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Definitions

• the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising, as active principle, at least one substance which interferes with the synthesis of nitric oxide by inhibiting NO synthase and at least one metabolic antioxidant involved in the redox status of the thiol groups, and optionally a pharmaceutically acceptable carrier.
• the invention also relates to a product comprising at least one NO synthase inhibiting substance and at least one metabolic antioxidant involved in the redox status of thiol groups, as a combination product, in separate form, of these active principles.
• a pharmaceutical composition and a product according to the invention are useful in the treatment of pathologies where nitric oxide and the metabolism of antioxidants (such as vitamin E or glutathione) as well as the redox status of the thiol groups are involved, and especially :
• cardiovascular and cerebrovascular disorders including, for example, migraine, high blood pressure, heart or brain infarction of ischemic or hemorrhagic origin, ischemia and thrombosis;
• disorders of the central or peripheral nervous system such as, for example, neurodegenerative diseases in which there may be mentioned in particular, cerebral infarction, senile dementia, including Alzheimer's disease, Huntington's chorea, Parkinson's disease, Creutzfeld Jacob's disease, prion diseases, amyotrophic lateral sclerosis but also pain, trauma to the brain or spinal cord, addiction to opiates, alcohol and addictive substances, erection and reproduction, cognitive disorders, encephalopathies, depression, anxiety, schizophrenia, epilepsy, sleep disorders, eating disorders (anorexia, bulimia ...);
• proliferative and inflammatory diseases such as, for example, cancer, atherosclerosis, pulmonary hypertension, glomerulonephritis, portal hypertension, cataracts, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis, inflammation of the gastrointestinal system (colitis, Crohn's disease) or of the pulmonary and airways system (asthma, sinusitis) as well as contact or delayed hypersensitivities;
• autoimmune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes and its complications including retinopathies, nephropathies and polyneuropathies, multiple sclerosis, myopathies;
• autosomal genetic diseases such as Unverricht-Lunborg disease
• pathologies characterized by production or dysfunction of nitric oxide and / or glutathione metabolism and the redox status of thiol groups.
• the subject of the invention is therefore a pharmaceutical composition
• a pharmaceutical composition comprising, as active principle, one or more substance (s) interfering with the synthesis of nitrogen monoxide by inhibition of NO synthase and one or more antioxidant substance (s) ) metabolic containing at least two thiol groups and involved in the redox status of thiol groups, and optionally a pharmaceutically acceptable carrier.
• a more particular subject of the invention is a pharmaceutical composition comprising, as active principle, a substance which interferes with the synthesis of nitrogen monoxide by inhibiting NO synthase and a metabolic antioxidant substance involved in the redox status of the thiol groups.
• NO synthase inhibitor we must understand any specific or non-specific inhibitor of one of its isoforms, whether constitutive (neuronal or endothelial) or inducible (Kerwin et al., Nitric oxide: a new paradigm for second messengers, J. Med. Chem. 38, 4343-4362, 1995).
• the NO synthase inhibitors according to the invention can be chosen, for example, from certain amino acid derivatives such as L-arginine derivatives, guanidines, isothioureas, nitro- or cyano-aryls, amino- pyridines or amino-pyrimidines, amidines, indazoles or imidazoles as defined below.
• metabolic antioxidant substance involved in the redox status of thiol groups it is necessary to understand any chemical substance having at least two thiol groups capable of forming by oxidation an intra or intermolecular disulfide bridge, this substance possibly being in the reduced or oxidized form .
• Such compounds allow the chelation of divalent cations, the regeneration of antioxidants such as vitamin E or glutathione, and are involved in the redox status of thiol groups.
• the metabolic antioxidant substances 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 below, the dimeric disulfide derivatives of penicillamine or of N-acetylcysteine, or else the peptides comprising at least two cysteine residues. These substances can be natural or synthetic.
• the inhibitor of NO synthase and the metabolic antioxidant substance can be present in separate form or in combined form by forming a salt.
• the formation of a salt is only envisaged if one of the active ingredients has an acid group and the other active ingredient has a basic group.
