WO2007096164A2 - Créatine pour le traitement des dyskinésies induites par l-dopa - Google Patents

Créatine pour le traitement des dyskinésies induites par l-dopa Download PDF

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Publication number
WO2007096164A2
WO2007096164A2 PCT/EP2007/001538 EP2007001538W WO2007096164A2 WO 2007096164 A2 WO2007096164 A2 WO 2007096164A2 EP 2007001538 W EP2007001538 W EP 2007001538W WO 2007096164 A2 WO2007096164 A2 WO 2007096164A2
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dopa
creatine
use according
general formula
compound
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PCT/EP2007/001538
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German (de)
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WO2007096164A3 (fr
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Maria Angela Cenci Nilsson
Barbara Catherine Valastro
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Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2007096164A2 publication Critical patent/WO2007096164A2/fr
Publication of WO2007096164A3 publication Critical patent/WO2007096164A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin

Definitions

  • the invention relates to the use of creatine kinase substrates, in particular creatine or creatine derivatives, in the treatment of motor disorders, in particular dyskinesia, caused by the administration of levodopa (L-dopa) in the treatment of Parkinson's disease as side effects be induced.
  • creatine kinase substrates in particular creatine or creatine derivatives
  • L-dopa levodopa
  • Parkinson's disease (Parkinson's disease, Parkinson's disease, Idiopathic Parkinson's disease) is the second most common neurodegenerative disease in the world after Alzheimer's disease.
  • the pathogenesis of the disease is generally characterized by a degeneration of catecholaminergic systems (Substantia nigra, Locus coeruleus et al.).
  • the focus is on dopamine deficiency in the striatum as a result of degeneration of the dopaminergic nigrostriatal projections, the consequent overactivity of the cholinergic interneurons in the striatum and the glutamatergic connections from the subthalamic nucleus to the globus pallidus internus, substantia nigra pars reticulata and substantia nigra pars compacte.
  • the resulting deficiency of dopamine in the striatum is responsible for most motor disorders, e.g. Bradykinesia, hypokinesia, rigidity and tremors. Furthermore, an abnormal gait and vegetative or mental disorders are possible.
  • L-Dopa levodopa
  • the aim is to compensate for dopamine deficiency in the brain by administering its biochemical precursor (dopamine replacement therapy).
  • dopamine replacement therapy Unlike dopamine, L-dopa can cross the blood-brain barrier.
  • Various formulations of L-Dopa, et al. also in combination with other active substances, are approved as drugs.
  • Some of the newly developed drug formulations aim to influence the metabolism of L-dopa. So were u.a. Inhibitors of monoamine oxidase type B (MAOB), catechol-O-methyltransferase (COMT), aromatic L-aminoacetic acid decarboxylase (AADC) and the mechanism of dopamine reuptake (see, for example, TH Johnston et al., Current opinion in investigational drugs, 2004, 5 (7), 720-6; WJ Weiner, Archives of Neurology, 2004, 61 (12), 1966-9; CE Clarke, Lancet Neurology, 2004, 3 (8), 466-74; Fernandez-Espejo, Molecular Neurobiology, 2004, 29 (1), 15-30; and BM Ravina et al., Neurology, 2003, 60 (8), 1234-40).
  • MAOB monoamine oxidase type B
  • COMP catechol-O-methyltransferase
  • AADC aromatic L-aminoacetic acid decarboxylase
  • neuroprotective properties ie are able to slow the degeneration of the neurons and thus treat the Parkinson's disease causally.
  • neuronal degeneration may involve several factors, including gene mutations, toxins or inflammatory diseases, with mitochondrial dysfunction and oxidative stress also appearing to play a role.
  • substances with neuroprotective properties are anti-apoptotic kinase inhibitors, modulators of the function of the mitochondria (eg coenzyme Q 10 or creatine), growth factors, neuroimmunosome philine and estrogen.
  • selegiline, amantadine or dopamine agonists for example a combination treatment with a dopamine agonist, selegiline and / or amantadine.
  • L-dopa is still the most important drug in the treatment of Parkinson's disease.
