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WO2003016311A1 - Analogues de pyridine-2-one tricyclique utiles en tant que ligands pour les recepteurs gaba-a - Google Patents

Analogues de pyridine-2-one tricyclique utiles en tant que ligands pour les recepteurs gaba-a Download PDF

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Publication number
WO2003016311A1
WO2003016311A1 PCT/GB2002/003705 GB0203705W WO03016311A1 WO 2003016311 A1 WO2003016311 A1 WO 2003016311A1 GB 0203705 W GB0203705 W GB 0203705W WO 03016311 A1 WO03016311 A1 WO 03016311A1
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Prior art keywords
phenyl
diaza
dibenzo
dihydro
cyclohepten
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English (en)
Inventor
James Michael Crawforth
Karl Richard Gibson
Simon Charles Goodacre
David James Hallett
Richard Alexander Jelley
Michael Rowley
Francine Sternfeld
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Organon Pharma UK Ltd
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Merck Sharp and Dohme Ltd
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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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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.
  • Such 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; neurode eneration 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.
  • 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
  • emesis 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 e.g. in paraplegic patients
  • hearing disorders including tinnitus and age- related hearing impairment
  • urinary incontinence urinary incontinence
  • 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 anticonvulsant activity. There is no disclosure nor any suggestion therein, however, of compounds possessing a pyridinyl moiety attached via its 3- position to the 6-position of the pyridin-2-one ring.
  • WO 98/50384 describes a class of tricyclic pyridin-2-one analogues, substituted at the 3-position of the pyridone ring by an ester or thiazole moiety, which are stated to be selective ligands for GABA A receptors beneficial in the treatment and/or prevention of neurological disorders, including anxiety and convulsions.
  • the present invention provides a class of tricyclic pyridin-2-one analogues which possess desirable binding properties at various GABA A 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.
  • 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 N-oxide thereof:
  • E represents -(CH2)n-; n is 1, 2 or 3;
  • R 1 represents aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted; or halogen, -NHCOR 3 , -COR 3 or -CO2R 3 ;
  • R 2 represents aryl or heteroaryl, either of which groups may be optionally substituted
  • R 3 represents C3-6 alkyl, hydroxy(C ⁇ -6) alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, aryl(C ⁇ -6) alkyl, heteroaryl or he teroaryl(C ⁇ -6) alkyl, any of which groups may be optionally substituted; excluding compounds in which R 1 represents methylthiazolyl or hydroxy methylthiazolyl.
  • the groups R 1 , R 2 and R 3 as defined above may be unsubstituted, or substituted by one or more substituents. Typically, the groups R 1 , R 2 and/or R 3 will be unsubstituted, or substituted by one or two substituents. Suitably, the groups R 1 , R 2 and/or R 3 will be unsubstituted or monosubstituted. Examples of suitable substituents on the groups R 1 , R 2 and R 3 include Ci- ⁇ alkyl, halo (Ci- ⁇ ) alkyl, C3-7 cycloalkyl, halogen, formyl and C2-6 alkylcarbonyl.
  • 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.
  • 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, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as "halo(Ci. 6 )al r, "hydroxy(C ⁇ - 6 )alkyr, "C 1-6 alkoxy" and "C ⁇ - 6 alkylthio" are to be construed accordingly.
  • Suitable C2-6 alkenyl groups include vinyl, allyl and dimethylallyl groups.
  • Suitable C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Particular aryl groups include phenyl and naphthyl, especially phenyl.
  • Particular aryl(C 1 -e) alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl, especially benzyl.
  • Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups.
  • a particular C3-7 heterocycloalkenyl group is thiazolinyl.
  • Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, fu yl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
  • heteroaryl(C 1- 6)alkyl as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl and isoquinolinylmethyl.
  • halogen as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.
  • the compounds according to the invention may accordingly exist as enantiomers. Where the 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.
  • n is preferably 2 or 3 and most preferably 3.
  • Suitable values for the substituent R 1 include phenyl, pyrrolidinyl, thiazolinyl, pyridinyl, thienyl, pyrrolyl, isoxazolyl, thiazolyl, oxadiazolyl or thiadiazolyl, any of which groups may be optionally substituted; or iodo, -NHCOR 3 , -COR 3 or -CO 2 R 3 in which R 3 is as defined above.
  • Examples of typical substituents on the group R 1 include CI- G alkyl, halo (Ci-e) alkyl, C3-7 cycloalkyl, halogen and formyl.
