WO2003024964A1 - Analogues de pyridine-2-one tricycliques servant de ligands de recepteur gaba-a - Google Patents

Analogues de pyridine-2-one tricycliques servant de ligands de recepteur gaba-a Download PDF

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WO2003024964A1
WO2003024964A1 PCT/GB2002/003693 GB0203693W WO03024964A1 WO 2003024964 A1 WO2003024964 A1 WO 2003024964A1 GB 0203693 W GB0203693 W GB 0203693W WO 03024964 A1 WO03024964 A1 WO 03024964A1
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compounds
compound according
mmol
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alkyl
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PCT/GB2002/003693
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Sylvie Bourrain
James Michael Crawforth
Karl Richard Gibson
Simon Charles Goodacre
David James Hallett
Richard Alexander Jelley
Michael Rowley
Francine Sternfeld
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Merck Sharp & Dohme Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • A61P25/22—Anxiolytics

Definitions

  • the present invention relates to a class of fused tricyclic compounds based on a substituted pyridone ring, and to their use in therapy. More particularly, this invention is concerned with, tricyclic pyridin-2-one analogues which are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.
  • GABA gamma- aminobutyric acid
  • GABAA receptors which are members of the ligand-gated ion channel superfamily
  • GABAB receptors which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six ⁇ subunits, four ⁇ subunits, three ⁇ subunits, one ⁇ subunit, one ⁇ subunit and two p subunits.
  • the compounds of the present invention being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system.
  • disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; speech disorders, including stuttering; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work.
  • disorders for which selective ligands for GABAA receptors may be of benefit include pain and nociception; e esis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as motion sickness, and post-operative nausea and vomiting; eating disorders, including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; hearing disorders, including tinnitus and age- related hearing impairment; urinary incontinenence; and the effects of substance abuse and dependency, including alcohol withdrawal.
  • Selective ligands for GABAA receptors may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.
  • the compounds in accordance with the present invention may be useful as radioligands in assays for detecting compounds capable of binding to the human GABAA receptor.
  • EP-A-0183994 relates to bi- and tricyclic pyridone derivatives which are stated to have muscle relaxant, sedative-hypnotic, anxiolytic and/or auticonvulsant activity. There is no disclosure nor any suggestion therein, however, of compounds possessing a pyridinyl moiety attached via its 4- position to the 6-position of the pyridin-2-one ring.
  • WO 98/50384 relates to tricyclic pyridin-2-one compounds which are structurally similar to the compounds of the present invention. That publication relates only to specific substituent groups and we have found surprisingly that alternative substitution results in active compounds.
  • the present invention provides a class of tricyclic pyridin-2-one analogues which possess desirable binding properties at various GABAA receptor subtypes.
  • the compounds in accordance with the present invention have good affinity as ligands for the ⁇ 2 and/or ⁇ 3 subunit of the human GABAA receptor.
  • the compounds of this invention may interact more favourably with the ⁇ 2 and/or ⁇ 3 subunit than with the ⁇ l subunit. Desirably, the compounds of the invention will exhibit functional selectivity in terms of a selective efficacy for the ⁇ 2 and/or ⁇ 3 subunit relative to the ⁇ l subunit.
  • the compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the ⁇ 2 and/or ⁇ 3 subunit, as measured in the assay described hereinbelow, of 100 nM or less, typically of 50 nM or less, and ideally of 10 nM or less.
  • the compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the ⁇ 2 and/or ⁇ 3 subunit relative to the ⁇ l subunit.
  • the present invention provides a compound of formula (I), or a salt or iV-oxide thereof:
  • E represents -(CH2)n-; n is 1, 2 or 3; one of X, Y and Z represents -S- and the other two of X, Y and Z are independently selected from -N- and -CH-;
  • R 1 represents hydrogen, halogen, Ci- ⁇ alkyl, halo(C ⁇ -6)alkyl or C 3- cycloalkyl; and R 2 represents aryl or heteroaryl, either of which groups may be optionally substituted; provided that, when the X/Y/Z-containing ring is thiazolyl, then R 1 is not methyl.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • alkali metal salts e.g. sodium or potassium salts alkaline earth metal salts, e.g. calcium or magnesium salts
  • suitable organic ligands e.g. quaternary ammonium salts.
  • Suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups are methyl, ethyl, n.-propyl, isopropyl, isobutyl, teri-butyl and 2,2-dimethylpropyl. Derived expressions such as "halo(C ⁇ -6)alky ⁇ ", “Ci- ⁇ alkoxy” and "Ci- ⁇ alkylthio" are to be construed accordingly. Particular C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Particular aryl groups include phenyl and naphthyl.
  • Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolin l, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
  • halogen as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine.
  • compounds according to the invention may accordingly exist as enantiomers.
  • compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
  • Preferred compounds of formula (I) are those in which n represents 2 or 3, most preferred being those compounds of formula (I) in which n is 3.
  • X represents -S- and Y and Z are independently selected from -N- and -CH-.
  • X represents -S-
  • Y represents -CH-
  • Z represents -N-, in which case R 1 is other than methyl.
  • X represents -S-, and Y and Z both represent -CH-. In a further embodiment, X represents -S-, and Y and Z both represent -N-.
  • R 1 represents hydrogen, halogen, C2-6 alkyl, halo(C ⁇ -6)alkyl or C3-7 cycloalkyl.
  • R 1 represents hydrogen, halogen, halo(C ⁇ -6)alkyl or C3-7 cycloalkyl.
  • Typical values of R 1 include hydrogen, chloro, methyl (except when the X/Y/Z-containing ring is thiazolyl), fluoromethyl and cyclopropyl.
  • Suitable values for the substituent R 2 include phenyl, pyridinyl, benzofuryl and thienyl, any of which groups may be optionally substituted by one or more substituents.
  • R 2 include phenyl and pyridinyl, either of which groups may be optionally substituted by one or more substituents.
  • the group R 2 may be unsubstituted, or substituted by one or two substituents.
  • substituents on the group R 2 include halogen, hydroxy(C ⁇ -6) alkyl, d-e alkoxy, C1-3 alkylenedioxy, formyl and Ci-6 alkylthio.
  • R 2 Particular values of R 2 include phenyl, fluorophenyl, chlorophenyl, dichlorophenyl, hydroxymethyl-phenyl, methoxyphenyl, dimethoxyphenyl, (fluoro)(methoxy)phenyl, (chloro) (fluoro)phenyl, (chloro) (methoxy)phenyl, methylenedioxyphenyl, formylphenyl, methylthio-phenyl, pyridinyl, chloropyridinyl, benzofuryl and thienyl.
  • R 2 include phenyl and pyridinyl.
  • a particular sub-class of compounds according to the invention is represented by the compounds of formula (LA), and pharmaceutically acceptable salts and iV-oxides thereof:
  • Y 1 and Z 1 are independently selected from -N- and -CH-;
  • R 11 represents hydrogen, halogen, C 2 -e alkyl, halo (C ⁇ -6 ) alkyl or C 3-7 cycloalkyl;
  • W represents -N- or -CH-
  • R 3 represents hydrogen, halogen or Ci-e alkoxy.
  • Y 1 is -CH- and Z 1 is -N-. In another embodiment, Y 1 and Z 1 are both -CH-
  • Y 1 and Z 1 are both -N-
  • R 11 represents hydrogen, halogen, halo(C ⁇ -6)alkyl or C 3 - 7 cycloalkyl.
  • Suitable values of R 11 include hydrogen, chloro, fluoromethyl and cyclopropyl.
  • W is -N-.
  • W is -CH-.
  • R 3 examples include hydrogen, fluoro, chloro and methoxy, especially hydrogen.
  • Another sub-class of compounds according to the invention is represented by the compounds of formula (IB), and pharmaceutically acceptable salts and TY-oxides thereof: wherein
  • Y 2 and Z 2 are both -CH-, or Y 2 and Z 2 are both -N-; and R 1 , W and R 3 are as defined above. In one embodiment, Y 2 and Z 2 are both -CH-.
  • Y 2 and Z 2 are both -N-.
  • Specific compounds within the scope of the present invention include those compounds tabulated in the accompanying Examples; and salts, iV-oxides and prodrugs thereof.
  • a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.
  • a method for the treatment and/or prevention of convulsions e.g. in a patient suffering from epilepsy or a related disorder
  • convulsions e.g. in a patient suffering from epilepsy or a related disorder
  • the binding affinity (Ki) of the compounds according to the present invention for the ⁇ 3 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow.
  • the ⁇ 3 subunit binding affinity (Ki) of the compounds of the invention is ideally 10 nM or less, preferably 2 nM or less, and more preferably 1 nM or less.
  • the compounds according to the present invention will ideally elicit at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the ⁇ 3 subunit of the human GABAA receptor. Moreover, the compounds of the invention will ideally elicit at most a 30%, preferably at most a 20%, and more preferably at most a 10%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the ⁇ l subunit of the human GABA A receptor.
  • the potentiation of the GABA EC20 response in stably transfected cell lines expressing the ⁇ 3 and ⁇ l subunits of the human GABAA receptor can conveniently be measured by procedures analogous to the protocol described in Wafford et al., Mol. Pharmacol, 1996, 50, 670-678.
  • the procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltk- fibroblast cells.
