WO1993001195A1 - DERIVES DIBENZ[b,e]AZEPINES ET MEDICAMENTS LES CONTENANT - Google Patents

DERIVES DIBENZ[b,e]AZEPINES ET MEDICAMENTS LES CONTENANT Download PDF

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Publication number
WO1993001195A1
WO1993001195A1 PCT/EP1992/001465 EP9201465W WO9301195A1 WO 1993001195 A1 WO1993001195 A1 WO 1993001195A1 EP 9201465 W EP9201465 W EP 9201465W WO 9301195 A1 WO9301195 A1 WO 9301195A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
dibenz
compound
dihydro
group
Prior art date
Application number
PCT/EP1992/001465
Other languages
German (de)
English (en)
Inventor
Walter-Gunar Friebe
Herbert Leinert
Alfred Mertens
Wolfgang Schäfer
Harald Zilch
Original Assignee
Boehringer Mannheim Gmbh
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 Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Priority to CA002111710A priority Critical patent/CA2111710A1/fr
Priority to EP92913494A priority patent/EP0593536A1/fr
Priority to JP5501932A priority patent/JPH06508840A/ja
Publication of WO1993001195A1 publication Critical patent/WO1993001195A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to
  • Dibenz [b, e] azepine derivatives processes for their preparation and medicaments containing these compounds.
  • the invention relates to dibenz [b, e] azepine derivatives of the general formula I
  • A is a methylene, carbonyl, thiocarbonyl, carbimino, N-hydroxycarbimino or sulfonyl group
  • X is a valence bond or an oxygen or sulfur atom, a sulfinyl or sulfonyl group, a CH2S group or an NH group,
  • n is an integer from 1 to 3 and
  • R 1 to R 3 which can be the same or different independently of one another, are each a hydrogen atom, a straight-chain or branched, saturated or unsaturated aliphatic radical with 1-6 C-ato or C -C 6 -alkoxy, Cx-Cg-alkylmercapto, C 1 -Cs-alkylsulfinyl, Ci-Cg-alkylsulfonyl, A ino, C 1 -Cg-alkylamino, di- Ci-Cs-alkylamino, sulfonamido, C ⁇ -Cg alkoxycarbonyl, carboxy, halogen, hydroxy, nitro, cyano, azido, phenyl or benzyloxy and
  • R 4 is hydrogen or a straight-chain or branched, saturated or unsaturated aliphatic radical having 1-6 C atoms
  • the object of the present invention was to provide new dibenz [b, e] azepine derivatives. These compounds are used in particular for the production of medicaments.
  • the compounds of the present invention have valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections caused by DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr-Vl üs or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and the human immunodeficiency virus HIV-1 and -2.
  • DNA viruses such as e.g. the herpes simplex virus, the cytomegalovirus, papilloma viruses, the varicella zoster virus or Epstein-Barr-Vl üs or RNA viruses such as toga viruses or in particular retroviruses such as the oncoviruses HTLV-I and II, as well as the lentiviruses Visna and the human immunodefic
  • the compounds of the formula I appear to be particularly suitable for the treatment of the clinical manifestations of retroviral HIV infection in humans, such as persistent, generalized lymphadenopathy (PGL), the advanced stage of the AIDS-related complex (ARC) and the clinical picture of AIDS.
  • PDL generalized lymphadenopathy
  • ARC advanced stage of the AIDS-related complex
  • the compounds of general formula I according to the invention have a pronounced antiviral effect and are particularly suitable for the treatment of viral or retro-viral infections.
  • Viral infections in mammals, especially humans, are common.
  • Che otherapeutics which cause causally or symptomatically to interfere with the viral or retroviral-related illness with evidently substantial success.
  • AIDS Acquired Immune Deficiency Syndro
  • ARC AIDS-related complex
  • CMV cytomegalovirus
  • influenza influenza and other viral infections to heal or to chemically influence the symptoms favorably.
  • 3 '-azido-3' deoxythymidine (AZT) known as Zidovudine or Retrovir R
  • Zidovudine or Retrovir R 3 '-azido-3' deoxythymidine
  • AZT 3 '-azido-3' deoxythymidine
  • Zidovudine or Retrovir R 3 '-azido-3' deoxythymidine
  • Zidovudine or Retrovir R 3 '-azido-3' deoxythymidine