  • R 1 examples include methyl (except on a thiazolyl ring when the other substituent is hydrogen), ethyl, fluoromethyl, cyclopropyl, chloro and formyl.
  • Suitable values of R 3 include isopropyl, teri-butyl, hydroxyethyl, allyl, cyclop entyl, benzyl, thiazolyl or thiazolylmethyl, any of which groups may be optionally substituted.
  • Examples of typical substituents on the group R 3 include Ci- ⁇ alkyl, especially methyl.
  • R 3 examples include isopropyl, tert-butyl, hydroxyethyl, allyl, cyclopentyl, benzyl, methylthiazolyl or methyl-thiazolylmethyl.
  • R 1 Representative values of R 1 include phenyl, methylphenyl, pyrrolidinyl, thiazolinyl, pyridinyl, thienyl, methylthienyl, chlorothienyl, pyrrolyl, chloro-isoxazolyl, thiazolyl, dimethylthiazolyl, ethylthiazolyl, fluoromethyl-thiazolyl, cyclopropyl-thiazolyl, chlorothiazolyl, formylthiazolyl, methyloxadiazolyl, methylthiadiazoyl, iodo, tert- butylcarbonylamino, methylthiazolylcarbonyl, isopropyloxycarbonyl, tert- butyloxycarbonyl, hydroxyethoxycarbonyl, allyloxycarbonyl, cyclopentyloxycarbonyl, benzyloxycarbonyl and methylthiazolyl- methoxy
  • 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.
  • Illustrative values of 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, Ci-e alkoxy, C ⁇ -3 alkylenedioxy, formyl and Ci-e 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, 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 N-oxides thereof:
  • R 11 represents phenyl, pyrrolidinyl, thiazolinyl, pyridinyl, thienyl, pyrrolyl, isoxazolyl, oxadiazolyl or thiadiazolyl, any of which groups may be optionally substituted; or iodo, -NHCOR 3 , -COR 3 or -C0 2 R 3 ; W represents -N- or -CH-;
  • R 4 represents hydrogen, halogen or Ci-e alkoxy; and R 3 is as defined above.
  • Examples of typical substituents on the group R 11 include Ci- ⁇ alkyl and halogen. Examples of specific substituents on R 11 include methyl and chloro.
  • R 11 Particular values of R 11 include phenyl, methylphenyl, pyrrolidinyl, thiazolinyl, pyridinyl, thienyl, methylthienyl, chlorothienyl, pyrrolyl, chloro-isoxazolyl, methyloxadiazolyl, methylthiadiazolyl, iodo, tert- butylcarbonylammo, methylthiazolylcarbonyl, isopropyloxycarbonyl, tert- butyloxycarbonyl, hydroxyethoxy carbonyl, allyloxycarbonyl, cyclop entyloxycarbonyl, benzyloxycarbonyl and methylthiazolyl- methoxycarbonyl.
  • W is -N-. In another embodiment, W is -CH-.
  • Typical values of R 4 include hydrogen, fluoro, chloro and methoxy, especially hydrogen.
  • R 5 represents hydrogen, C2-6 alkyl, C3-7 cycloalkyl, halogen, formyl or C2-6 alkylcarbonyl;
  • W and R 4 are as defined above.
  • R 5 suitably represents hydrogen, halo (Ci-e) alkyl, C3-7 cycloalkyl, halogen or formyl.
  • Specific values of R 5 include hydrogen, ethyl, fluoromethyl, cyclopropyl, chloro and formyl.
  • R 5 include hydrogen, fluoromethyl, cyclopropyl, chloro and formyl.
  • R 5 represents hydrogen. In another embodiment, R 5 represents cyclopropyl. In a further embodiment, R 5 represents fluoromethyl.
  • Specific compounds within the scope of the present invention include: 1 l-phenyl-9-(thien-2-yl)-6, -dihydro-5H-2, 7a-diaza- dibenzo[ ⁇ ,c]cyclohepten-8-one; ll-phenyl-9-(thien-3-yl)-6,7-dihydro-5H-2,7a-diaza- dibenzo[ ⁇ ,e]cyclohepten-8-one; 9,ll-diphenyl-6,7-dihydro-5H-2,7a-diazadibenzo[ ⁇ ,c]cyclohepten-8-one; 9-(5-methylthien-2-yl)-ll-phenyl-6,7-dihydro-5H-2,7a-diaza- dibenzo [a,c] cyclohepten-8-one; ll-phenyl-9-(m , -tolyl)-6,7-dihydro-5H-2,7a-diazadibenz
  • Also provided by the present invention is 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
  • 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.
