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WO1995007887A1 - Derives d'indole utilises comme antagonistes d'acides amines excitateurs - Google Patents

Derives d'indole utilises comme antagonistes d'acides amines excitateurs Download PDF

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Publication number
WO1995007887A1
WO1995007887A1 PCT/EP1994/003101 EP9403101W WO9507887A1 WO 1995007887 A1 WO1995007887 A1 WO 1995007887A1 EP 9403101 W EP9403101 W EP 9403101W WO 9507887 A1 WO9507887 A1 WO 9507887A1
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Prior art keywords
group
compound
formula
compounds
protecting group
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Application number
PCT/EP1994/003101
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English (en)
Inventor
Alfredo Cugola
Original Assignee
Glaxo S.P.A.
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 Glaxo S.P.A. filed Critical Glaxo S.P.A.
Priority to AU76577/94A priority Critical patent/AU7657794A/en
Publication of WO1995007887A1 publication Critical patent/WO1995007887A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to novel indole derivatives to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • indole derivatives which are potent and specific antagonists of excitatory amino acids.
  • U.S. Patent No. 4960786 discloses that certain known 2-carboxylic indole derivatives are antagonists of excitatory amino acids.
  • EP-A 0396124 also teaches certain 2-carboxylic indole derivatives as being therapeutical ly effective in the treatment of CNS disorders resulting from neurotoxic damage or neurodegenerative diseases.
  • Further 3-substituted-2-carboxyindole derivatives which are useful in the treatment of neurodegenerative diseases including cerebrovasular disorders are disclosed in W092/16205.
  • R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, triflu omethyl, trifluoromethoxy, nitro, cyano, S ⁇ 2R2 ⁇ >r COR2 wherein R 2 represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2; A represents an optionally substituted ethenyl, in the trans configuaration; R., represents an optionally substituted fused bicyclic carbocyclic group.
  • trans configuration refers to the relative configuration of the 3-indolyl group and the group CONHR-, attached to the ethenyl group A.
  • salts of the compounds of formula (I) will be physiologically acceptable thereof.
  • Other salts may be useful in the preparation of the compounds of formula (I) or physiologically acceptable salts thereof. Therefore unless otherwise stated references to salts includes both physiologically acceptable salts and non-physiologically acceptable salts of compounds of formula (I).
  • Suitable physiologically acceptable salts of compounds of the invention include base addition salts and where appropriate acid addition salts.
  • Suitable physiologically acceptable base addition salts of compounds of formula (I) include alkali metal or alkaline metal salts such as sodium, potassium,, calcium, and magnesium, and ammonium salts, formed with amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).
  • the compounds of formula (I) and or salts thereof may form solvates (e.g. hydrates) and the invention includes ail such solvates.
  • the compound of formula (I) may be produced in vivo by metabolism of a suitable prodrug.
  • suitable prodrugs may be for example physiologically acceptable metabolically labile esters of compounds of the general formula (I). These may be formed by esterification, for example of any of the carboxylic acid groups in the parent compound of general formula (I) with where appropriate prior protection of any other reactive groups present in the molecule followed by deprotection if required.
  • metabolically labile esters include C ⁇ _ alkyl esters e.g. methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (e.g.
  • pivaloyloxymethyl 1-pivaloyloxyethyl, acetoxymethyl, 1- acetoxyethyl, 1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl, 1- benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1 -isopropoxycarbonyioxyethyl, cyclohexylcarbonyioxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyioxymethyl, 1 -cyclohexyloxycarbonyloxyethyl, 1 -(4- tetrahydropyranyloxy)carbonyloxyethyl or 1 -(4- tetrahydropyranyl)carbonyloxyethyl.
  • Preferred metabolically labile esters of compounds of formula (I) include C-
  • the group R may be at any of the four possible positions on the fused benzene ring and when m is 2 the two R groups may be the same or different.
  • alkyl as used herein as a group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atom examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom.
  • optionally substituted ethenyl means an ethenyl group optionally substituted by 1 or 2 alkyl groups e.g. methyl groups. Examples of such groups include ethenyl, 1-methylethenyl, 2-methylethenyl and/or 1 ,2-dimethylethenyl.