  • the positive effect i. the alleviation of symptoms as a reaction of the patient to the administration of L-dopa is considered to be one of the essential criteria for the diagnosis of Parkinson's disease.
  • the vast majority of patients are treated with L-dopa.
  • L-Dopa-induced side effects such as e.g. "L-dopa-induced motor disorders”, for example "L-dopa-induced dyskinesias” (LID).
  • L-Dopa-induced dyskinesias one usually distinguishes between different species, which i.a. characterized by the time of their occurrence after the administration of L-dopa:
  • a contribution to understanding the pathophysiology of LID is the recognition that interim and repeated stimulation of di-dopamine receptors results in modulation of brain function, resulting in dopamine replacement therapy.
  • One approach is based on a switch from L-dopa to Da / D ⁇ -selective agonists that bypass stimulation of di-dopamine receptors.
  • Other therapeutic concepts are based on the transdermal delivery of drugs to avoid fluctuations in plasma concentration.
  • Combination preparations have been developed in which dopamine replacement therapy is continued with the administration of L-dopa, accompanied by the administration of other agents to suppress LID.
  • amantadine may be mentioned.
  • the invention has for its object to provide a pharmaceutical composition for the treatment of Parkinson's disease, which has advantages over the compositions of the prior art.
  • the composition should allow the administration of L-dopa or one of its derivatives to have the therapeutic effect of treating or preventing Parkinson's disease, but suppressing L-dopa-induced motor disorders as much as possible.
  • L-dopa-induced motor disorders e.g. LID
  • Creatine is a widely used nutritional supplement and is considered a promising candidate for the treatment of neurodegenerative and mitochondrial diseases. Research has shown that creatine is tolerated in daily doses of 10 to 20 g. In the organism, creatine is enzymatically synthesized from guanidinoacetate (GAA). The reaction is catalyzed by guanidinoacetate methyltransferase (GAMT). Subsequently, creatine is converted into creatine phosphate by catalysis of creatine kinase, which can transfer a phosphate group to ADP and thus act as an energy buffer for the cell.
  • GAA guanidinoacetate
  • GAAMT guanidinoacetate methyltransferase
  • creatine is converted into creatine phosphate by catalysis of creatine kinase, which can transfer a phosphate group to ADP and thus act as an energy buffer for the cell.
  • creatine is reportedly inappropriate for preventing haloperidol-induced oral dyskinesia in rats (H.A. Jorgensen et al., Society of Neuroscience Abstracts, (2000) Vol. 26, No. 1-2, pp. Abstract).
  • guanidinoacetate methyltransferase (GAMT) seems to play an important role in LID.
  • proteomic methods it was surprisingly found that guanidinoacetate methyltransferase apparently has a defect in rats with LID, so that guanidinoacetate (GAA) is no longer converted into creatine and as a result creatine deficiency occurs.
  • GAA guanidinoacetate
  • Konradi et al., Neurobiology of Disease, 2005, 17, 219-236 disclose a transcriptome analysis of L-DOPA-induced dyskinesias in the rat model. Using gene-chip technology, more than 8,000 genes and expressed sequence tags (ESTs) of the striatum were studied in rats. In this study, the rat model was used to define changes in striatal gene expression associated with L-DOPA-induced dyskinesias. However, there is no evidence for a causal relationship between L-DOPA-induced motor disorders and creatine deficiency, let alone that L-DOPA-induced motor disorders can be treated with creatine.
  • the invention relates to the use of a creatine kinase substrate for the manufacture of a medicament for the treatment of L-dopa-induced motor disorders.
  • Creatine kinase (creatine N-phosphotransferase, EC 2.7.3.2) catalyzes the reversible phosphorylation of creatine involving ATP. This produces phosphocreatine and ADP or creatine and ATP.
  • each compound is preferably to be understood as a substrate of creatine kinase, which is phosphorylated and / or dephosphorylated by enzymatic catalysis involving the creatine kinase.
  • Suitable test methods as to whether or not a particular substance is a creatine kinase substrate are known to those skilled in the art.
  • the enzymatic phosphorylation of a suitable substrate can be followed, for example, by measuring the ATP consumption. Suitable assays are commercially available.
  • the dephosphorylation can be detected for example by radioactive labeling experiments.
