WO1996004900A1 - Composition and method for protection against drug dependency - Google Patents
Composition and method for protection against drug dependency Download PDFInfo
- Publication number
- WO1996004900A1 WO1996004900A1 PCT/US1995/010317 US9510317W WO9604900A1 WO 1996004900 A1 WO1996004900 A1 WO 1996004900A1 US 9510317 W US9510317 W US 9510317W WO 9604900 A1 WO9604900 A1 WO 9604900A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- agonist
- hexane
- acts
- dependence
- pharmaceutical
- Prior art date
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Classifications
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- C07—ORGANIC CHEMISTRY
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
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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
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/38—Unsaturated compounds containing keto groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/18—All rings being cycloaliphatic the ring system containing six carbon atoms
Definitions
- the present invention relates to treatments for substance dependence.
- Substance dependence is a major problem, both for individuals suffering from it, and for society at large.
- the condition is characterized by a need for repeated, and often increasing doses of a substance.
- the condition is associated, with some substances, with increased levels of crime, including theft and crimes of violence, as sufferers seek to obtain supplies of the substance.
- the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, causing excitation of this receiving neuron.
- L-Glutamate which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA) .
- EAA excitatory amino acid
- the receptors that respond to glutamate are called excitatory amino acid receptors
- Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed “ionotropic. " This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists iV-methyl-D-aspartate (NMDA) , ⁇ -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) , and kainic acid (KA) .
- the second general type of receptor is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor.
- This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in cAMP formation, and changes in into channel function.
- Schoepp and Conn Trends in Pharmacol . Sci . , 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life.
- Schoepp, Bockaert, and Sladeczek Trends in Pharmacol . Sci . , 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990) .
- the metabotropic glutamate receptors are a highly heterogeneous family of glutamate receptors that are linked to multiple second-messenger pathways. Generally, these receptors function to modulate the presynaptic release of glutamate, and the postsynaptic sensitivity of the neuronal cell to glutamate excitation.
- the metabotropic glutamate receptors (mGluR) have been pharmacologically divided into two subtypes. One group of receptors is positively coupled to phospholipase C, which causes hydrolysis of cellular phosphoinositides (PI) . This first group are termed Pl ⁇ unked metabotropic glutamate receptors.
- the second group of receptors is negatively coupled to adenyl cyclase, which prevents the forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) .
- cAMP cyclic adenosine monophosphate
- Schoepp and Conn Trends Pharmacol . Sci . , 14, 13 (1993).
- Receptors within this second group are termed cAMP-linked metabotropic glutamate receptors.
- Nicotine dependence which is induced through smoking, affects hundreds of millions of people around the world. For many, it leads to illness and premature death. Stopping smoking (smoking cessation) may evoke a range of symptoms in dependent individuals, including craving, depression, anxiety, difficulty in concentrating and weight gain.
- a variety of treatments are available for smoking cessation, including counseling, hypnosis, aversion conditioning, relaxation training, acupuncture, and nicotine replacement therapy.
- smoking cessation including counseling, hypnosis, aversion conditioning, relaxation training, acupuncture, and nicotine replacement therapy.
- Benzodiazepine dependence arises through the use of the benzodiazepines as pharmaceuticals to treat other disorders.
- the dependence- inducing properties of the benzodiazepines limits their therapeutic use. Withdrawal produces symptoms such as anxiety, irritability, insomnia and impaired concentration.
- Benzodiazepine withdrawal Animal models for the treatment of nicotine and diazepam withdrawal have been described in Helton sL al. ; Psychopharmacology (1993), 113:205-210 and Rasmussen eji al. : Neuroreport 5, 154-156 (1993).
- the present invention provides the use of an agonist which acts at negatively coupled cAMP-linked metabotropic glutamate receptors for protecting a warm blooded mammal from dependence on a substance. It has been found that a novel compound which is an agonist that acts selectively at negatively coupled cAMP- linked metabotropic glutamate receptors, (+)-2- aminobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid is effective in the rat startle models for nicotine and diazepam withdrawal.
- any compound which acts as an agonist at negatively coupled cAMP-linked metabotropic glutamate receptors will be useful for the treatment of the withdrawal or cessation of these and other dependence- producing substances.