  • optionally fused bicylic carbocyclic group preferably refers to a 5,66,5 or 6,6 bicyclic carbocyclic ring system containing 9 or 10 carbon atoms which may be saturated or unsaturated and which may be substituted by 1 to 3 groups selected from halogen, alkyl, alkoxy, amino, alkylamine, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, S0 2 R 2 or COR 2 wherein R 2 represents hydroxy, methoxy, amino, alkylamino or dialkylamino.
  • R., groups include optionally substituted naphthyl, tetrahydronaphthyl, decahydronaphthyl, indenyl or indanyl.
  • SUBSTITUTE SHEET (RULE 26; A preferred class of compounds of formula (I) are those wherein m is 1 or 2 and within this class those wherein R is at the 4 and/or 6 position are particularly preferred.
  • the group R is preferably a chlorine atom.
  • A is a subsituted ethenyl group
  • the substituent is preferably in the ⁇ - position, with respect to the group CONHR-,. e.g 1 -methylethenyl .
  • Compounds of formula (I) wherein A is an unsubstituted ethenyl group or ⁇ - substituted ethenyl group e.g. 1 -methylethenyl represent a preferred class of compounds according to the invention, of which those wherein A is unsubstituted ethenyl group are particulalry preferred.
  • R. is naphthyl e.g. 1-naphthyl, or tetrahydronaphthyl, e.g. 1-1 ,2,3,4,-tetrahydronaphthyl or 1-5,6,7,8 tetrahydronaphthyl represents a further preferred class of compounds according to the invention.
  • R* ⁇ is naphthyl e.g. 1-naphthyl are particularly preferred.
  • a preferred group of compounds of formula (I) are those wherein m is 2, R is chlorine in the 4 and 6 positions and R-
  • a particularly preferred compound according to the invention is: (E)-3-[2'-(1"- naphthyl carbamoyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid and physiologically acceptable salts thereof e.g. sodium or potassium salts or metabolically labile esters thereof.
  • the compounds of formula (I) and or physiologically acceptable salts thereof are excitatory amino acid antagonists. More particularly they are potent antagonists at the strychnine insensitive glycine binding site associated with the NMDA receptor complex. As such they are potent antagonists of the NMDA receptor complex. Moreover the compounds of the invention exhibit an advantageous profile of activity including good bioavailibility. These compounds are therefore useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Thus the compounds are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasc- ⁇ am, hypoglycemia, anaesia, hypoxia, anoxia, perinatal asphyxia cardiac arrest.
  • the compounds are useful in the treatment of chronic neurodegenerative diseases such as; Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodengeration , (e.g. AIDS, encephalopaties), Down syndrome, epilepsy, schizophrenia, depression, anxiety, pain, neurogenic bladder, irritative bladder disturbances, drug dependency, including withdrawal symptoms from alcohol, cocaine, opiates, nicotine, benzodiazepine, and emesis.
  • chronic neurodegenerative diseases such as; Huntingdon's disease, Alzheimer's senile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodengeration , (e.g.
  • the potent and sei action of the compound of the invention at the strychnine- insensitive . ycine binding site present on the NMDA receptor complex may be readily determined using conventional test procedures.
  • the ability to bind at the strychnine insensitive glycine binding site was determined using the procedure of Kishimoto H et al. J Neurochem 1981 , 37
  • the invention therefore provides for the use of a compound of formula (I) and or physiologically acceptable salt or metabolically labile ester thereof for use in therapy and in particular use as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
  • the invention also provides for the use of a compound of formula (I) and/or a physiologically acceptable salt or metabolically labile ester thereof for the manufacture of a medicament for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
  • the invention also provides for a method for antagonising the effects of excitatory amino acids upon the NMDA receptor complex, comprising administering to a patient in need thereof an antagonistic amount of a compound of formula (I) and/or a physiologically acceptable salt or metabolically labile ester thereof.
  • a compound of the invention required for use in treatment will vary with the nature of the condition being treated the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 2 to 800mg per day, dependent upon the route of administration.
  • a daily dose will typically be in the range 20- 100mg preferably 60-80mg per day.