  • creatine kinase is human creatine kinase (see EC Mariman et al., Genomics 1 (2), 126-137 (1987); RC Haas et al., J. Biol. Chem. 264 (5), 2890-2897 (1989); TD Wood et al., Proc. Natl. Acad. Be. USA 92 (25), 11451-11455 (1995); and L. Tang et al., Acta Crystallogr. D Biol. Crystallogr. 55 (Pt 3), 669-670 (1999)).
  • the substrate of the creatine kinase is a compound of the general formula (I)
  • n 0 or 1
  • X is -CO 2 H, -CO 2 C 1-6 Al kVl, -CONHC 1-6 Al kVl, -CON (C 1-6 alkyl) 2 , -PO 2 H 2 , -PO 3 H 2 or -OPO 3 H 2 is;
  • Y is -H, -PO 2 H 2 or -PO 3 H 2 ;
  • R 1 , R 2 , R 3 and R 4 are -H or -C 1-6 alkyl; or R 1 forms together with one of the radicals R 2 , R 3 or R 4 via an alkylene or an alkenylene bridge a 4-, 5-, 6- or 7-membered ring;
  • Suitable pharmaceutically acceptable salts are derived from inorganic or organic acids such as HCl, HBr, H 2 SO 4 , H 3 PO 4 , formic, acetic, propionic, oxalic, glutaric, tartaric, malic, lactic, citric, fumaric , Benzoic acid, salicylic acid, ascorbic acid, gluconic acid, glycolic acid, nicotinic acid, pyruvic acid, glutamic acid, aspartic acid, etc.
  • inorganic or organic acids such as HCl, HBr, H 2 SO 4 , H 3 PO 4 , formic, acetic, propionic, oxalic, glutaric, tartaric, malic, lactic, citric, fumaric , Benzoic acid, salicylic acid, ascorbic acid, gluconic acid, glycolic acid, nicotinic acid, pyruvic acid, glutamic acid, aspartic acid, etc.
  • salts of these functional groups are preferably selected from alkali metal salts (especially sodium or potassium), quaternary ammonium salts (especially N (C 1 -C 6 -alkyl) 4 + ) and alkaline earth metal salts (especially magnesium and calcium). Particularly preferred are sodium, potassium, calcium and magnesium salts.
  • Salts of X are preferably selected from the group consisting of -CO 2 Na 1 -CO 2 K, -PO 2 HNa, -PO 2 Na 2 , -PO 2 HK 1 -PO 2 K 2 , -PO 3 HNa, -PO 3 Na 2 , -PO 3 HK, -PO 3 K 2 , -OPO 3 HNa, -OPO 3 Na 2 , -OPO 3 HK and -OPO 3 K 2 .
  • Salts of Y are preferably selected from the group consisting of -PO 2 HNa, -PO 2 Na 2 , -PO 2 HK, -PO 2 K 2 , -PO 3 HNa, -PO 3 Na 2 , -PO 3 HK and - PO 3 K. 2
  • Preferred solvates are derived from water, ethanol, acetone, tetrahydrofuran, ethyl acetate, cyclohexane or pentane.
  • Preferred hydrates are the hemihydrates, monohydrates, dihydrates, trihydrates or tetrahydrates.
  • n O, A> N- and R 3 -H; R 2 -H and / or R 4 -H; X is -CO 2 H 1 -PO 2 H 2 or -PO 3 H 2 ; and / or R 1 -CH 3 .
  • Y is -H or -PO 3 H 2 .
  • n 0, A> N-, R 1 is -CH 3 , R 2 is -H, R 3 is -H, R 4 is -H, X is -CO 2 H, and Y is -H or -PO 3 H 2 .
  • creatine in particular creatine anhydrate [CAS 57-00-1] and creatine monohydrate [CAS 6020-87-7]
  • their pharmaceutically acceptable salts in particular the citrates, ascorbates or pyruvates, hydrates and / or solvates.
  • the daily dose of the creatine kinase substrate is preferably in the range of from 0.1 mg to 20,000 mg, more preferably from 1 mg to 15,000 mg, even more preferably from 5 mg to 10,000 mg.