  • AZT 3 '-azido-3' deoxythymidine
  • Zidovudine or Retrovir R 3 '-azido-3' deoxythymidine
  • AZT 3 '-azido-3' deoxythy
  • the mentioned compounds are advantageously used prophylactically or therapeutically in the treatment of diseases in which a retroviral infection is of pathophysiological, symptomatic or clinical relevance.
  • the separation of the race ate into the enantiomers can be carried out analytically, semi-preparatively and preparatively chromatographically on suitable optically active phases with common eluents.
  • Suitable optically active phases are, for example, optically active polyacrylamides or polyethacrylamides, some also on silica gel (e.g. ChiraSpher (R) from Merck, Chiralpak (R) OT / OP from Baker), cellulose esters / carbamates (e.g. Chiracel (R ) OB / OY from Baker / Daicel), phases based on cyclodextrin or crown ether (for example Crownpak (R) from Daicel) or microcrystalline cellulose triacetate (Merck).
  • silica gel e.g. ChiraSpher (R) from Merck, Chiralpak (R) OT / OP from Baker
  • cellulose esters / carbamates e.g. Chiracel (R ) OB / OY from Baker / Daicel
  • phases based on cyclodextrin or crown ether for example Crownpak (R) from Daicel
  • Merck microcrystalline cellulose tria
  • A denotes in particular a carbonyl, methylene or thiocarbonyl group, the carbonyl group being preferred.
  • X represents in particular an oxygen or sulfur atom or a sulfinyl or sulfonyl group.
  • n is preferably the number 1 or 2.
  • R 1 to R 3 are hydrogen, C] _- C3-alkyl, C2-C4-alkenyl, C2-C -alkynyl, C ⁇ ⁇ C3-alkoxy, C_-C 3 -alkylmercapto, C ⁇ ⁇ C 3 -alkylamino , C ] _-C 3 alkoxycarbonyl, amino, halogen, hydroxy, cyano and azido preferred.
  • the ring system can be substituted in the 7-, 8-, 9- or 10-position by R 1 , the 8- and 9-position being preferred.
  • R 1 represents a halogen atom or a Ci-Cg-alkyl group.
  • R 2 and R 3 can be in the 1-, 2-, 3- or 4- position of the ring system, the 3- and 4-position are preferred.
  • R 2 represents a hydrogen atom and R 3 represents a hydrogen or halogen atom, a Ci-Cg-alkyl or Ci-Cg-alkoxy group.
  • R 3 is in particular a chlorine atom, or a methyl or methoxy group.
  • radical R 4 hydrogen, C 1 -C 3 -alkyl, C 2 -C 4 -alkenyl and C 2 -C 4 -alkynyl are preferred.
  • R 1 to R 3 independently of one another, hydrogen, methyl, ethyl, isopropyl, allyl, methoxy, ethoxy, methyl ercapto, ethyl mercapto, methylamino, methoxycarbonyl, ethoxycarbonyl, amino, azido, cyano, hydroxy and halogen, with chlorine and bromine are preferred for halogen.
  • R 4 hydrogen, methyl, ethyl, isopropyl and allyl are particularly preferred.
  • the aliphatic radical in the definition of R 1 -R 4 can be straight-chain or branched, saturated or unsaturated and contain a total of up to six carbon atoms.
  • Ci-Cg-alkyl groups are possible as saturated residues, such as. B. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.
  • Unsaturated radicals are in particular C2-Cg-alkenyl and C2-C 6 -alkynyl groups, which can also be branched, such as. As allyl, vinyl, 2-butenyl or propargyl.
  • the medicaments containing at least one compound of the formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form.
  • the usual forms of application come into question, such as tablets, capsules, dragees, syrups, solutions or suspensions.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, solubilizers and buffers.
  • additives are tartrate and Citrate buffer, ethanol, complexing agents such as ethylene diamine tetraacetic acid and its non-toxic salts, high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation.
  • Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules.
  • Solid carriers are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, higher molecular fatty acids, such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high-molecular polymers, such as polyethylene glycols, etc.
  • suitable for applications can, if desired, contain flavorings or sweeteners.
  • Pharmacologically acceptable salts are the acid addition salts with inorganic or organic acids, such as. B. halogen acids (HC1, HBr, etc.), sulfuric acid, phosphoric acid, tartaric acid, succinic acid, oxalic acid, acetic acid.
