EP1411939A2 - Modulateurs du recepteur gaba a a activite antagoniste nmda - Google Patents

Modulateurs du recepteur gaba a a activite antagoniste nmda

Info

Publication number
EP1411939A2
EP1411939A2 EP02791466A EP02791466A EP1411939A2 EP 1411939 A2 EP1411939 A2 EP 1411939A2 EP 02791466 A EP02791466 A EP 02791466A EP 02791466 A EP02791466 A EP 02791466A EP 1411939 A2 EP1411939 A2 EP 1411939A2
Authority
EP
European Patent Office
Prior art keywords
receptor
gaba
nmda
hydrogen
lipoic acid
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Withdrawn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
EP02791466A
Other languages
German (de)
English (en)
Inventor
Christopher BRÜCKNER
Rainer Dorow
Roland Neuhaus
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.)
Bayer Pharma AG
Original Assignee
Schering AG
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.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP1411939A2 publication Critical patent/EP1411939A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • GABA A receptor modulators with NMDA-antagonistic activity GABA A receptor modulators with NMDA-antagonistic activity
  • the invention relates to the use of GABA A receptor modulators with NMDA-antagonistic activity for the manufacture of a medicament for neuroprotection and the combination of GABA A receptor modulators with NMDA-antagonistic activity and ⁇ -lipoic acid or dihydro- ⁇ -lipoic acid.
  • Glutamate is an indispensable, exciting transmitter in the body of humans and mammals. Elevated glutamate levels lead to severe damage to nerve tissue, which can lead to neurodegeneration.
  • the NMDA (N-methyl-D-aspartate) receptor plays the most important role pathologically within the glutamate receptors. The NMDA receptor acts simultaneously depending on the voltage and ligand. At the normal resting potential of the neuron of -60 mV, the receptor's ion channel is closed by Mg 2+ ions (Mayer ML et al, Nature 1984; 309 (5965): 261-3), and a ligand cannot activate the receptor.
  • Mg 2+ leaves the ion channel and the receptor can be activated by a ligand, which leads to the influx of Ca 2+ and Na + and the outflow of K + .
  • the non-NMDA receptors are almost not permeable to Ca 2+ . Excessive activation of the NMDA receptor causes an increased Ca 2+ influx, which has a cell-toxic effect. This Ca 2+ influx triggers apoptosis (Riveros N et al, Neuroscience 1986; 17 (3): 541-6) and later necrosis processes in the cell, which ultimately lead to cell death.
  • NMDA receptor antagonists In the advanced stage of a neurodegenerative disease, the cells occupied with NMDA receptors preferentially die, which means that as the neurodegeneration progresses, NMDA receptor antagonists lose their effectiveness more and more.
  • the cells, on the other hand, which carry GABA receptors are protected by the inhibitory effect of this transmitter (GABA) and are also accessible to pharmacological effects in the state of advanced neurodegeneration.
  • GABA this transmitter
  • the above-described excessive activation of NMDA receptors can cause increased intracellular Ca 2+ levels. These often lead to an increased formation of free radicals, e.g. B. by release of arachidonic acid or the conversion of xanthine dehydrogenase to xanthine oxidase.
  • Glutation from food or oral intake does not take place.
  • oral intake of ⁇ -lipoic acid leads to a marked increase in cellular glutathione levels.
  • Neuroprotective therapy is the form of treatment that leads to a reduction or prevention of damage or destruction of neuronal cells. This can be done by reducing the effects of elevated glutamate levels, e.g. B. by blocking the Ca 2+ influx into the cell, as well as by reducing the glutamate release.
  • NMDA receptor antagonists would be extremely desirable for neuroprotective purposes, but is almost always associated with serious side effects in clinical trials, e.g. B. the so-called vacuolization of cells (Fritz Kl et al, Brain Res. 1999; 816 (2): 438-45), which ultimately made clinical introduction impossible. In addition, almost all NMDA receptor antagonists show moderate to severe psychiatric side effects. When using GABA receptor potentiating and NMDA receptor antagonizing
  • GABA gamma-amino-butyric acid
  • 1,4-Benzodiazepines are among the most common G AB A A receptor modulators. Compounds from this group of substances, such as midazolam and flunitrazepam, have a strong affinity for a specific binding site for benzodiazepines, the benzodiazepine receptor. This is part of the GABA A receptor. If GABA binds to the GABAA receptor, this triggers a chloride inflow. If benzodiazepines bind to the benzodiazepine receptor at the same time, this chloride influx is increased. This results in increased hyperpolarization of the cell. The mechanism for this is assumed to be an increased probability of opening the chloride channel. Binding of benzodiazepines to the benzodiazepine receptor increases the affinity of the GABA A receptor for GABA and vice versa.