• the salt is formed from a derivative of the NO synthase inhibitor substance containing at least one basic group and from a derivative of the metabolic antioxidant containing an acid group.
• the inhibitor of NO synthase can be chosen, for example, from the compounds as defined below.
• the metabolic antioxidant can be chosen, for example, from lipoic acid or its derivatives as defined below, the dimeric disulfide derivatives of penicillamine or of N-acetylcysteine.
• the invention also relates to a product comprising one or more substance (s) inhibitor (s) of NO synthase and one or more metabolic antioxidant substance (s) containing at least two thiol groups and involved in the redox status of the thiol groups, as a combination product, in separate form, for simultaneous or sequential use in the treatment of pathologies in which nitric oxide and the redox status of the thiol groups are involved such as cardiovascular disorders and cerebrovascular, septic shock, radioactive radiation, solar radiation, organ transplants, disorders of the central or peripheral nervous system particularly well represented by Parkison's disease, proliferative and inflammatory diseases, autoimmune and viral diseases, diabetes and its complications, autosomal genetic diseases and all pathologies are characterized by a production or a dysfunction of nitric oxide and / or implying the redox status of thiol groups.
• substance (s) inhibitor (s) of NO synthase and one or more metabolic antioxidant substance (s) containing at least two thiol groups
• the inhibitor of NO synthase and the metabolic antioxidant can be present in doses which can be identical or different.
• the dosages are chosen according to the compounds associated with appropriate diluents or excipients.
• the NO synthase inhibitor and the metabolic antioxidant can be administered simultaneously or sequentially, by the same route of administration or by different routes, depending on whether they are presented in separate or combined form.
• the routes of administration are oral, parenteral or topical.
• Amino acid type NO synthase inhibitors can be compounds as described in applications WO 95/00505, WO 94/12163, WO 96/06076, WO 98/28257, or alternatively derivatives of L-arginine, ornithine or lysine as described in 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 natural substrate for NO synthase).
• Non-amino acid NO synthase inhibitors can be compounds of the family of guanidines, isothioureas, nitro- or cyano-aryls, amino-pyridines or amino-pyrimidines, amidines, indazoles or imidazoles as well as substituted heterocycles or condensed piperidines.
• the NO synthase inhibitor guanidines can be the compounds 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 the compounds as defined 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 can be the compounds as defined in application WO 94/12163.
• amino syntidins or amino pyrimidines inhibitors of NO synthase can 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.
• the NO synthase inhibiting amidines can be the compounds as defined in applications WO 95/1 1014, 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.
• the indazoles inhibitors of NO synthase can be the compounds as defined in application WO 98/02442 or else compounds of general formula IA
• R represents one or more substituents chosen from the hydrogen atom, the nitro, halo, lower alkyl or lower alkoxy radical.
• NO synthase inhibitor imidazoles can be the compounds of general formula HA
• R 2 and R 3 independently represent the hydrogen atom, the halo, hydroxy, amino, alkyl or alkoxy radical, or R 2 and R 3 are linked together and form the phenyl radical condensed with the imidazole ring, phenyl radical being optionally substituted by one or more substituents chosen from hydroxy, trifluoromethyl, halo, carboxy, lower alkyl, lower alkoxy or lower alkenyl radicals;
• R 4 represents a hydrogen atom, a lower alkyl, amino, lower alkyl amino or phenyl radical, the phenyl radical being optionally substituted by one or more substituents chosen from hydroxy, trifluoromethyl, halo, carboxy, lower alkyl, lower alkoxy radicals or lower alkenyl;
• R 5 represents the hydrogen atom, a lower alkyl, amino, lower alkyl amino radical.
• the lower term with reference to alkyl and alkoxy groups denotes saturated, linear, or branched aliphatic hydrocarbon groups having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl , butyl, t-butyl, methoxy and ethoxy.
• alkenyl groups the lower term denotes groups containing from 2 to 6 carbon atoms and one or more double or triple bonds such as, for example, vinyl, allyl, propenyl, isopropenyl, pentenyl, butenyl, hexanyl, propenyl groups. and butadienyl.
• halo means chloro, bromo, iodo or fluoro.