  • 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.
  • 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 GABAA 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.
  • compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
  • these 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.
  • sohd 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.
  • a variety of materials can be used for such 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.
  • the 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)
  • AIBN l,l'-azobisisobutyronitrile
  • the compounds in accordance with the present invention may be prepared by a process which comprises cyclising a compound of formula (III):
  • 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,N-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 dichloromethane.
  • DEAD diethyl azodicarboxylate
  • the intermediates of formula (II) above may suitably be prepared by reacting a compound of formula (IN) 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 ? ⁇ -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. iodo or bromo; or a sulfonyloxy moiety, e.g. trifluoromethanesulfonyloxy (triflyloxy) ox p- toluenesulfonyloxy (tosyloxy).
  • L 3 is iodo or triflyloxy.
  • a suitable transition metal catalyst of use in the reaction between compounds (VI) and (VII) comprises diehlorobis(triphenylphosphine)- palladium(II) or tetrakis(triphenylphosphine)palladium (0).
  • reaction between compounds (VI) and (VII) is conveniently effected in an inert solvent such as N,N-dimethylformamide, typically in the presence of potassium phosphate at an elevated temperature.
  • an inert solvent such as N,N-dimethylformamide
  • the intermediates of formula (VI) above wherein L 3 represents triflyloxy may be prepared by methods analogous to those described in WO 98/50384.
  • R 1 represents an optionally substituted aryl or heteroaryl moiety
  • R 1 represents an optionally substituted aryl or heteroaryl moiety
  • E, R 2 , M and L 3 are as defined above, and R la represents aryl or heteroaryl, either of which groups may be optionally substituted; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds (VI) and (VII).
  • R 1 represents an optionally substituted aryl or heteroaryl moiety
  • R 1 represents an optionally substituted aryl or heteroaryl moiety
  • the intermediates of formula (X) wherein M represents -Sn(Alk)3 may be prepared from the corresponding compound of formula (VIII) wherein L 3 is iodo by treatment with [Sn(Alk)3J2 in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium (0).
  • a transition metal catalyst such as tetrakis(triphenylphosphine)palladium (0).
  • the compounds according to the present invention wherein R 1 represents an optionally substituted thiazolyl or thiazolinyl moiety may be prepared by reacting a compound of formula (XII):
  • E and R 2 are as defined above; with the appropriate ⁇ - bromoketone or 1,2-dibromoalkane derivative respectively.
  • E and R 2 are as defined above, and Alk 1 represents methyl or ethyl, typically methyl; with the appropriate amide oxime derivative.
  • the intermediates of formula (XIV) may be prepared by methods analogous to those described in WO 98/50384.
  • R 1 represents 5-chloroisoxazol-3-yl
  • R 1 represents 5-chloroisoxazol-3-yl
  • a process which comprises reacting a compound of formula (XIII) as defined above with sodium nitrite at 0°C in aqueous mineral acid, e.g. dilute hydrochloric acid; then treating the product thereby obtained with vinylidene chloride, advantageously in the presence of triethylamine.
  • R 1 represents -NHCOR 3
  • R 1 represents -NHCOR 3
  • the compounds of formula (VIII) above wherein L 3 represents halogen may be prepared by diazotising the corresponding compound of formula (XV) by treatment with sodium nitrite, followed by treatment with the appropriate copper(I) halide, or with potassium halide in the presence of metallic copper, under acidic conditions.
  • L 3 in the compounds of formula (VIII) above represents halogen the resulting compounds of formula (VIII) are compounds according to the invention in their own right, and may consequently be prepared by any other appropriate method as described herein for the preparation of compounds in accordance with the invention.
  • R 1 represents -COR 3
  • R 1 represents -COR 3
  • the anion (XVIir), as appropriate, may be in the form of a Grignard reagent R 3 -MgBr; or it may be generated from a starting compound R 3 -H by treatment with 7i-butyllithium.
  • the compounds according to the present invention wherein R 1 represents -CO2R 3 may be prepared by a process which comprises reacting a compound of formula (XIX) with a compound of formula (XX):
  • R 1 represents -CO2R 3 and R 3 represents ieri-butyl
  • R 1 represents -CO2R 3 and R 3 represents ieri-butyl
  • intermediates of formula (XVII) above may be prepared by reacting a compound of formula (XIX) with dimethylhydroxylamine hydrochloride, typically in the presence of DMAP and pyridine.