  • B. halogen acids HC1, HBr, etc.
  • sulfuric acid phosphoric acid
  • tartaric acid tartaric acid
  • succinic acid oxalic acid
  • acetic acid acetic acid
  • the dosage can depend on various factors, such as the mode of application, species, age or individual condition.
  • the compounds according to the invention are usually applied in amounts of 0.1-100 mg, preferably 0.2-80 mg per day and per kg of body weight. It is preferred to distribute the daily dose over 2-5 applications, 1-2 applications with an active ingredient content of 0.5-500 mg being administered for each application.
  • the tablets can also be delayed, which reduces the number of applications per day to 1-3.
  • the ⁇ content of active substance of the retarded tablets can be 2 - mg 1000th
  • the active ingredient can also be given by continuous infusion, the amounts of 5-1000 mg per day being normally sufficient.
  • n has the meaning given above and Y 'and Y ", which are the same or different, have the meaning of Y,
  • A, X, n and R 1 to R 4 have the meaning given above and Z represents a reactive radical, cyclizes or
  • Racemates can be separated into the antipodes, for example, by chromatography on suitable optically active phases such as cellulose triacetate.
  • reactive residues X, Y, Y 1 and Y ".
  • the groups HY, HY 1 and HY" are advantageously eliminated in a solvent in the presence of a base such as for example an alkali alcoholate in the corresponding alcohol, potassium carbonate in acetone or butanone, sodium hydride in toluene or dimethylformamide.
  • a base such as for example an alkali alcoholate in the corresponding alcohol, potassium carbonate in acetone or butanone, sodium hydride in toluene or dimethylformamide.
  • reactive radicals Z can also be lower alkoxy groups, optionally substituted phenoxy groups or the azide radical.
  • the reduction of a carbonyl group to a CH2 group is advantageously carried out using complex metal hydrides such as lithium aluminum hydride or sodium borohydride or using catalytically excited hydrogen.
  • the test system contains the purified RT from HIV-1, which was expressed by genetic engineering methods in E. coli, as well as the components of the initiation complex, such as the in vitro transcripts of the HIV-LTR with the neighboring primer binding site as a template and one for Primer binding site complementary 18mer oligonucleotide as a primer.
  • the [ 3 H] -thymidine-5'-triphosphate incorporation was measured by counting in the ß-counter.
  • the table below shows the ICsoth for the compounds examined. This value corresponds to the concentration of the test substance which causes an inhibition of the reverse transcriptase activity by 50%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention a pour objet des dérivés dibenz[b,e]azépines de formule (I), dans laquelle A désigne un groupe méthylène, carbonyle, thiocarbonyle, carbimino, N-hydroxycarbimino ou sulfonyle, X est une liaison de valence ou un atome d'oxygène ou un atome de soufre, un groupe sulfinyle ou sulfonyle, un groupe CH2S ou un groupe NH, n est un nombre entier de 1 à 3, et R1 à R4, qui peuvent être identiques ou différents indépendamment l'un de l'autre, représentent chacun un atome d'hydrogène, un reste aliphatique de 1 à 6 atomes de carbone, ainsi que leurs tautomères, énantiomères, diastéréomères et leurs sels physiologiquement compatibles. En outre, l'invention concerne des médicaments renfermant des composés de formule (I), notamment pour le traitement d'infections virales.
PCT/EP1992/001465 1991-07-05 1992-06-30 DERIVES DIBENZ[b,e]AZEPINES ET MEDICAMENTS LES CONTENANT WO1993001195A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002111710A CA2111710A1 (fr) 1991-07-05 1992-06-30 Derives de la dibenz[b,e]asepine et medicaments en renfermant
EP92913494A EP0593536A1 (fr) 1991-07-05 1992-06-30 DERIVES DIBENZ b,e]AZEPINES ET MEDICAMENTS LES CONTENANT
JP5501932A JPH06508840A (ja) 1991-07-05 1992-06-30 ジベンゾ〔ｂ，ｅ〕アゼピン誘導体およびそれを含む医薬組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4122240A DE4122240A1 (de) 1991-07-05 1991-07-05 Dibenz(b,e)azepinderivate und diese enthaltende arzneimittel
DEP4122240.7 1991-07-05