  • the medicament preferably contains an amount of at least 1 mg, more preferably at least 10 mg, even more preferably at least 100 mg, most preferably at least 1 g and in particular in the range of 1 g to 20 g.
  • the medicament preferably contains an amount of at least 0.01 mg, more preferably at least 0.1 mg, even more preferably at least 1.0 mg, most preferably in the range of 1.0 mg to 25 mg and especially in the range of 2.0 mg to 20 mg.
  • L-dopa-induced motor disorders are, according to the invention, preferably to be understood as all motor disturbances which can be induced by the administration of L-dopa or one of its derivatives, in particular dyskinesias (abnormal involuntary movements, AIM) and dystonias (persistent) Muscle contractions causing abnormal postures, especially of the face, head, trunk and extremities).
  • dyskinesias abnormal involuntary movements, AIM
  • dystonias persistent Muscle contractions causing abnormal postures, especially of the face, head, trunk and extremities.
  • twitching for example, twitching, facial twitching, tremor, akathisia, asterixis, athetosis, choreactosis, chorea, spasms, hyperkinetic movement disorders, restless leg syndrome, hemiballism, myoclonus, and uncontrollable vocalizations are included, as long as these induce L-dopa become.
  • motor disorders refer to 21st Century Complete Medical Guide to Movement Disorders, Chorea, Tardive Dyskinesia, Dystonia, Authoritative Government Documents, Clinical References, ... for Patients and Physicians, PM Medical Health News; and RL Rodnitzky, Drug-induced movement disorders, Clin Neuropharmacol, 2002, 25 (3), 142-152.
  • L-Dopa-induced dyskinesia may be referred to JG Nutt, Clinical pharmacology of levodopa-induced dyskinesia, Ann. Neural., 2000, 47 (Suppl. 1), 160-166.
  • the L-dopa-induced motor disorders are dyskinesias, in particular L-dopa-induced hypostimulatory dyskinesias and / or L-dopa-induced hyperstimulatory dyskinesias.
  • L-dopa or its derivatives which is the cause of the L-dopa-induced side effects, is preferably in the treatment of Parkinson's disease.
  • L-dopa or its derivatives are administered with other objectives and the L-dopa-induced motor disorders occur as side effects in connection with this therapy.
  • the medicament according to the invention is preferably formulated for oral administration.
  • other forms of administration are also conceivable, in particular parenterally, for example by injection (eg intravenous, intraarterial, intraperitoneal, subcutaneous, intracutaneous, intramuscular), transmucosal (eg inhalative, pulmonary, nasal, buccal, sublingual, rectal, vaginal) or transdermal ,
  • the drug is solid.
  • it is in the form of a powder, tablet, dragee, film-coated tablet, suppository, multiparticulate, e.g. as Granule, pellet, biologypellet etc., possibly bottled in capsules.
  • multiparticulate e.g. as Granule, pellet, biologypellet etc.
  • it may also be formulated as a solution, suspension, emulsion, syrup, drop, paste, ointment, gel, lotion, cream, spray, transdermal therapeutic system, etc.
  • the creatine kinase substrate is formulated together with conventional excipients. Suitable auxiliaries are known to the person skilled in the art.
  • Compatible pharmaceutical excipients are preferably selected from the group consisting of excipients, fillers, solvents, diluents, surfactants, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and binders.
  • excipients fillers, solvents, diluents, surfactants, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and binders.
  • physiologically acceptable excipients and the amounts to be used depend on whether the drug is administered orally, parenterally, For example, by injection (eg, intravenous, intraarterial, intraperitoneal, subcutaneous, intracutaneous, intramuscular), transmucosal (eg inhalation, pulmonary, nasal, buccal, sublingual, rectal, vaginal) or transdermally administered.
  • injection eg, intravenous, intraarterial, intraperitoneal, subcutaneous, intracutaneous, intramuscular
  • transmucosal eg inhalation, pulmonary, nasal, buccal, sublingual, rectal, vaginal
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferred for oral administration, solutions, suspensions, readily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration.
  • excipients examples include sugars, e.g. Dextrose, fructose or sucrose, maltodextrins, sorbitol, magnesium stearate, microcrystalline cellulose.
