiator or even a synergy between the two types of compounds.
Claims (24)
synthase et une ou plusieurs substance(s) antioxydante(s) métabolique(s) contenant au moins deux groupements thiols et intervenant dans le statut redox des groupements thiols, en tant que produit de combinaison sous forme séparée, pour une utilisation simultanée ou séquentielle dans le traitement de pathologies dans lesquelles le monoxyde d'azote et le statut redox des groupements thiols sont impliqués. 13. Product comprising one or more NO inhibiting substance(s) synthase and one or more metabolic antioxidant substance(s) containing at less two thiol groups and involved in the redox status of the groups thiols, in as a combination product in separate form, for use simultaneous or sequential in the treatment of pathologies in which monoxide nitrogen and the redox status of the thiol groups are involved.
synthase est un composé de type amino-acide ou un composé de la familles des guanidines, des isothiourées, des nitro- ou cyano-aryles, des amino-pyridines ou amino-pyrimidines, des amidines, des indazoles ou des imidazoles. 19. Product according to one of claims 13 to 18, in which the inhibitor from NO
synthase is an amino acid type compound or a compound of the family of guanidines, isothioureas, nitro- or cyano-aryls, amino-pyridines Where amino-pyrimidines, amidines, indazoles or imidazoles.
synthase de type amino-acide est un dérivé de la L-arginine, de l'ornithine ou de la lysine. 20. Product according to claim 19, in which the NO inhibitor synthase of amino acid type is a derivative of L-arginine, ornithine or lysine.
synthase est choisi parmi la L-nitro-arginine, l'ester méthylique de la L-nitro-arginine, la L-N-monométhylarginine, l'aminoguanidine, l'agmatine, la 2-amino-1-(méthylamino)benzimidazole, le 5-nitro-indazole, 6-nitro-indazole, le 7-nitro-indazole, le 1,2-(trifluorométhylphényl) imidazole, la 2-amino-4-méthyl-6-(2-aminoéthyl)pyridine, la 2-iminopipéridine, la 2-iminohomopipéridine, la 2-imino-5,6-dihydro-1,3-thiazine, la 2-imino-5,6-dihydro-1,3-oxazine, la 2-iminotétrahydropyrimidine, la N-phényl-2-thiophènecarboximidamide, la S-éthylisothiourée, la S-méthyl-L-thiocitrulline ou la S-éthyl-L-thiocitrulline. 21. Product according to one of claims 13 to 19, in which the inhibitor from NO
synthase is chosen from L-nitro-arginine, the methyl ester of L-nitro arginine, LN-monomethylarginine, aminoguanidine, agmatine, 2-amino-1-(methylamino)benzimidazole, 5-nitro-indazole, 6-nitro-indazole, 7-nitro-indazole, 1,2-(trifluoromethylphenyl)imidazole, 2-amino-4-methyl-6-(2-aminoethyl)pyridine, 2-iminopiperidine, 2-iminohomopiperidine, 2-imino-5,6-dihydro-1,3-thiazine, 2-imino-5,6-dihydro-1,3-oxazine, 2-iminotetrahydropyrimidine, N-phenyl-2-thiophenecarboximidamide, S-ethylisothiourea, S-methyl-L-thiocitrulline or S-ethyl-L-thiocitrulline.
synthase est un inhibiteur de NO synthase neuronale et/ou inductible. 24. Product according to one of claims 13 to 23, in which the inhibitor from NO
synthase is a neuronal and/or inducible NO synthase inhibitor.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR99/04134 | 1999-04-02 | ||
| FR9904134A FR2791571B1 (en) | 1999-04-02 | 1999-04-02 | ASSOCIATION OF NO SYNTHASE INHIBITOR (S) AND METABOLIC ANTIOXIDANT (S) |
| PCT/FR2000/000812 WO2000059448A2 (en) | 1999-04-02 | 2000-03-31 | Association of no-synthase inhibitor(s) and metabolic antioxidant(s) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2365500A1 true CA2365500A1 (en) | 2000-10-12 |
Family
ID=9543945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002365500A Abandoned CA2365500A1 (en) | 1999-04-02 | 2000-03-31 | Association of no-synthase inhibitor(s) and metabolic antioxidant(s) |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1169005A2 (en) |
| JP (1) | JP2002541077A (en) |
| AR (1) | AR023219A1 (en) |
| AU (1) | AU3663700A (en) |
| CA (1) | CA2365500A1 (en) |
| FR (1) | FR2791571B1 (en) |
| MY (1) | MY133230A (en) |
| NO (1) | NO20014770L (en) |
| WO (1) | WO2000059448A2 (en) |
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| FR2816509B1 (en) * | 2000-11-15 | 2004-02-06 | Sod Conseils Rech Applic | ASSOCIATION OF CALPAIN INHIBITORS AND OXYGEN REACTIVE TRAPS |