  • the intermediates of formula (XIX) wherein Hal is chloro may be prepared by treating the corresponding compound of formula (XXI) with oxalyl chloride.
  • the intermediates of formula (XV) may be prepared by treating the corresponding compound of formula (XXI) with PI12PON3 and ierf-butanol, typically in the presence of triethylamine at reflux, followed by hydrolysis of the resulting ter ⁇ -butyloxycarbonylamino derivative thereby obtained by treatment with trifluoroacetic acid.
  • the intermediates of formula (XII), (XIII) and (XXI) above may be prepared from the corresponding compound of formula (I) wherein R 1 is cyano by treatment with gaseous hydrogen sulfide or with hydroxylamine hydrochloride or with refluxing hydrochloric acid respectively.
  • the starting materials of formula (III), (IV), (V), (VII), (IX), (XI), (XVI), (XX) and (XXII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
  • 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.
  • a compound of formula (I) initially obtained wherein R 1 represents iodo may be converted into the corresponding compound wherein R 1 represents pyrrolidin-1-yl by treatment with pyrrolidine, typically in the presence of a transition metal catalyst such as tris(dibenzyhdeneacetone)dipalladium(0).
  • a compound of formula (I) initially obtained wherein the R 1 moiety is substituted by carboxy may be converted into the corresponding compound wherein the R 1 moiety is substituted by hydroxymethyl by treatment with a reducing agent, e.g.
  • a compound of formula (I) initially obtained wherein the R 1 moiety is substituted by carboxy may be converted into the corresponding compound wherein the R 1 moiety is substituted by -CON(CH 3 )OCH 3 by treatment with N,0- dimethylhydroxylamine hydrochloride, typically in the presence of bis(2- oxo-3-oxazoHdinyl)phosphinic chloride (BOP-C1) and triethylamine; and the resulting product may in turn be converted into the corresponding compound wherein the R 1 moiety is substituted by formyl by treatment with a reducing agent such as diisobutylaluminium hydride (DIBAL-H).
  • DIBAL-H diisobutylaluminium hydride
  • 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
  • the novel compounds may also be resolved by formation of diastereomeric esters or
  • 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 following Examples illustrate the preparation of compounds according to the invention.
  • 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 KH2PO4, 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.
  • Each tube contains:
  • Expected values for total binding are 3000-4000 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Ki can be calculated for each test compound.
  • the reaction was allowed to warm to room temperature and stirred for 2 h before the reaction was quenched by pouring onto ice/water and the pH adjusted to neutral with citric acid.
  • the aqueous was extracted with ethyl acetate (4 x 500 ml) and the combined organic extracts were washed with water (4 x 250 ml), brine (2 x 250 ml), dried (Na 2 SO 4 ) and the solvent removed in vacuo.
  • the crude product was purified by flash chromatography (ethyl acetate) to afford the title compound as an oil (33.5 g, 81%).
  • Lithium hexamethyldisilazide (0.94 ml, 0.94 mmol) was added to a cold (-78°C) solution of l- ⁇ 4-[3-(tert- butyldimethylsilanyloxy)propyl]pyridin-3-yl ⁇ -3-dimethylamino-2- phenylpropenone (0.1 g, 0.235 mmol) and 2-(thien-2-yl)acetamide (37 mg, 0.26 mmol) in dry tetrahydrofuran (20 ml).
  • the reaction was allowed to warm to room temperature and stirred for 1 h before quenching by the addition of N ⁇ 4 C1 solution (20 ml, sat. aqueous).
  • the reaction was poured into ethyl acetate (10 ml) and the layers separated.
  • the aqueous was extracted with ethyl acetate (3 x 10 ml).
  • the combined organic extracts were washed with water (10 ml) and brine (20 ml), dried (Na2SO 4 ) and evaporated.
  • the reaction was partly purified through a plug of silica (ethyl acetate).
  • the product was dissolved in N,N- dime thy lformamide (2 ml) and IN HCl added (2 ml).
  • the yellow solid was dissolved in methanol/dichloromethane (2:1) (150 ml) and p ⁇ r ⁇ -toluenesulphonic acid added (3.5 g, 18 mmol). Solvent was removed in vacuo and water was added. Solid sodium bicarbonate was added until pH 5 was obtained and a yellow sohd precipitated out. The title compound was obtained after drying as a pale yellow solid (2.50 g, 44%).