- an agonist which acts at negatively coupled cAMP-linked metabotropic glutamate receptors will also be useful for the treatment of substance dependence and tolerance, and indeed generally to protect a warm blooded mammal from dependence on a dependence-producing substance.
- the dependence-producing substance may be, for example, an opiate, benzodiazepine, nicotine, ***e or ethanol.
- the present invention provides the use of an agonist which acts at negatively coupled cAMP-linked metabotropic glutamate receptors for the treatment of drug tolerance, withdrawal or cessation.
- the present invention provides the use of an agonist which acts at negatively coupled cAMP-linked metabotropic glutamate receptors for the treatment of smoking cessation.
- the particular dose of agonist administered will of course be determined by the particular circumstances surrounding the case, including the activity of the particular agonist administered, the route of administration, the particular condition being treated, and similar considerations.
- the agonist can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the agonist may be administered by continuous infusion.
- a typical daily dose will contain from about 0.001 mg/kg to about 100 mg/kg of the agonist.
- daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 20 mg/kg.
- the present invention provides the use of an agonist as defined hereinabove for use in a method of protecting a warm ⁇ blooded mammal from dependence on a dependence-producing pharmaceutical, for example, a benzodiazepine such as diazepam.
- the agonist may be administered before said pharmaceutical is first administered, after said pharmaceutical has been administered or after said pharmaceutical has been withdrawn, or it may be co-administered with said pharmaceutical.
- Agonists which act at negatively coupled cAMP- linked metabotropic glutamate receptors may be identified using the following experiment. Firstly, the affinity of a test compound for metabotropic glutamate receptors may be demonstrated by the selective displacement of ( 1S. 3R)-1-aminocyclopentane-l,3- dicarboxylic acid-sensitive [ 3 H]glutamate binding to rat brain cell membranes. The binding of [ 3 H]glutamate ([ 3 H]Glu) is conducted with crude membranes of rat forebrain as described by Schoepp and True. Schoepp and True, Neuroscience Lett . , 145, 100-104 (1992); Wright, McDonald, and Schoepp, J. Neurochem .
- the affinity of a test compound for the receptor may be expressed as the concentration of the test compound that inhibits 50% binding (IC50), or the percent displacement of [ 3 H]Glu at a 10 ⁇ M or 100
- IC50 concentration of the test compound that inhibits 50% binding
- test compounds are tested for their ability to decrease forskolin-stimulated cAMP formation in the rat hippocampus and the rat cerebral cortex, using the procedures described in Schoepp and Johnson. Schoepp and Johnson, Neurochem. Int . , 22, 277-283 (1993). In this test, (+)-2-aminobicyclo[3.1.0]hexane-2,6- dicarboxylic acid was found to give the result shown in Table II below.
- Rat cerebral cortex .055 ⁇ .017 Rat hippocampus .036 ⁇ .015 The ability of negatively coupled cAMP-linked metabotropic receptor agonists to protect a warm blooded mammal from the effects of drug withdrawal or cessation may be demonstrated using an auditory startle model.
- animals are dosed with a drug (nicotine or diazepam) , then dosing is discontinued. This cessation of drug dosing elicits an increased startle response to auditory stimuli. Test compounds are then administered to animals to determine whether they are capable of attenuating the increased startle response.
- Rats Long Evans rats (200-400 g; Harlan Sprague Dawley, Columbus, IN) were individually housed in a controlled environment on a 12 hour light-dark cycle and given free access to food (Purina Rodent Chow) and water. Rats were anesthetized with isoflurane and Alzet osmotic pumps (Alza Corporation) were implanted subcutaneously.
- Test compound was dissolved in a vehicle of purified water and neutralized with 5N NaOH to a PH of 7-8 when applicable.
- Diazepam (Sigma Chemical Company, St. Louis, MO) was suspended in a vehicle consisting of 40% PEG 300, 10% EtOH, 2% benzyl alcohol, 1% Tween 80, and 47% purified water.
- Nicotine Research Biochemicals Inc., Natick, MA
- Nicotine withdrawal Pumps were filled to deliver nicotine (6mg/kg/day s.c), diazepam (lOmg/kg/day s.c), test compound (0,l,3,10mg/kg s.c.) or vehicle.