Publications (1)

Publication Number Publication Date
WO1993001195A1 true WO1993001195A1 (fr) 1993-01-21

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PCT/EP1992/001465 WO1993001195A1 (fr) 1991-07-05 1992-06-30 DERIVES DIBENZ[b,e]AZEPINES ET MEDICAMENTS LES CONTENANT

Country Status (6)

Country Link
EP (1) EP0593536A1 (fr)
JP (1) JPH06508840A (fr)
AU (1) AU2194292A (fr)
CA (1) CA2111710A1 (fr)
DE (1) DE4122240A1 (fr)
WO (1) WO1993001195A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419861B1 (fr) * 1989-08-29 1995-11-02 Boehringer Ingelheim Pharmaceuticals Inc. Utilisation de dibenzo[b,f][1,4]oxazépine (et thiazépine)-11(10H)-ones et -thiones pour l'obtention d'un médicament destiné à la prévention ou le traitement du SIDA

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0419861B1 (fr) * 1989-08-29 1995-11-02 Boehringer Ingelheim Pharmaceuticals Inc. Utilisation de dibenzo[b,f][1,4]oxazépine (et thiazépine)-11(10H)-ones et -thiones pour l'obtention d'un médicament destiné à la prévention ou le traitement du SIDA

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8841323B2 (en) 2006-03-15 2014-09-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US9266834B2 (en) 2006-03-15 2016-02-23 Janssen Pharmaceuticals, Inc. 1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
US9067891B2 (en) 2007-03-07 2015-06-30 Janssen Pharmaceuticals, Inc. 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mGluR2-receptors
US8906939B2 (en) 2007-03-07 2014-12-09 Janssen Pharmaceuticals, Inc. 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
US9132122B2 (en) 2007-09-14 2015-09-15 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US9114138B2 (en) 2007-09-14 2015-08-25 Janssen Pharmaceuticals, Inc. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′] bipyridinyl-2′-ones
US11071729B2 (en) 2007-09-14 2021-07-27 Addex Pharmaceuticals S.A. 1′,3′-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-ones
US8691849B2 (en) 2008-09-02 2014-04-08 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
US8691813B2 (en) 2008-11-28 2014-04-08 Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
US9085577B2 (en) 2009-05-12 2015-07-21 Janssen Pharmaceuticals, Inc. 7-aryl-1,2,4-triazolo[4,3-A]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9737533B2 (en) 2009-05-12 2017-08-22 Janssen Pharmaceuticals. Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8946205B2 (en) 2009-05-12 2015-02-03 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9226930B2 (en) 2009-05-12 2016-01-05 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US8937060B2 (en) 2009-05-12 2015-01-20 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of prevention of neurological and psychiatric disorders
US10071095B2 (en) 2009-05-12 2018-09-11 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo [4,3-A] pyridine derivatives and their use for the treatment of neurological and psychiatric disorders
US8993591B2 (en) 2010-11-08 2015-03-31 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a] pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
US9012448B2 (en) 2010-11-08 2015-04-21 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of MGLUR2 receptors
US10106542B2 (en) 2013-06-04 2018-10-23 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US10584129B2 (en) 2013-06-04 2020-03-10 Janssen Pharmaceuticals Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
US9708315B2 (en) 2013-09-06 2017-07-18 Janssen Pharmaceutica Nv 1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of MGLUR2 receptors
US10537573B2 (en) 2014-01-21 2020-01-21 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11103506B2 (en) 2014-01-21 2021-08-31 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US11369606B2 (en) 2014-01-21 2022-06-28 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
US12048696B2 (en) 2014-01-21 2024-07-30 Janssen Pharmaceutica Nv Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

Also Published As

Publication number Publication date
AU2194292A (en) 1993-02-11
CA2111710A1 (fr) 1993-01-21
JPH06508840A (ja) 1994-10-06
DE4122240A1 (de) 1993-01-07
EP0593536A1 (fr) 1994-04-27

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