  • Trifluoroacetic acid (5 ml) was added to a solution of (8-oxo-ll- phenyl-5,6,7,8-tetrahydro-2,7a-diazadibenzo[ ⁇ ,c]cyclohepten-9-yl)carbamic acid feri-butyl ester (0.7 g, 1.73 mmol) in dichloromethane (50 ml). The reaction was stirred for 2 h and then evaporated to dryness. A solid crystallised upon addition of Et2 ⁇ . The solid was collected by filtration and dried under vacuum to afford the product as the trifluoroacetate salt (0.65 g, 90%), mp 142-147°C.
  • Tetrahydrofuran (2 ml) was added and the reaction stirred at room temperature. The reaction was stirred for 5 days. The reaction was partitioned between water (5 ml) and ethyl acetate (5 ml). The layers were separated and the aqueous extracted with ethyl acetate (2 5 ml). The combined organic extracts were washed with ammonium chloride (5 ml, sat. aq.) and brine (5 ml), dried (Na2S ⁇ 4) and evaporated. The residue was purified by prep tic (ethyl acetate).
  • the reaction was partitioned between water (25 ml) and ethyl acetate (25 ml). The layers were separated and the aqueous extracted with ethyl acetate (20 ml). The combined organic extracts were washed with NaHC0 3 (2 x 10 ml, sat. aq.), water (2 x 10 ml), brine (10 ml), dried (Na2S0 4 ) and evaporated to afford crude Weinreb amide.
  • the reaction was vortexed for 30 seconds and the reaction allowed to stand for 4 h.
  • the reaction was quenched by partitioning between water (50 ml) and ethyl acetate (25 ml). The layers were separated and the aqueous was extracted with ethyl acetate. The organic extracts were washed with brine and dried (Na2S0 4 ). The residue was purified by preparative tic (ethyl acetate) to afford the desired compound (20 mg, 43%).
  • N- ⁇ ydroxy-8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[ ⁇ ,c]cycloheptene-9-carboxamidine (0.265 g, 0.78 mmol) was dissolved in water (8 ml) and concentrated hydrochloric acid (3 ml). The reaction was cooled to 0°C and sodium nitrite (66 mg, 0.96 mmol) in water (2 ml) was added. Solvent was removed in vacuo and azeotroped with toluene (x 3).
  • N- ⁇ ydroxy-8-oxo-ll-phenyl-5,6,7,8-tetrahydro-2,7a-diaza- dibenzo[ ⁇ -c]cycloheptene-9-carboxamidine 50 mg, 0.14 mmol was dissolved in acetic anhydride (8 ml) and heated at 140°C for 18 h. Solvent was removed in vacuo and the residue basified to pH 7 with sodium bicarbonate, the aqueous was extracted with ethyl acetate (x 3), dried (MgSO ) and solvent removed in vacuo. The crude product was purified on silica gel chromatography eluting with ethyl acetate.
  • Methylcarboxamidine (6 mg, 0.09 mmol) was dissolved in tetrahydrofuran (3 ml).
  • Sodium hydride (60% dispersion in oil) (3 mg, 0.09 mmol) was added followed by 8-oxo-ll-phenyl-5,6,7,8-tetrahydro- 2,7a-diazadibenzo[ ⁇ ,c]cycloheptene-9-carboxylic acid methyl ester (prepared according to procedure C; 30 mg, 0.09 mmol) in tetrahydrofuran (3 ml) and the reaction heated to reflux for 1 h.
  • the aqueous was extracted with ethyl acetate (x 3); organics were combined and washed with water (x 2), brine (x 2), dried (MgSO 4 ) and solvent removed in vacuo.
  • the solid (30 mg, 0.074 mmol) was dissolved in tetrahydrofuran (20 ml) and triphenylphosphine (24 mg, 0.093 mmol) added followed by diethyl azodicarboxylate (0.016 ml, 0.093 mmol) and the reaction stirred for 0.25 h. The reaction was quenched by the addition of water (10 ml) and then poured into ethyl acetate (10 ml).
  • the reaction was cooled to -78°C and quenched by the addition of water (0.5 ml), 4N sodium hydroxide (0.5 ml) and methanol (0.2 ml).
  • the reaction was filtered through hyflo and washed with dichloromethane. Solvent was removed in vacuo and the residue purified on silica gel chromatography eluting with methanol/dichloromethane (2:98) to give the product as a white solid (1.4 mg, 6%).

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Abstract

La présente invention concerne une classe de composés tricycliques fusionnés substitués basés sur une fraction pyridinone substituée qui sont puissants et constituent des ligands fonctionnellement sélectifs pour la sous-unité α2/α3 du récepteur humain GABA-A et qui sont donc efficaces dans le traitement de l'anxiété. Cette invention concerne un composé représenté par la formule (I), ou bien un sel ou un N-oxyde de ce dernier. Dans la formule, E représente -(CH2)n-; n représente 1, 2 ou 3; R1 représente aryle, hétérocycloalkyle C¿3-7?, hétéroaryle ou hétérocycloalcényle C3-7, n'importe lequel de ces groupes pouvant être éventuellement substitué; ou halogène, -NHCOR?3, -COR3¿ ou CO¿2R?3; R2 représente aryle ou hétéroaryle, un quelconque de ces groupes pouvant être substitué; et R3 représente alkyle C¿3-6?, alkyle(C1-6)hydroxy, alcényle C2-6, cycloalkyle C3-7, aryle, alkyle(C1-6)aryle, hétéroaryle ou alkyle(C1-6)hétéroaryle, tous ces groupes pouvant être éventuellement substitués; lesdits substituants possibles sur R?1, R2 et R3¿ étant indépendamment sélectionnés parmi alkyle C¿1-6?, halo alkyle(C1-6), cycloalkyle C3-7, halogène, formyle et alkylcarbonyle C2-6; excepté les composés dans lesquels R?1¿ représente méthylthiazolyle ou hydroxyméthylthiazolyle. Formule (I)
PCT/GB2002/003705 2001-08-14 2002-08-09 Analogues de pyridine-2-one tricyclique utiles en tant que ligands pour les recepteurs gaba-a Ceased WO2003016311A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4072681A (en) * 1977-03-02 1978-02-07 E. R. Squibb & Sons, Inc. 3,7-Dihydro- and 1,7-dihydro-4H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-4-ones
EP0183994A1 (fr) * 1984-11-06 1986-06-11 F. Hoffmann-La Roche Ag Dérivés tricycliques de la pyridone
US5328912A (en) * 1990-07-24 1994-07-12 Neurogen Corporation Certain azacycloalkyl imidazopyrimidines; a new class of GABA brain receptor ligands
WO1994015937A1 (fr) * 1993-01-06 1994-07-21 Neurogen Corporation Certaines imidazopyrazinones a substitution aryle; une nouvelle classe de ligands de recepteurs cerebraux gaba
WO1994025461A1 (fr) * 1992-04-08 1994-11-10 Neurogen Corporation Pyrrolopyridines cycloalkylees et azacycloalkylees constituant une nouvelle categorie de ligands des recepteurs cerebraux du gaba
WO1998050384A1 (fr) * 1997-05-01 1998-11-12 Merck Sharp & Dohme Limited Analogues de pyridone tricyclique utilises comme ligands de recepteurs gaba-a

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4072681A (en) * 1977-03-02 1978-02-07 E. R. Squibb & Sons, Inc. 3,7-Dihydro- and 1,7-dihydro-4H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-4-ones
EP0183994A1 (fr) * 1984-11-06 1986-06-11 F. Hoffmann-La Roche Ag Dérivés tricycliques de la pyridone
US5328912A (en) * 1990-07-24 1994-07-12 Neurogen Corporation Certain azacycloalkyl imidazopyrimidines; a new class of GABA brain receptor ligands
WO1994025461A1 (fr) * 1992-04-08 1994-11-10 Neurogen Corporation Pyrrolopyridines cycloalkylees et azacycloalkylees constituant une nouvelle categorie de ligands des recepteurs cerebraux du gaba
WO1994015937A1 (fr) * 1993-01-06 1994-07-21 Neurogen Corporation Certaines imidazopyrazinones a substitution aryle; une nouvelle classe de ligands de recepteurs cerebraux gaba
WO1998050384A1 (fr) * 1997-05-01 1998-11-12 Merck Sharp & Dohme Limited Analogues de pyridone tricyclique utilises comme ligands de recepteurs gaba-a

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NADIN, ALAN ET AL: "Synthesis of tricyclic pyridones by radical cyclization", TETRAHEDRON LETTERS (1999), 40(21), 4073-4076, XP002945931 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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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