  • a daily dose will typically be within the range 200-800mg e.g. 400-600mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or metabilcially labile ester thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, inhalation or insufflation, implant, or rectal administration. Parenteral administration is preferred.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or ⁇ rdium starch glycollate, or wetting agents such as sodium lauryl sulphate.
  • the icDlets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p- hydroxybenz
  • compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • suppositories e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • composition according to the invention may be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser.
  • a suitable propellant such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser.
  • a suitable propellant such as dichlorod
  • the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable carrier such as lactose or starch.
  • a suitable carrier such as lactose or starch.
  • the powder composition may be presented in unit dosage form in for example capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
  • composition according to the invention may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions according to the invention may contain between 0.1 - 99% of the active ingredient, conveniently from 30- 95% for tablets and capsules and 3- 50% for liquid preparations.
  • R3 is a carboxyl protecting group and R 8 represents hydrogen or a nitrogen protecting group with the amine
  • have the meanings defined above, followed where necessary by subsequent removal of the carboxyl protecting group R3 and any nitrogen protecting group R 8 .
  • Suitable activated derivatives of the carboxyl group include the corresponding acyl halide, mixed anhydride, activated ester such as a thioester or the derivative formed between the carboxylic acid group and a coupling agent such as that used in peptide chemistry, for example carbonyl diimidazole or a diimidide such as dicyclohexylcarbodiimide.
  • the reaction is preferably carried out in an aprotic solvent such as a hydrocarbon, a halohydrocarbon, such as dichloromethane or an ether such as tetrahydrofuran.
  • an aprotic solvent such as a hydrocarbon, a halohydrocarbon, such as dichloromethane or an ether such as tetrahydrofuran.
  • Suitable carboxyl protecting groups R3 for use in these reactions include allyl, alkyl, trichloroalkyl, t alkylsilylalkyl or arylmethyl groups such as benzyl, nitrobenzyl or trityl.
  • Suitable nitrogen protecting groups R 8 include alkoxycarbonyl e.g. t- butoxycarbonyl, arylsulphonyl e.g. phenysulphonyl or 2- trimethylsilylethoxymethyl.
  • the activated derivatives of the carboxylic acid (II) may be prepared by conventional means.
  • a particularly suitable activated derivative for use in this reaction is thioester such as that derived from pyridine-2-thiol.
  • These esters may conveniently be prepared by treating the carboxylic acid (II) with 2,2'- dithiopyridine and triphenylphosphine in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran, a halohydrocarbon e.g. dichloromethane, an amide e.g. N,N-dimethylformamide or acetonitrile.
  • Compounds of formula (I) may also be prepared from compound (IV) in which R and m have the means given above, R3 is a carboxyl protecting group, R4 is a hydrogen atom or a C-
  • R 8 is a nitrogen protecting examples of suitable groups include alkoxycarbonyl e.g. t-butoxycarbonyl or 2-trimethylsiiylethoxymethyl or arylsulphonyl e.g. phenylsulphonyl.
  • Suitable carboxyl protecting groups include allyl, alkyl, trichloroalkyl, trialkylsilylalkyl or arylmethyl groups such as benzyl, nitrobenzyl or trityl.
  • reaction may be carried using a phosphorus ylide of formula (V)
  • R5 is an alkyl or phenyl group, and R-
  • reaction is carried out in aprotic solvent such as acetonitrile or an ether such as 1 ,4-dioxane and preferably with heating e.g. 40-120°.
  • aprotic solvent such as acetonitrile or an ether such as 1 ,4-dioxane
  • heating e.g. 40-120°.
  • the reaction is carried out using a phosphonate of formula (VI)
  • R5 represents hydrogen or C-
  • reaction is carried out in an aprotic solvent such as tetrahydrofuran and optionally with heating.
  • aprotic solvent such as tetrahydrofuran
  • the carboxyl protecting group R3 may be removed by conventional procedures known for removing such groups.
  • R3 is an alkyl group
  • this may be removed by hydrolysis using an alkali metal hydroxide e.g. lithium hydroxide or sodium hydroxide in a solvent such as an alkanol e.g. ethanol or isopropanol, followed where desired or necessary by that addition of a suitable acid e.g. hydrochloric acid to give the corresponding free carboxylic acid.
  • an alkali metal hydroxide e.g. lithium hydroxide or sodium hydroxide
  • a solvent such as an alkanol e.g. ethanol or isopropanol