  • Benzodiazepines are widely used systemically in the treatment of epilepsy, anxiety, spasms and sleep disorders. Their toxic hazard potential is relatively low because their effectiveness is limited by the amount of GABA present. There is also a selective benzodiazepine receptor antagonist, flumazenil, which can be used to immediately antagonize any overdoses. Barbituric acid derivatives such as B. phenobarbital, the opening of the GABA chloride ion channel.
  • ⁇ -carbolines are known to have affinity for the benzodiazepine receptors and, depending on the structure of the compounds, to the properties known from the benzodiazepines to be antagonistic, inverse exert agonistic and agonistic effects.
  • Some compounds from this class of substances show only strong affinity for a specific binding site for benzodiazepines, which is part of the GABA A receptor, some ß-carbolines simultaneously bind to receptors for other neurotransmitters and some ß-carbolines only bind to receptors for other neurotransmitters and show no affinity for the benzodiazepine receptor.
  • WO 93/20820 describes that certain ⁇ -carbolines act on the modulation site of the quisqualate receptor and correct the pathologically changed form of this receptor.
  • GABAA receptor modulators change the affinity or the effectiveness of GABA on the receptor, in the absence of GABA they are ineffective.
  • the administration of GABA A receptor modulators is therefore significantly less dangerous than that of agonists, since agonists act more and more with increasing concentration regardless of the amount of the neurotransmitter present.
  • the administration of GABA A receptor modulators therefore has a significantly lower toxic risk compared to GABA agonists.
  • R 1 is hydrogen or -OR 5
  • R 3 is hydrogen or C 1-4 alkyl
  • R 4 is hydrogen, C -4 alkyl or -CH2-O-CH 3 ,
  • R 5 is hydrogen, phenyl, benzyl or phenyl substituted with Cl.
  • Alkyl in each case means straight-chain or branched alkyl such as methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert. Butyl, sec. Butyl.
  • R 3 preferably represents isopropyl.
  • the substituent R 1 is preferably in the 5- or 6-position or twice in the 6-, 7-position.
  • Particularly preferred embodiments are 5- (4-chlorophenoxy) -4-methoxymethyl- ⁇ -carboline-3-carboxylic acid isopropyl ester and in particular 6-benzyloxy-4-methoxymethyl-ß-carboline-3-carboxylic acid isopropyl ester (Abecarnil).
  • GABAA receptor modulators which are suitable according to the invention and which, in addition to their GABA receptor-modulating action, have an NMDA receptor-modulating action are suitable for the neuroprotective therapy of neurodegenerative diseases, for example after a stroke, cranial brain trauma and cerebral ischemia. Furthermore, such compounds are suitable for the therapy of other diseases of the central and peripheral nervous system, such as, for. B.
  • Figure 1 shows the results of the investigation of the neuroprotective properties of Abecamil. The measurements were carried out on primary cell cultures of rat cortical neurons. After the cells had grown in culture, the following experiment was carried out:
  • OGD Oxygen and glucose deprivation
  • Abecamil was added simultaneously with the oxygen and glucose withdrawal.
  • the LDH (lactate dehydrogenase) level in the solution above the cells was measured as the damage parameter for the neurons.
  • LDH lactate dehydrogenase is an extremely reliable stress parameter for the cells. The stronger the neuronal stress or the more cells have already died, the more the LDH levels in the medium rise. A drug with a neuroprotective effect is expected to reduce the LDH levels in the medium.
  • Figure 1 shows the values of such a measurement. If the LDH levels under OGD were 25.1, they were at 0.1 ⁇ M Abecamil 11.0. At 1 ⁇ M Abecamil 6.2, at 10 ⁇ M Abecamil 14.9 and at 100 ⁇ M Abecamil 15 (after 24 hours). With an Abecarnil concentration of 1 ⁇ M, this corresponds to an LDH reduction of over 75%!
  • Ss-Carbolines suitable according to the invention act via two receptor systems: on the one hand, they have a positive modulating effect on the benzodiazepine receptor, that is, they increase the inhibitory activity of GABA, but at the same time they also have an NMDA receptor antagonistic effect, ie. H. they reduce the harmful effects of glutamate. Both together result in an even more extensive neuroprotection than when using a pure GABAA receptor modulator.
  • the invention also relates to the use of the compounds of the formula I for the manufacture of a medicament for symptomatic and preventive purposes