• the condensed piperidines can be the compounds as defined in application EP 870763.
• the substituted heterocycles can be the compounds as defined in applications WO 98/50372, WO 98/42667, WO 98/4661 1, WO 99/05131, WO 99/01455, JP 98/182618.
• the NO synthase inhibitor is an amino acid type compound and more particularly a derivative of L-arginine, ornithine or lysine, or a compound of the family of guanidines, isothioureas, nitro- or cyano-aryls, 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 (in racemic or enantiomeric form) and its derivatives, the dimeric disulfide compounds of penicillamine or of N-acetylcysteine, and the peptides comprising at least two cysteine residues.
• the derivatives of lipoic acid are the compounds such as defined in applications EP 855396, EP 236929, EP 869126, FR 2707983, WO 99/45922 and JP 94227979.
• the invention relates more particularly to a composition or a product as defined above, characterized in that the inhibitor of NO synthase is chosen from L-nitro-arginine (LNA), the methyl ester of L -nitro-arginine (LNAME), LN- monomethylarginine (LNMMA), aminoguanidine, agmatine, 2-amino- l- (methylamino) benzimidazole, 5-nitro-indazole, 6-nitro-indazole, 7-nitro-indazole, l, 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,
• the invention more particularly relates to a composition or a product as defined above, characterized in that the metabolic antioxidant is lipoic acid, in racemic or enantiomeric form.
• the invention also relates to a composition or a product as defined above, characterized in that the inhibitor of NO synthase is an inhibitor of neuronal NO synthase and / or inducible.
• NO synthase inhibitor compounds and metabolic antioxidants are commercially available or can be prepared by methods known to those skilled in the art (or analogy to them) (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)).
• 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 (1 -methyl-4-phenyl-1, 2,3,6-tetrahydropyridine).
• the administration of MPTP produces a syndrome similar to Parkinson's disease 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 l-methyl-4-phenyl- 1,2,5,6-tetrahydropyridine, N. Engl. J. Med.
• 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)].
• mice 15-20 mg / kg of MPTP is injected three times at 2 hour intervals intraperitoneally into mice (C57BL6) weighing 15-25 g.
• the products are injected orally 90 minutes before each injection of MPTP and 90 minutes after the last and 24 hours after the first injection of MPTP.
• the mice are sacrificed 24 hours after the last injection of MPTP.
• the striatum is removed and its dopamine level is measured by high performance liquid chromatography coupled with electrochemical detection.
• the coefficient of effectiveness of the compounds is calculated by the ratio of the 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 beneficial.
• A be the inhibitor of NO synthase and B the metabolic antioxidant.
• 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, a metabolic antioxidant.
• Example 1 Composed of Example 1: 4 groups of animals are made up:
• 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.
• Compound AB combination of active ingredients A and B.
• Compound A N G nitro-arginine, a powerful inhibitor of constitutive and inducible NO synthases.
• Compound B the reduced form of lipoic acid, a metabolic antioxidant.
• Example 2 Composed of Example 2: 4 groups of animals are made up:
• 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.
• N G nitro-arginine used as an inhibitor of NO synthases active at a dose of 3 mg / kg, has an increased effectiveness when combined with lipoic acid.

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  • 1999-04-02 FR FR9904134A patent/FR2791571B1/fr not_active Expired - Lifetime
• 2000
  • 2000-03-29 MY MYPI20001265A patent/MY133230A/en unknown
  • 2000-03-30 AR ARP000101440A patent/AR023219A1/es unknown
  • 2000-03-31 CA CA002365500A patent/CA2365500A1/fr not_active Abandoned
  • 2000-03-31 JP JP2000609013A patent/JP2002541077A/ja active Pending
  • 2000-03-31 WO PCT/FR2000/000812 patent/WO2000059448A2/fr active Search and Examination
  • 2000-03-31 EP EP00915262A patent/EP1169005A2/fr not_active Withdrawn
  • 2000-03-31 AU AU36637/00A patent/AU3663700A/en not_active Abandoned
• 2001
  • 2001-10-01 NO NO20014770A patent/NO20014770L/no not_active Application Discontinuation

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