- Auditory startle responding was significantly increased through the first three days following cessation of chronic nicotine exposure when compared to control rats receiving water. Rats given a replacement dose of nicotine at doses of 0.03 mg/kg, i.p. or higher did not display the same heightened startle response seen for animals with no nicotine replacement. Pretreatment with (+)-2-aminobicyclo[3.1.0]hexane-2,6- dicarboxylic acid produced a dose-dependent blockade of the withdrawal-induced increase in startle responding as well. A significant attenuation of the heightened startle was apparent at 3mg/kg, p.o. dose of the compound when compared to nicotine controls mg/kg i.p. ) .
- Diazepam ithdrawal Auditory startle responding was significantly increased through the first four days following cessation of chronic diazepam exposure when compared to control rats receiving vehicle. Replacement doses of 3 and 10 mg/kg, i.p. diazepam did not block the increased startle responding and in some instances further increased reactivity indicating tolerance. Rats which received 30 mg/kg, i.p. diazepam replacement daily 60 minutes before evaluation of startle responding, did not show increased reactivity following diazepam cessation on days 1 through 4 when compared to the diazepam control.
- (+)-2-Aminobicyclo[3.1.0]hexane-2, 6-dicarboxylic acid may be prepared by reacting carbethoxymethyl dimethylsulfonium bromide with 2-cyclopenten-l-one in the presence of a base, such as 1,8- diazabicyclo[5. .0]undec-7-ene to afford ethyl 2- oxobicyclo[3.1.0]hexane-6-carboxylate.
- This ester may then be reacted with an aqueous solution of potassium cyanide or sodium cyanide and ammonium carbonate to produce an intermediate hydantoin, (the Bucherer-Bergs reaction) , which is then hydrolysed using sodium hydroxide, to afford a diastereomeric mixture of diethyl 2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylates.
- the desired diastereomer may be obtained by crystallization with oxalic acid.
- This diastereomer may then be resolved by forming a crystalline salt with (+)-di-p- toluoyl-D-tartaric acid and recovering (-) -diethyl 2- aminobicyclo[3.1.0]hexane-2, 6-dicarboxylate. Hydrolysis of this diester using aqueous sodium hydroxide gives (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid. Alternatively, the ethyl 2-oxobicyclo[3.1.0]hexane-6- carboxylic acid may be hydrolysed using sodium hydroxide to give 2-oxobicyclo[3.1.0]hexane-6-carboxylic acid.
- This acid may then be resolved by forming a crystalline salt with (S) -1-phenylethylamine and recovering (+)-2- oxobicyclo[3.1.0]hexane-6-carboxylic acid.
- This acid may then be converted into (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid by reaction with an aqueous solution of potassium cyanide or sodium cyanide and ammonium carbonate to produce an intermediate hydantoin (the Bucherer-Bergs reaction) followed by hydrolysis of the hydantoin using sodium hydroxide.
- This procedure may also be modified by performing the resolution step on the hydantoin rather than on the 2- oxobicyclo[3.1.0]hexane-6-carboxylic acid.
- (R) -1-phenylethylamine has been found to be a suitable resolving agent.
- the agonists are preferably formulated prior to administration in combination with one or more pharmaceutically-acceptable carriers, diluents, or excipients.
- the pharmaceutical formulations are prepared by known procedures using well-known and readily available ingredients.
- the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container.
- the carrier serves as a diluent, it may be a solid, semi- solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, dermal patch, subcutaneous implant, and sterile packaged powders.
- Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, stearic acid, and mineral oil.
- the formulations can additionally include lubricating agents, wetting agents (surfactants) , emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
- Compositions may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
- compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg, more preferably about 5 mg to about 200 mg of the active ingredient.
- unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient.
- suitable pharmaceutical carrier diluent, or excipient.
- Hard gelatin capsules are prepared using the following ingredients:
- the above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
- a tablet is prepared using the ingredients below:
- An aerosol solution is prepared containing the following components:
- the active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to -30°C and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container.
- Tablets each containing 60 mg of active ingredient are made as follows:
- Talc m ⁇ Total 150 mg The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
- the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
- the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
- the sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
- Capsules each containing 80 mg of active ingredient are made as follows:
- the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities.
- Suppositories each containing 225 mg of active ingredient may be made as follows:
- the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
- the benzoic acid solution, flavor and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
- An intravenous formulation may be prepared as follows
- Proton nuclear magnetic resonance ( ⁇ H NMR) spectra were obtained on a GE QE-300 spectrometer at 300.15 MHz, a Bruker AM-500 spectrometer at 500 MHz, or a Bruker AC-200P spectrometer at 200 MHz.