  • the nitrogen protecting group may be removed by conventional procedures known for removing such groups, for example by acid or base hydrolysis.
  • R 8 is alkoxycarbonyl e.g. t-butoxycarbonyl may be removed by alkaline hydrolysis using for example lithium hydroxide in a suitable solvent such as tetrahydrofuran or an alkanol e.g. isopropanol.
  • Physiologically acceptable salts of compounds of formula (I) may be prepared by treating the corresponding acid with an appropriate base in a suitable solvent.
  • alkali and alkaline metal salts may be prepared from an alkali or alkaline metal hydroxide, or the corresponding carbonate or bicarbonate thereof.
  • alkali or alkaline metal salts may be prepared by direct hydrolysis of carboxyl protected derivative of compound of formula (I) with the appropriate alkali or alkaline metal hydroxide.
  • Metabolically labile esters of compounds of formula (I) may be prepared by esterification of the carboxylic acid group or a salt thereof or by trans esterfication using conventional procedures.
  • acyloxyalkyl esters may be prepared by reacting the free carboxylic acid or a salt thereof with the appropriate acyloxylalkyl halide in a suitable solvent such as dimethylformamide.
  • a suitable solvent such as dimethylformamide.
  • this reaction is preferably carried out in the presence of a quaternary ammonium halide such as tetrabutylammonium chloride or benzyltriethylammonium chloride.
  • Aminoalkyl esters may be prepared by transesterfication of a corresponding alkyl ester e.g. methyl or ethyl ester by reaction with the corresponding aminoalkanol at an elevated temperature e.g. 50-150°.
  • Compounds of formula (II) are either known compounds or may be prepared by analogous methods to those described for known compounds.
  • R, R 3 , R 8 and m are as defined above with N- methylformanilide and phosphorous oxychloride in a solvent such as 1 ,2-dichloroethane.
  • the indoles of formula (VII) are either known compounds or may be prepared by analogous methods to these described for the known compounds.
  • EA ethyl acetate
  • CH cyclohexane
  • DCM dichloromethane
  • Tic refers to thin layer chromatography on silica plates. Solution were dried over anhydrous sodium sulphate.
  • Example 2 (264 mg) was suspended in isopropyl alcohol (20 ml), sodium hydroxide (92.3 mg) was added and the mixture was heated to 60° for 6 hours. The solvent was removed and the residue was suspended in water and filtered to give the title compound (250 mg, ).
  • Magnesium Stearate 1.5mg The active ingredient is blended with the other excipients.
  • the blend can be used to fill gelatine capsules or compressed to form tablets using appropriate punches.
  • the tablets can be coated using conventional technqiues and coatings.
  • the active ingredient is blended with lactose, microcrystalline cellulose and part of the croscarmellose sodium.
  • the blend is granulated with povidone after dispersing in a suitable solvent (i.e. water).
  • a suitable solvent i.e. water
  • the granule, after drying and comminution is blended with the remaining excipients.
  • the blend can be compressed using appropriate punches and the tablets coated using conventional techniques and coatings.
  • the formulation may be packed in glass (ampoules) with a rubber stopper (vials, syringes) and a plastic/metal overseal (vials only).
  • the active ingredient is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer.
  • the powder blend is filled into a proper unit dose container as blister or capsule for use in a suitable inhalation or insufflation device.
  • Example 4 had an EDso of 0.4mg/kg when administered by i.v and 7.0mg/kg when given orally.
  • the compounds of the invention are essentially non toxic at therapeutical ly useful doses.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule générale (I), ou un de leurs sels ou de leurs esters métaboliquement labiles, ainsi que leurs procédés de préparation. Dans cette formule, R représente un groupe choisi parmi halogène, alkyle, alcoxy, amino, alkylamino, dialkylamino, hydroxy, trifluorométhyle, trifluorométhoxy, nitro, cyano, SO2R2 ou COR2 dans lequel R2 représente hydroxy, méthoxy, amino, alkylamino ou dialkylamino; m est zéro ou un nombre entier qui peut être 1 ou 2; A représente un éthényle éventuellement substitué, dans la configuration trans; R1 représente un groupe carbocyclique bicyclique fusionné éventuellement substitué, possédant une activité antagoniste de N-méthyle-D-aspartate (NMDA).
PCT/EP1994/003101 1993-09-17 1994-09-16 Derives d'indole utilises comme antagonistes d'acides amines excitateurs WO1995007887A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU76577/94A AU7657794A (en) 1993-09-17 1994-09-16 Indole derivatives as antagonists of excitatory amino acids