  • the compounds according to the present invention exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are substantially non-sedating, as may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al., J. PsychopharmacoL, 1996, 10, 206- 213).
  • the compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501.
  • the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called "blood-brain barrier".
  • the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.
  • the invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • the compounds in accordance with the present invention may be prepared by a process which comprises cyclising a compound of formula (II):
  • L 1 represents a readily displaceable group.
  • the readily displaceable group L 1 is suitably a halogen atom, e.g. bromo, in which case the cyclisation is conveniently carried out by treating the compound of formula (II) with tributyltin hydride in the presence of a radical initiator such as l,l'-azobisisobutyronitrile (AIBN), typically in an inert solvent such as benzene.
  • a radical initiator such as l,l'-azobisisobutyronitrile (AIBN)
  • the compounds in accordance with the present invention may be prepared by a process which comprises cyclising a compound of formula (III):
  • E, X, Y, Z, R 1 and R 2 are as defined above, and L 2 represents a readily displaceable group.
  • the readily displaceable group L 2 may suitably be a halogen atom, e.g. bromo, in which case the cyclisation of compound (III) is conveniently effected by treatment with sodium hydride in the presence of lithium bromide, in a solvent system which may typically be a mixture of 1,2- dimethoxyethane and iV, ⁇ -dimethylformamide.
  • the readily displaceable group L 2 may be hydroxy, in which case the cyclisation of compound (III) is conveniently effected by treatment with triphenylphosphine in the presence of diethyl azodicarboxylate (DEAD), typically in an inert solvent such as tetrahydrofuran or dichlorome thane.
  • DEAD diethyl azodicarboxylate
  • the intermediates of formula (II) above may suitably be prepared by reacting a compound of formula (IV) with a compound of formula (V):
  • the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula (VI) with a compound of formula (VII):
  • M represents -B(OH> 2 or -Sn(Alk)3 in which Alk represents a Ci- ⁇ alkyl group, typically n,-butyl, and L 3 represents a suitable leaving group; in the presence of a transition metal catalyst.
  • the leaving group L 3 is suitably a halogen atom, e.g. bromo; or a sulfonyloxy moiety, e.g. trifluoromethanesulfonyloxy (triflyloxy) or p- toluenesulfonyloxy (tosyloxy).
  • L 3 is triflyloxy.
  • a suitable transition metal catalyst of use in the reaction between compounds (VI) and (VII) comprises dichlorobis(triphenylphosphine)- palladium(II) or tetrakis(triphenylphosphine)palladium(0).
  • the reaction between compounds (VI) and (VII) is conveniently effected in an inert solvent such as ⁇ iV-dimethylformamide, typically in the presence of potassium phosphate at an elevated temperature.
  • any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific or enantioselective synthesis or by resolution.
  • novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l- tartaric acid, followed by fractional crystallization and regeneration of the free base.
  • optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l- tartaric acid, followed by fractional crystallization and regeneration of the free base.
  • optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l- tartaric acid
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compounds in accordance with this invention potently inhibit the binding of [ 3 H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the ⁇ 2 or ⁇ 3 subunit stably expressed in Ltk- cells.
  • PBS Phosphate buffered saline
  • Assay buffer 10 mM KH 2 P0 4 , 100 mM KC1, pH 7.4 at room temperature.
  • Supernatant is removed from cells.
  • PBS approximately 20 ml
  • the cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed.
  • the cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cm x 25 cm) of cells.
  • Assay Can be carried out in deep 96-well plates or in tubes. Each tube contains:
  • buffer or solvent carrier e.g. 10% DMSO
  • test compound or flunitrazepam to determine non-specific binding
  • Potassium silanolate (1.37 g, 10.7 mmol) was added to a solution of the product of step d) (2.75 g, 8.89 mmol) in dry ether (125 ml) under nitrogen and the suspension stirred at room temperature for 3 days. The solid was filtered off, washed twice with ether, dissolved in water and acidified with 10% aqueous citric acid.
  • Examples 2, 3, 4, 5 and 6 were prepared following the procedure given for Example 1 using the appropriate acetamide in step h).
  • the acetamides were prepared from the corresponding esters as described for Intermediate 1 step c).
  • Examples 7, 8 and 9 were prepared following the procedure described for Example 1 using the appropriate acetate in step f) and the appropriate acetamide in step h).