  • the invention also includes the combination of GABAA receptor modulators with NMDA-antagonistic action and ⁇ -lipoic acid or dihydro- ⁇ -lipoic acid.
  • ⁇ -Lipoic acid (1,2-dithiolan-3-valerian acid) together with its reduced form, dihydrolipoic acid (DHP), forms a redox system.
  • DHP dihydrolipoic acid
  • This redox system has a very strong antioxidant effect in the mammalian organism.
  • ⁇ -lipoic acid binds free radicals, chelates metals and reactivates important cellular antioxidants and radical scavengers such as.
  • the combination treatment enhances the neuroprotective effect and reduces the cell-toxic damage of an increased Ca 2+ influx.
  • compositions or compositions of the invention are produced using conventional solid or liquid carriers or diluents and customary pharmaceutical and technical auxiliaries in accordance with the desired type of application with a suitable dosage in a manner known per se.
  • Preferred preparations exist in a dosage form which is for oral, enteral or parenteral, for example i.p. (intraperitoneal), i.v. (intravenous), in. (intramuscular) or percutaneous, application is suitable.
  • Such dosage forms are, for example, tablets, film-coated tablets, dragees, pills, capsules, powders, creams, ointments, lotions, liquids, such as syrups, gels, injectable liquids, for example for i.p., i.v., im. or percutaneous injection, etc.
  • Depot forms such as implantable preparations, and suppositories are also suitable.
  • the individual preparations give off the benzimidazole derivatives according to the invention gradually, depending on their type, or the entire amount in a short time to the body.
  • capsules, pills, tablets, coated tablets and liquids or other known oral dosage forms can be used as pharmaceutical preparations.
  • the medicinal products can be formulated in such a way that they either release the active substances in a short time and release them to the body or have a depot effect have, so that a longer-lasting, slow supply of active ingredient to
  • the dosage units can contain one or more pharmaceutically acceptable ones
  • Contain carriers for example substances to adjust the rheology of the drug, surface-active substances, solubilizers, microcapsules,
  • Gelatin also fillers, such as silica and talc, lubricants, dyes,
  • Corresponding tablets can be obtained, for example, by mixing the active ingredient with known auxiliaries, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate , The tablets can also consist of several layers.
  • auxiliaries for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate ,
  • auxiliaries for example in
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents commonly used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar.
  • the coated tablet can also consist of several layers, wherein the auxiliaries mentioned above for the tablets can be used.
  • Capsules containing active ingredients can be produced, for example, by mixing the active ingredient with an inert carrier such as milk sugar or sorbitol and encapsulating it in gelatin capsules.
  • an inert carrier such as milk sugar or sorbitol
  • the active ingredients can also be formulated in the form of a solution which is intended for oral administration and which is in addition to the active one
  • Benzimidazole derivative as components are a pharmaceutically acceptable oil and / or a pharmaceutically acceptable lipophilic, surface-active substance and / or a pharmaceutically acceptable hydrophilic, surface-active Contains substance and / or a pharmaceutically acceptable water-miscible solvent.
  • the compounds can also be formulated as cyclodextrin chlate.
  • the compounds are reacted with a, ⁇ - or ⁇ -cyclodextrin or their derivatives.
  • compositions that can be used externally are to be used, they must be such that the compounds according to the invention are supplied to the body in sufficient quantities.
  • dosage forms contain auxiliaries, for example substances for adjusting the rheology of the pharmaceuticals, surface-active agents, preservatives, solubilizers, thinners, substances for increasing the permeability for the benzimidazole derivatives according to the invention through the skin, dyes, fragrances and skin protection agents, such as conditioners and moisture regulators.
  • other active substances can also be present in the medicament (Ulimanns Enzyklopadie der Technische Chemie, Volume 4 (1953), pages 1 - 39; J. Pharm.
  • the active substances can also be used in suitable solutions, such as, for example, physiological saline, as infusion or injection solutions.
  • suitable solutions such as, for example, physiological saline, as infusion or injection solutions.
  • the active ingredients can be dissolved or suspended in a physiologically compatible diluent.
  • Particularly suitable diluents are oily solutions, such as solutions in sesame oil, castor oil and cottonseed oil.