  • the medicament contains a buffering agent such that the pH of the composition is in the range of 7 to 14.
  • buffering agent such that the pH of the composition is in the range of 7 to 14.
  • Suitable buffer substances are, for example, soda ash, magnesium glycerol phosphate, hydroxides, carbonates, bicarbonates, phosphates, etc.
  • Suitable pharmaceutical compositions and dosage forms of creatine kinase substrates are known in the art. In this connection, reference may be made, for example, in full to US 2005/0227996, US-A 2004/0102419, US-A 2004/0106680, US 6,399,661 and US 6,706,764. Combination preparations with L-Dopa are known, for example, from WO 99/51097.
  • the medicament contains adjuvants to increase the bioavailability of the creatine kinase substrate. These adjuvants sometimes facilitate the penetration of the creatine kinase substrate into the cells. As examples can be mentioned:
  • Penetration improvers eg fatty acids, Labrasol, Gelucire 44/14, polycationic dendrons with a lipophilic core, saponins, mono-N-carboxymethyl-chitosan, Carbopol 934P, a combination of thiolated polycarbophil and glutathione, sodium N- [8- ( 2-hydroxybenzoyl) amino] caprylate (SNAC), sodium N- [10- (2-hydroxybenzoyl) amino] decanoate (SNAD), dendritic polymers (dendrimers, eg polyamidoamine dendrimers (PAMAM)) or dendritic branches (dendrons); Co-solvents, for example polyethylene oxides of various chain lengths, Tween 20, Tween 80, propylene glycol, ethanol, glycerol or ethanol;
  • Co-solvents for example polyethylene oxides of various chain lengths, Tween 20, Tween 80, propylene glycol, ethanol,
  • Nano or microparticles e.g. biodegradable nanoparticles, for example, polylactides, polyamino acids, polybutyl cyanoacrylate, polysorbate-coated nanoparticles, polyvinylpyrrolidone, N-isopropylacetamide, and combinations thereof; or non-biodegradable nanoparticles, for example, iron oxide, silica, alumina;
  • coated nanoparticles e.g. Cholic acid / polyethylene oxide nanoparticles with or without sugar residue, such as e.g. galactose;
  • natural or artificial liposomes for example based on phosphoridylcholine, sphingomyelin, etc .;
  • Cyclodextrins for example hydroxypropyl- ⁇ -cyclodextrin or sulfonated ⁇ -cyclodextrin;
  • polymeric micelles derived from copolymers, e.g. Polyethylene oxide-polypropylene oxide block copolymers, polyethylene oxide-polyester block copolymers, polyethylene oxide-polyamino acid block copolymers or polycaprolactone-polyethylene oxide block copolymers;
  • Transport proteins transport peptides or cell-penetrating proteins, e.g. Peptides with a high content of arginine, TAT peptides or transan.
  • the daily dose of the creatine kinase substrate is in the gram range, it may also be preferable to add the creatine kinase substrate to a conventional foodstuff such as a bar or powder.
  • a conventional foodstuff such as a bar or powder.
  • creatine such products are commercially available and are particularly used as sports nutrition (see MH Williams et al., Creatine: The Power Supplement, Human Kinetics Publishers, 1999, and JA Debi, The Ultimate Creatine Handbook: The Safe Alternative for Healthy Muscle Building, Woodland Publishing, 2003).
  • the medicament is formulated once or twice a day.
  • the drug may be formulated so as to release the substrate of creatine kinase immediately (immediate release) or at least partially retarded.
  • sustained release the following types may be considered: extended release, delayed release, sustained release, sustained release, and sustained release.
  • the invention relates to the treatment of side effects induced by the administration of L-dopa.
  • the administration of L-dopa or a suitable precursor of L-dopa, for example an ester of L-dopa may be carried out separately or together with the medicament according to the invention.
  • the dose used is customarily adapted to the particular needs of the patient.
  • the medicament additionally contains a compound of the general formula (II)
  • Z is -H or -Ci -6 alkyl.
  • the compound of general formula (II) is selected from the group consisting of L-dopa (levodopa), melevodopa and etilevodopa.