- Free atom bombardment mass spectroscopy (FABMS) was performed on a VG ZAB-2SE instrument.
- Field desorption mass spectroscopy (FDMS) was performed using either a VG 70SE or a Varian MAT 731 instrument.
- Optical rotations were measured with a Perkin-Elmer 241 polarimeter.
- Chromatographic separation on a Waters Prep 500 LC was generally carried out using a linear gradient of the solvents indicated in the text.
- TLC thin layer chromatography
- Thin layer chromatography was performed using E. Merck Kieselgel 60 F254 plates, 5 cm X 10 cm, 0.25 mm thickness. Spots were detected using a combination of UV and chemical detection (plates dipped in a eerie ammonium molybdate solution [75 g of ammonium molybdate and 4 g of cerium (IV) sulfate in 500 mL of 10% aqueous sulfuric acid] and then heated on a hot plate) . Flash chromatography was performed as described by Still, et al . Still, Kahn, and Mitra, J. Org. Chem. , 43, 2923 (1978) .
- Elemental analyses for carbon, hydrogen, and nitrogen were determined on a Control Equipment Corporation 440 Elemental Analyzer, or were performed by the Universidad Complutense Analytical Centre (Facultad de Farmacia, Madrid, Spain) . Melting points were determined in open glass capillaries on a Gallenkamp hot air bath melting point apparatus or a B ⁇ chi melting point apparatus, and are uncorrected.
- a solution of the compound prepared as described in Example 1 (22.81g) in ethanol (200mL) was treated with an aqueous solution of potassium cyanide (9.71g) and ammonium carbonate (21.2g) in water (200mL) .
- the resulting mixture was heated to about 50 * C.
- the reaction mixture was allowed to cool to room temperature and treated with sodium hydroxide (16.2g).
- the resulting mixture was heated to reflux.
- the reaction mixture was allowed to cool to room temperature, then cooled to O'C.
- the pH of the cold mixture was adjusted to pH 1 by the addition of concentrated hydrochloric acid. This mixture was concentrated to dryness in vacuo .
- the enantiomeric excess was determined by conversion to the methyl ester with diazomethane followed by chiral HPLC on a Chiralpak AS column at 40°C eluted with 10% isopropanol/90% hexane at 1 ml/min with detection at 210 nm.
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- Animal Behavior & Ethology (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP50756396A JP3618104B2 (en) | 1994-08-12 | 1995-08-14 | Compositions and methods for protection against drug addiction |
AU33250/95A AU3325095A (en) | 1994-08-12 | 1995-08-14 | Composition and method for protection against drug dependency |
EP95929519A EP0776200A4 (en) | 1994-08-12 | 1995-08-14 | Composition and method for protection against drug dependency |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28995794A | 1994-08-12 | 1994-08-12 | |
US08/289,957 | 1994-08-12 | ||
US33734994A | 1994-11-10 | 1994-11-10 | |
US08/337,349 | 1994-11-10 | ||
US08/496,642 | 1995-06-29 | ||
US08/496,642 US5661184A (en) | 1994-08-12 | 1995-06-29 | Psychiatric agents |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996004900A1 true WO1996004900A1 (en) | 1996-02-22 |
Family
ID=27403948
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/010317 WO1996004900A1 (en) | 1994-08-12 | 1995-08-14 | Composition and method for protection against drug dependency |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0776200A4 (en) |
JP (1) | JP3618104B2 (en) |
AU (1) | AU3325095A (en) |
CA (1) | CA2195779A1 (en) |
WO (1) | WO1996004900A1 (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0774455A1 (en) * | 1995-11-16 | 1997-05-21 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
EP0774454A1 (en) * | 1995-11-16 | 1997-05-21 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