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Abstract

La présente invention concerne une classe de composés tricycliques fondus, substitués de manière sélective, basés sur un groupe pyridinone substitué. Ces composés constituent des ligands sélectifs puissants et fonctionnels pour la sous-unité α2/α3 du récepteur GABA-A humain et sont par conséquent efficaces pour traiter l'angoisse.
PCT/GB2002/003693 2001-08-14 2002-08-09 Analogues de pyridine-2-one tricycliques servant de ligands de recepteur gaba-a WO2003024964A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007532613A (ja) * 2004-04-19 2007-11-15 コミツサリア タ レネルジー アトミーク ハロゲン化気体化合物の検出または定量のために使用される、化合物、メソ構造化多孔性ハイブリッド有機−無機材料および感知器
US7425556B2 (en) 2005-12-20 2008-09-16 Astrazeneca Ab Compounds and uses thereof
US7465795B2 (en) 2005-12-20 2008-12-16 Astrazeneca Ab Compounds and uses thereof

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Publication number Priority date Publication date Assignee Title
EP0183994A1 (fr) * 1984-11-06 1986-06-11 F. Hoffmann-La Roche Ag Dérivés tricycliques de la pyridone
WO1998050384A1 (fr) * 1997-05-01 1998-11-12 Merck Sharp & Dohme Limited Analogues de pyridone tricyclique utilises comme ligands de recepteurs gaba-a
WO1998055480A1 (fr) * 1997-06-06 1998-12-10 Merck Sharp & Dohme Limited Derives de 1h-pyridinyl-2-ones substituees ligands au recepteur gabaaalpha 2/3

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0183994A1 (fr) * 1984-11-06 1986-06-11 F. Hoffmann-La Roche Ag Dérivés tricycliques de la pyridone
WO1998050384A1 (fr) * 1997-05-01 1998-11-12 Merck Sharp & Dohme Limited Analogues de pyridone tricyclique utilises comme ligands de recepteurs gaba-a
WO1998055480A1 (fr) * 1997-06-06 1998-12-10 Merck Sharp & Dohme Limited Derives de 1h-pyridinyl-2-ones substituees ligands au recepteur gabaaalpha 2/3

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007532613A (ja) * 2004-04-19 2007-11-15 コミツサリア タ レネルジー アトミーク ハロゲン化気体化合物の検出または定量のために使用される、化合物、メソ構造化多孔性ハイブリッド有機−無機材料および感知器
US7425556B2 (en) 2005-12-20 2008-09-16 Astrazeneca Ab Compounds and uses thereof
US7465795B2 (en) 2005-12-20 2008-12-16 Astrazeneca Ab Compounds and uses thereof

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