  • Solubilizers such as, for example, benzyl benzoate or benzyl alcohol, can be added to increase the solubility.
  • Any liquid carrier in which the compounds according to the invention are dissolved or emulsified can be used to formulate an injectable preparation. These liquids often also contain substances for regulating the viscosity, surface-active substances, preservatives, solubilizers, thinners and other additives with which the solution is adjusted isotonic.
  • implants can contain, for example, biodegradable polymers or synthetic silicones, for example silicone rubber.
  • the dosage of the active ingredients can vary depending on the type of application, age and weight of the patient, type and severity of the disease to be treated and similar factors.
  • the daily dose can be given as a single dose to be administered once or divided into two or more daily doses.
  • the compounds are introduced in a dose unit of 0.05 to 100 mg of active substance in a physiologically acceptable carrier. Generally, a dose of 0.1 to 500 mg / day, preferably 0.1 to 50 mg / day, is used.
  • the active compounds can be present in one formulation or in separate formulations, the entire dose being administered once or divided into several doses.
  • the daily dose of the active substances in the combination preparations is 0.1 mg to 500 mg for the ⁇ -carboline derivative and 10 mg to 1000 mg for the ⁇ -lipoic acid or dihydro- ⁇ -lipoic acid, doses of 600 mg are particularly suitable.
  • the effectiveness of the GABA A receptor modulators, which also have an NMDA receptor antagonizing effect, was determined using the tests described below:
  • GBSS Greenwich's buffered salt solution, Sigma
  • HEPES N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid
  • pH 7.3 adjusted with NaOH
  • the culture media used were: DMEM (Sigma), containing glucose, horse serum 10% (Sigma) and glutamine.
  • DMEM Sigma
  • the cells were distributed in such a way that at the beginning of the culture there were 50,000 cells per plate.
  • the medium was changed after preparation after 24 hours and then after 3 days each.
  • synaptic spontaneous activity developed in vitro from the tenth day.
  • the extracellular measurement solution had the following composition (in mM): NaCl 140; KCI 5.4; CaCI 2 2; HEPES 10; MgC1 1; Glucose 25.
  • the pH was adjusted to 7.4 with NaOH.
  • IPSCs were obtained by adding 1, 2,3,4, -tetrahydro-6-nitro-2,3-di-oxo-benzo-quinoxaline-7-sulfonamide (NBQX 10 ⁇ M) and DL-2-amino-5-phosphonovaleric acid (+ -APV 30 ⁇ M) isolated.
  • EPSCs were isolated by adding bicuculline (10 ⁇ M) and picrotoxin (20 ⁇ M). A Ringer's solution without MgCl 2 was used in the investigation of the EPSCs.
  • the pipette solution had the following composition (in mM): KC1 120; MgCl 2 2; CaCI 2 1; HEPES 10; EGTA 11; Glucose 20, the pH was 7.2
  • the measurements were made at room temperature.
  • a silver-silver chloride pellet was used as a reference.
  • -60 mV was selected as the holding potential.
  • the signals coming from the amplifier were generated with the help of repeaters amplified and low-pass filtered at 1 kHz.
  • the signals modulated in this way were displayed using a storage oscilloscope and recorded using a thermal recorder.
  • the signals were recorded by a digital / analog converter and recorded on video tape.
  • the saved data was later played back, digitized again and then evaluated "offline" with a PC.
  • the TIDA program HEKA, Germany
  • J. Dempster Universality of Strathclyde, UK
  • Inhibitory postsynaptic currents were obtained by adding the
  • the amplitudes of the IPSCs dropped in biexponential kinetics, i.e. a superposition of two components was found, the first time constant representing the faster falling portion of the IPSC and therefore being referred to as ⁇ fast or fast time constant, while the second time constant describes the slower portion of the IPSC and is therefore referred to as ⁇ slow or slow time constant.
  • the average decay time of the fast component ⁇ fast was 6.9 ⁇ 4.8 ms, that of the slow component ⁇ slow 34.1 ⁇ 12.5 ms.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne l'utilisation de modulateurs du récepteur GABAA à activité antagoniste NMDA pour produire un médicament de neuroprotection et la combinaison de modulateurs du récepteur GABAA à activité antagoniste NMDA et d'acide α-liponique ou d'acide dihydro-α-liponique.
EP02791466A 2001-07-23 2002-07-22 Modulateurs du recepteur gaba a a activite antagoniste nmda Withdrawn EP1411939A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10136842 2001-07-23
DE10136842A DE10136842A1 (de) 2001-07-23 2001-07-23 GABA¶A¶-Rezeptor-Modulatoren mit NMDA-antagonistischer Aktivität
PCT/EP2002/008166 WO2003011264A2 (fr) 2001-07-23 2002-07-22 Modulateurs du recepteur gaba a a activite antagoniste nmda