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9319243.3 1993-09-17
GB939319243A GB9319243D0 (en) 1993-09-17 1993-09-17 Heterocyclic compounds

Publications (1)

Publication Number Publication Date
WO1995007887A1 true WO1995007887A1 (fr) 1995-03-23

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GB (1) GB9319243D0 (fr)
WO (1) WO1995007887A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014427A1 (fr) * 1996-09-30 1998-04-09 Hoechst Marion Roussel, Inc. Antagonistes du nmda (n-methyl-d-aspartate)
US7579347B2 (en) * 2001-12-10 2009-08-25 Amgen Inc. Vanilloid receptor ligands and their use in treatments
WO2014011590A2 (fr) 2012-07-12 2014-01-16 Javitt Daniel C Composition et méthode pour le traitement de la dépression et de la psychose chez l'homme
WO2018229744A1 (fr) 2017-06-12 2018-12-20 Glytech Llc. Traitement de la dépression avec des antagonistes du nmda et de la d2/5ht2a ou des antagonistes de la 5ht2a sélectifs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992016205A2 (fr) * 1991-03-18 1992-10-01 Warner-Lambert Company Nouveaux derives de 2-carboxyindoles ayant une action pharmaceutique
EP0568136A1 (fr) * 1992-04-16 1993-11-03 GLAXO S.p.A. Dérivés de l'acide indole-2-carboxylique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992016205A2 (fr) * 1991-03-18 1992-10-01 Warner-Lambert Company Nouveaux derives de 2-carboxyindoles ayant une action pharmaceutique
EP0568136A1 (fr) * 1992-04-16 1993-11-03 GLAXO S.p.A. Dérivés de l'acide indole-2-carboxylique

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998014427A1 (fr) * 1996-09-30 1998-04-09 Hoechst Marion Roussel, Inc. Antagonistes du nmda (n-methyl-d-aspartate)
US7579347B2 (en) * 2001-12-10 2009-08-25 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7582657B2 (en) 2001-12-10 2009-09-01 Amgen Inc. Vanilloid receptor ligands and their use in treatments
WO2014011590A2 (fr) 2012-07-12 2014-01-16 Javitt Daniel C Composition et méthode pour le traitement de la dépression et de la psychose chez l'homme
EP3263108A1 (fr) 2012-07-12 2018-01-03 Glytech LLC Composition et procédé de traitement de la dépression et de psychoses chez les humains
WO2018229744A1 (fr) 2017-06-12 2018-12-20 Glytech Llc. Traitement de la dépression avec des antagonistes du nmda et de la d2/5ht2a ou des antagonistes de la 5ht2a sélectifs

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AU7657794A (en) 1995-04-03

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