  • L-dopa levodopa
  • melevodopa melevodopa
  • etilevodopa etilevodopa
  • the animals were randomly divided into the following two groups:
  • Creatine was administered per os by ingesting the food pellets. The body weight of the animals was monitored prior to treatment with L-dopa to ensure that no significant change in weight due to the different diets occurred.
  • L-Dopa The administration of L-Dopa was carried out with the aid of a steel dosing syringe i.p. at a constant dose volume of 1 ml of the dosing solution per kg of body weight. The volume administered was determined every other day by the weight of each animal at the time of administration.
  • the animals of group 1 were already fed one month before treatment with L-Dopa with the 2% -enriched creatine diet ⁇ Lactamin AB, Sweden). Following this month, all animals of both groups were i.p. once a day for 22 consecutive days. treated with L-dopa (6 mg / kg + 15 mg / kg benserazide). The separate diet for both groups was continued during this time (53 days in total).
  • locomotion locomotive AIMs
  • locomotive AIMs i. increased locomotion with contralateral lateral tilt
  • the oral administration of creatine was also effective in reducing dyskinesia affecting the orolingual area (orolingual component).
  • the frequency of orolingual movement was significantly reduced in the creatine-treated group compared to the other group ( Figure 1C, multi-factorial ANOVA with p ⁇ 0.0493 for group effect and p ⁇ 0.0001 for time effect).
  • the amplitude of the movements of the anterior extremities was also reduced by the administration of creatine in comparison of both groups ( Figure 1 D 1 multifactorial ANOVA with p ⁇ 0.0523 in terms of group effect and p ⁇ 0.0001 in terms of time effect).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation d'un substrat de la créatine kinase pour la fabrication d'un médicament destiné à traiter les troubles moteurs induits par L-Dopa, en particulier les dyskinésies induites par L-Dopa.
PCT/EP2007/001538 2006-02-23 2007-02-22 Créatine pour le traitement des dyskinésies induites par l-dopa WO2007096164A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104109171A (zh) * 2013-04-19 2014-10-22 上海和臣医药工程有限公司 N-[亚氨基(膦氨基)甲基]-n-甲基甘氨酸二钠水合物及其制备方法
EP2792359A1 (fr) * 2013-04-19 2014-10-22 Merz Pharma GmbH & Co. KGaA Traitement de la dyskinésie induite par L-DOPA avec OPC-14523 ou OPC-34712

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WO1999051097A1 (fr) * 1998-04-02 1999-10-14 Avicena Group, Inc. Compositions contenant de la creatine combinee a un second agent
WO2006015774A1 (fr) * 2004-08-06 2006-02-16 Bioghurt Biogarde Gmbh & Co. Kg Composition physiologiquement acceptable contenant de l'acide alpha-lipoique, de la creatine et un phospholipide

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1999051097A1 (fr) * 1998-04-02 1999-10-14 Avicena Group, Inc. Compositions contenant de la creatine combinee a un second agent
WO2006015774A1 (fr) * 2004-08-06 2006-02-16 Bioghurt Biogarde Gmbh & Co. Kg Composition physiologiquement acceptable contenant de l'acide alpha-lipoique, de la creatine et un phospholipide

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KONRADI C ET AL: "Transcriptome analysis in a rat model of l-DOPA-induced dyskinesia" NEUROBIOLOGY OF DISEASE, BLACKWELL SCIENCE, OXFORD, GB, Bd. 17, Nr. 2, November 2004 (2004-11), Seiten 219-236, XP004592561 ISSN: 0969-9961 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104109171A (zh) * 2013-04-19 2014-10-22 上海和臣医药工程有限公司 N-[亚氨基(膦氨基)甲基]-n-甲基甘氨酸二钠水合物及其制备方法
EP2792359A1 (fr) * 2013-04-19 2014-10-22 Merz Pharma GmbH & Co. KGaA Traitement de la dyskinésie induite par L-DOPA avec OPC-14523 ou OPC-34712
CN104109171B (zh) * 2013-04-19 2017-02-08 上海华拓医药科技发展有限公司 N‑[亚氨基(膦氨基)甲基]‑n‑甲基甘氨酸二钠水合物及其制备方法

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