Publications (1)

Publication Number Publication Date
EP1411939A2 true EP1411939A2 (fr) 2004-04-28

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP02791466A Withdrawn EP1411939A2 (fr) 2001-07-23 2002-07-22 Modulateurs du recepteur gaba a a activite antagoniste nmda

Country Status (5)

Country Link
EP (1) EP1411939A2 (fr)
JP (1) JP2004537567A (fr)
AU (1) AU2002333262A1 (fr)
DE (1) DE10136842A1 (fr)
WO (1) WO2003011264A2 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085149A2 (fr) * 2000-05-05 2001-11-15 University Of Virginia Patent Foundation Composes derives de felbamate

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3609699A1 (de) * 1986-03-20 1987-09-24 Schering Ag 5- oder 6-substituierte-(beta)-carbolin-3-carbonsaeureester
EP0632008B1 (fr) * 1993-06-01 1998-02-04 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide pentanoique
ATE229954T1 (de) * 1998-06-12 2003-01-15 Sod Conseils Rech Applic Betacarbolinverbindungen
AU4363600A (en) * 1999-04-22 2000-11-10 Department Of The Army, U.S. Government Treatment of and/or prophylaxis against brain and spinal cord injury
CN1813723A (zh) * 2001-02-13 2006-08-09 曼·格哈德博士化学药物制造股份有限公司 β－咔啉在制备预防和/或治疗眼部神经变性疾病的药物组合物中的应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001085149A2 (fr) * 2000-05-05 2001-11-15 University Of Virginia Patent Foundation Composes derives de felbamate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BAHRAM ET AL, EUR.J.PHARM., vol. 415, no. 2-3, 2001, pages 135 - 140 *
See also references of WO03011264A3 *

Also Published As

Publication number Publication date
AU2002333262A1 (en) 2003-02-17
WO2003011264A3 (fr) 2003-12-04
WO2003011264A2 (fr) 2003-02-13
JP2004537567A (ja) 2004-12-16
DE10136842A1 (de) 2003-02-13

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