EP0774461A1 (en) * | 1995-11-16 | 1997-05-21 | Eli Lilly And Company | Excitatory amino acid derivatives |
US5688826A (en) * | 1995-11-16 | 1997-11-18 | Eli Lilly And Company | Excitatory amino acid derivatives |
EP0878463A1 (en) * | 1997-05-14 | 1998-11-18 | Eli Lilly And Company | Excitatory amino acid receptor modulators |
US5912248A (en) * | 1995-11-16 | 1999-06-15 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
US5916920A (en) * | 1995-11-16 | 1999-06-29 | Eli Lilly And Company | 3-substituted Bicyclo 3.1.0!hexane-6-carboxylic acids |
US6407284B1 (en) | 1999-04-16 | 2002-06-18 | Sumitomo Chemical Company, Limited | Method of resolving 2-oxobicyclo [3.1.0] hexane-6-carboxylic acid derivatives |
US11878001B2 (en) | 2017-07-31 | 2024-01-23 | Novartis Ag | Use of mavoglurant in the reduction of ***e use or in preventing relapse into ***e use |
-
1995
- 1995-08-14 EP EP95929519A patent/EP0776200A4/en not_active Withdrawn
- 1995-08-14 JP JP50756396A patent/JP3618104B2/en not_active Expired - Fee Related
- 1995-08-14 CA CA002195779A patent/CA2195779A1/en not_active Abandoned
- 1995-08-14 WO PCT/US1995/010317 patent/WO1996004900A1/en not_active Application Discontinuation
- 1995-08-14 AU AU33250/95A patent/AU3325095A/en not_active Abandoned
Non-Patent Citations (4)
Title |
---|
BRITISH JOURNAL OF PHARMACOLOGY, Volume 109, issued 1993, ISHIDA et al., "A Novel Metabotropic Glutamate Receptor Agonist: Marked Depression of Monosynaptic Excitation in the Newborn Rat Isolated Spinal Cord", pages 1169-1177. * |
NEUROSCIENCE LETTERS, Volume 162, issued 1993, TIZANNO et al., "Intracerebral 1S,3R-1-Aminocyclopentane-1,3-Dicarboxylic Acid (1S,3R-ACPD) Produces Limbic Seizures That are Not Blocked by Ionotropic Glutamate Receptor Antagonists", pages 12-16. * |
See also references of EP0776200A4 * |
XIITH INTERNATIONAL CONGRESS OF PHARMACOLOGY ABSTRACTS, Volume 72, Supplement 1, issued 24 July 1994, M.E. FUNDYTUS et al., "Acute ICV Injection of the Metabotropic Glutamate Receptor Agonist Trans-ACPD Attenuates Morphine Withdrawal in Rats", page 349, Abstract No. P13.5.18. * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0774455A1 (en) * | 1995-11-16 | 1997-05-21 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
EP0774454A1 (en) * | 1995-11-16 | 1997-05-21 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
EP0774461A1 (en) * | 1995-11-16 | 1997-05-21 | Eli Lilly And Company | Excitatory amino acid derivatives |
US5688826A (en) * | 1995-11-16 | 1997-11-18 | Eli Lilly And Company | Excitatory amino acid derivatives |
US5912248A (en) * | 1995-11-16 | 1999-06-15 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
US5916920A (en) * | 1995-11-16 | 1999-06-29 | Eli Lilly And Company | 3-substituted Bicyclo 3.1.0!hexane-6-carboxylic acids |
EP0878463A1 (en) * | 1997-05-14 | 1998-11-18 | Eli Lilly And Company | Excitatory amino acid receptor modulators |
US5958960A (en) * | 1997-05-14 | 1999-09-28 | Eli Lilly And Company | Excitatory amino acid receptor modulators |
US6160009A (en) * | 1997-05-14 | 2000-12-12 | Eli Lilly And Company | Excitatory amino acid receptor modulators |
US6268507B1 (en) | 1997-05-14 | 2001-07-31 | Eli Lilly And Company | Hydantoin derivatives |
US6407284B1 (en) | 1999-04-16 | 2002-06-18 | Sumitomo Chemical Company, Limited | Method of resolving 2-oxobicyclo [3.1.0] hexane-6-carboxylic acid derivatives |
US11878001B2 (en) | 2017-07-31 | 2024-01-23 | Novartis Ag | Use of mavoglurant in the reduction of ***e use or in preventing relapse into ***e use |
Also Published As
Publication number | Publication date |
---|---|
AU3325095A (en) | 1996-03-07 |
EP0776200A1 (en) | 1997-06-04 |
EP0776200A4 (en) | 2001-01-17 |
JPH10504038A (en) | 1998-04-14 |
CA2195779A1 (en) | 1996-02-22 |
JP3618104B2 (en) | 2005-02-09 |
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