| US6476073B1 (en) * | 2000-11-21 | 2002-11-05 | Arthur Vanmoor | Method of treating a hangover by enhancing the effectiveness of the human immune system |
| EP1596854A4 (en) * | 2003-02-14 | 2007-06-06 | Childrens Hosp & Res Ct Oak | TREATMENT OF PATHOLOGICAL CONDITIONS ASSOCIATED WITH REDUCED BIOAVAILABILITY OF NITRIC OXIDE, INCLUDING PATHOLOGICAL CONDITIONS CAUSED BY HIGH ACTIVITY OF ARGINASE |
| SI1754478T1 (en) | 2005-08-04 | 2009-06-30 | Encrypta Gmbh | Liquid Composition comprising arginine and alpha-lipoic acid and its use for improvement of sexual function |
| WO2009111037A2 (en) * | 2008-03-04 | 2009-09-11 | Indigene Pharmaceuticals Inc. | Compositions and methods for treating nos-associated diseases |
| EP2297183A4 (en) * | 2008-05-09 | 2012-07-04 | Univ Duke | TREATMENT OF DISEASES BASED ON DISCOVERY THAT THIOREDOXIN INDUCES NITRIC OXIDE RELEASE IN CELLS |
| TWI592156B (en) * | 2011-10-04 | 2017-07-21 | 艾可達醫療公司 | Method for treating sensory motion damage associated with stroke using aminopyridine |
| EP2821069A4 (en) * | 2012-03-02 | 2015-06-03 | Kyowa Hakko Bio Co Ltd | STIMULATOR OF FOOD ACTIVITY AND / OR GASTROINTESTINAL ACTIVITY |
| CA2915793A1 (en) * | 2012-07-03 | 2014-01-09 | Jay Pravda | Methods for treating, diagnosing and/or monitoring progression of oxo associated states |
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| FR4630M (en) * | 1965-06-09 | 1966-11-28 | ||
| ZA716628B (en) * | 1970-10-15 | 1972-06-28 | Richardson Merrell Spa | Composition and method for treatment of hepatic disease and mental fatigue |
| US5091180A (en) * | 1987-11-20 | 1992-02-25 | Administrators Of The Tulane Educational Fund | Protection against rhabdomyolysis-induced nephrotoxicity |
| US5455279A (en) * | 1991-04-19 | 1995-10-03 | The Children's Medical Center Corporation | Regimen method of mediating neuronal damage using nitroglycerine |
| US5852058A (en) * | 1993-06-11 | 1998-12-22 | The Board Of Trustees Of The Leland Stanford Junior University | Intramural delivery of nitric oxide enhancer for inhibiting lesion formation after vascular injury |
| GB9404400D0 (en) * | 1994-03-07 | 1994-04-20 | Wood Pauline J | Potentiation of bioreductive agents |
| DE4420102A1 (en) * | 1994-06-09 | 1995-12-14 | Asta Medica Ag | Combination prepns. contg. alpha-liponic acid or its metabolites |
| AU5317296A (en) * | 1995-03-24 | 1996-10-16 | Francis V. Defeudis | Methods for treating conditions associated with excess nitri c oxide |
| US5951990A (en) * | 1995-05-15 | 1999-09-14 | Avon Products, Inc. | Ascorbyl-phosphoryl-cholesterol |
| EP0891719A1 (en) * | 1997-07-14 | 1999-01-20 | N.V. Nutricia | Nutritional composition containing methionine |
| WO1999006040A1 (en) * | 1997-08-04 | 1999-02-11 | Berry Christopher J | Method of treating disease using a tocotrienol and alpha-lipoic acid or derivatives or an ester thereof |
| AU759467B2 (en) * | 1998-04-02 | 2003-04-17 | Avicena Group, Inc. | Compositions containing a combination of a creatine compound and a second agent |
-
1999
- 1999-04-02 FR FR9904134A patent/FR2791571B1/en not_active Expired - Lifetime
-
2000
- 2000-03-29 MY MYPI20001265A patent/MY133230A/en unknown
- 2000-03-30 AR ARP000101440A patent/AR023219A1/en unknown
- 2000-03-31 AU AU36637/00A patent/AU3663700A/en not_active Abandoned
- 2000-03-31 WO PCT/FR2000/000812 patent/WO2000059448A2/en active Search and Examination
- 2000-03-31 CA CA002365500A patent/CA2365500A1/en not_active Abandoned
- 2000-03-31 EP EP00915262A patent/EP1169005A2/en not_active Withdrawn
- 2000-03-31 JP JP2000609013A patent/JP2002541077A/en active Pending
-
2001
- 2001-10-01 NO NO20014770A patent/NO20014770L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1169005A2 (en) | 2002-01-09 |
| JP2002541077A (en) | 2002-12-03 |
| NO20014770L (en) | 2001-11-23 |
| AU3663700A (en) | 2000-10-23 |
| FR2791571B1 (en) | 2002-10-04 |
| WO2000059448A3 (en) | 2001-03-08 |
| AR023219A1 (en) | 2002-09-04 |
| FR2791571A1 (en) | 2000-10-06 |
| NO20014770D0 (en) | 2001-10-01 |
| MY133230A (en) | 2007-10-31 |
| WO2000059448A2 (en) | 2000-10-12 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |