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WO2004076452A1 - 5,8-difluoroimidazo[1,2-a]pyridines constituant des ligands gaba-a ?2/?3 utilises dans le traitement de l'anxiete et/ou de la depression - Google Patents

5,8-difluoroimidazo[1,2-a]pyridines constituant des ligands gaba-a ?2/?3 utilises dans le traitement de l'anxiete et/ou de la depression Download PDF

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Publication number
WO2004076452A1
WO2004076452A1 PCT/GB2004/000696 GB2004000696W WO2004076452A1 WO 2004076452 A1 WO2004076452 A1 WO 2004076452A1 GB 2004000696 W GB2004000696 W GB 2004000696W WO 2004076452 A1 WO2004076452 A1 WO 2004076452A1
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phenyl
trifluoromethyl
hydrogen
alkyl
formula
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PCT/GB2004/000696
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English (en)
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William Robert Carling
Kevin William Moore
Leslie Joseph Street
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Merck Sharp & Dohme Limited
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Priority claimed from GB0304416A external-priority patent/GB0304416D0/en
Priority claimed from GB0304417A external-priority patent/GB0304417D0/en
Application filed by Merck Sharp & Dohme Limited filed Critical Merck Sharp & Dohme Limited
Publication of WO2004076452A1 publication Critical patent/WO2004076452A1/fr

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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
    • C07D471/02—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 two hetero rings
    • C07D471/04—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
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a class of substituted imidazo- pyridine derivatives and to their use in therapy. More particularly, this invention is concerned with 5,8-difluoroimidazo[l,2-a]pyridine analogues which are substituted in the 3-position by a substituted phenyl or heteroaromatic ring. These compounds are ligands for GABAA receptors and are therefore useful in the therapy of adverse neurological disorders.
  • Receptors for the major inhibitory neurotransmitter gamma- aminobutyric acid (GABA) are divided into two main classes- (l) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) 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.
  • Receptor subtype assemblies which do exist include, amongst many others, ⁇ l ⁇ 2 ⁇ 2, c ⁇ l, ⁇ 2 ⁇ 2/3 ⁇ 2, ⁇ 3 ⁇ 2/3, ⁇ 4 ⁇ , ⁇ 5 ⁇ 3 ⁇ 2/3, ⁇ 6 ⁇ 2 and ⁇ 6 ⁇ .
  • Subtype assemblies containing an ⁇ l subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat.
  • Subtype assemblies containing ⁇ 2 and ⁇ 3 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat.
  • Subtype assemblies containing an ⁇ 5 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat.
  • a characteristic property of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site.
  • the BZ binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect.
  • the benzodiazepine binding site was historically subdivided into two subtypes, BZl and BZ2, on the basis of radioligand binding studies.
  • the BZl subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the ⁇ l subunit in combination with a ⁇ subunit and ⁇ 2. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain.
  • GABAA receptor agonists Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are referred to hereinafter as "GABAA receptor agonists".
  • GABAA receptor agonists Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists.
  • the ⁇ l-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZl binding site is mediated through GABAA receptors containing the ⁇ l subunit.
  • GABAA receptor agonists which interact more favourably with the ⁇ 2 and/or ⁇ 3 subunit than with ⁇ l will be effective in the treatment of anxiety with a reduced propensity to cause sedation.
  • agents which are inverse agonists of the ⁇ 5 subunit are likely to be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer's disease.
  • agents which are antagonists or inverse agonists at ⁇ l might be employed to reverse sedation or hypnosis caused by ⁇ l agonists.
  • 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 ischemiaJ attention deficit hyperactivity disorder; Tourette's syndrome; 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; 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; muscle spasm or spasticity, e.g. in paraplegic patients; hearing disorders, including tinnitus and age- related hearing impairment; urinary incontinence; and the effects of substance abuse or dependency, including alcohol withdrawal.
  • Selective ligands for GABAA receptors may be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer's disease; and 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.
  • WO 01/38326 describes a class of 3-phenylimidazo[l,2-a]pyridine derivatives which are stated to be selective ligands for GABAA receptors, in particular having high affinity for the ⁇ 2 and/or ⁇ 3 subunit thereof, and accordingly to be of benefit in the treatment and/or prevention of neurological disorders, including anxiety and convulsions.
  • substitution with a fluorine atom at the 5-position or the 8-position of the imidazo[l,2- ajpyridine nucleus still less of disubstitution with fluorine atoms at both the 5-position and the 8-position of the imidazo[l,2-a]pyridine nucleus.
  • the present invention provides a class of imidazo-pyridine derivatives 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 and/or ⁇ 5 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; and/or may interact more favourably with the ⁇ 5 subunit than with 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 and/or ⁇ subunit, as measured in the assay described hereinbelow, of 200 nM or less, typically of 100 nM or less, and ideally of 20 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 and or ⁇ 5 subunit relative to the ⁇ l subunit.
  • compounds which are not selective in terms of their binding affinity for the ⁇ 2 and/or ⁇ 3 and or ⁇ 5 subunit relative to the ⁇ l subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of zero or weak (positive or negative) efficacy at the ⁇ l subunit and (i) a full or partial agonist profile at the ⁇ 2 and/or ⁇ 3 subunit, and/or (ii) an inverse agonist profile at the ⁇ 5 subunit.
  • the compounds according to the present invention possess remarkable receptor occupancy at low doses, and interesting pharmacokinetic properties, notably in terms of improved oral bioavailability and enhanced metabolic stability.
  • the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof
  • W represents an optionally substituted five-membered heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole, " or
  • W represents an optionally substituted six-membered heteroaromatic ring selected from pyridine, pyrazine, pyrimidine and pyridazine; or
  • W represents a phenyl group substituted by X 1 and X 2 and meta to the imidazopyridine core by -Y-Z wherein:
  • X 1 represents hydrogen, halogen, Ci- ⁇ alkyl, trifluoromethyl or Ci- ⁇ alkoxyJ
  • X 2 represents hydrogen or halogen
  • Y represents a chemical bond, an oxygen atom, or a -NH- linkage
  • Z represents aryl, heteroaryl or pyridin-2-on-l-yl, any of which groups may be optionally substituted;
  • R a and R b independently represent hydrogen, hydrocarbon or a heterocyclic group.
  • the aryl, heteroaryl or pyridin-2-on-l-yl group Z in the compounds of formula I above may be unsubstituted, or substituted by one or more substituents.
  • the group Z will be unsubstituted, or substituted by one or two substituents.
  • the group Z is unsubstituted or monosubstituted.
  • W in the compounds of formula I above represents a five- membered heteroaromatic ring
  • this ring may be optionally substituted by one or, where possible, two substituents.
  • Z represents an oxadiazole, thiadiazole or tetrazole ring
  • only one substituent will be possible; otherwise, one or two optional substituents may be accommodated around the five- membered heteroaromatic ring Z.
  • W in the compounds of formula I above represents a six- membered heteroaromatic ring, this ring may be optionally substituted by one or more substituents, typically by one or two substituents.
  • the group W is unsubstituted or monosubstituted.
  • optional substituents on the five-membered or six- membered heteroaromatic ring as specified for W include halogen, cyano, trifluoromethyl, Ci- ⁇ alkyl, halo(C ⁇ - ⁇ ) alkyl, dihalo(C ⁇ -6)alkyl, hydroxy(C ⁇ - ⁇ )alkyl, Ci- ⁇ alkoxy (Ci- ⁇ ) alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, benzyHetrahydropyridinyl, oxy, hydroxy, Ci- ⁇ alkoxy, methyltriazolyl(C ⁇ -6)alkoxy, Ci- ⁇ alkylthio, Ci- ⁇ alkylsulphonyl, C2-6 alkylcarbonyl, amino, Ci- ⁇ alkylamino, di(C ⁇ -6)alkylamino, C2-6 alkylcarbonylamino, phen
  • 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.
  • hydrocarbon as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C ⁇ -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, indanyl, aryl and aryl(C ⁇ -6)alkyl.
  • a heterocyclic group as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur.
  • the heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon.
  • suitable heterocyclic groups include C3-7 heterocycloalkyl, C3-7 heterocycloaLkyl(C ⁇ -6)alkyl, heteroaryl and heteroaryl(C ⁇ - ⁇ )alkyl groups.
  • 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, 22-propyl, isopropyl, isobutyl, terfrbutyl and 2,2-dimethylpropyl. Derived expressions such as "Ci- ⁇ alkoxy", “Ci- ⁇ alkylamino” and "Ci- ⁇ alkylsulphonyl" are to be construed accordingly.
  • Suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl and dimethylallyl groups.
  • Suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
  • Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
  • C3-7 cycloalkyl(C ⁇ -6)alkyl groups include cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.
  • Particular indanyl groups include indan-1-yl and indan-2-yl.
  • Particular aryl groups include phenyl and naphthyl, preferably phenyl.
  • Particular aryl(C ⁇ - ⁇ )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.
  • Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolin l, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazol l, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
  • heteroaryl(Ci-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.
  • the hydrocarbon and heterocyclic groups may in turn be optionally substituted by one or more groups selected from Ci- ⁇ alkyl, adamantyl, phenyl, halogen, Ci- ⁇ haloalkyl, Ci- ⁇ aminoalkyl, trifluoromethyl, hydroxy, C ⁇ -6 alkoxy, aryloxy, keto, C1-3 alkylenedioxy, nitro, cyano, carboxy, C2-6 alkoxycarbonyl, C2-6 alkoxycarbonyl(C ⁇ -e)alkyl, C2-6 alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C2-6 alkylcarbonyl, arylcarbonyl, Ci- ⁇ alkylthio, Ci- ⁇ alkylsulphinyl, Ci- ⁇ alkylsulphonyl, arylsulphonyl, -NR V R W , -NR v CO w , -NR v C0 2 R w , -NR
  • 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.
  • the present invention includes within its scope tautomers of the compounds of formula I as defined above.
  • Z represents an optionally substituted 2-hydroxypyridine moiety
  • this may co-exist, in whole or in part, with the corresponding 2-pyridone tautomer.
  • group W represents an optionally substituted five- membered heteroaromatic ring
  • this is suitably a thiophene, thiazole or thiadiazole ring, either of which may be optionally substituted by one or, where possible, two substituents.
  • W represents an optionally substituted six- membered heteroaromatic ring
  • this is suitably a pyridinyl or pyrimidinyl ring, either of which may be optionally substituted by one or more substituents, typically by one or two substituents.
  • W represents monosubstituted pyridinyl.
  • W represents monosubstituted pyrimidinyl.
  • Illustrative examples of optional substituents on the group W include fluoro, chloro, bromo, iodo, cyano, trifluoromethyl, methyl, isopropyl, tertrhntyl, chloromethyl, fluoropropyl (especially 2-fluoroprop-2- yl), difluoroethyl (especially 1,1-difluoroethyl), hydroxypropyl (especially 2- hydroxyprop-2-yl), methoxymethyl, cyclopent l, pyrrolidinyl, morpholinyl, benzyl-tetrahydropyridinyl, oxy, hydroxy, methoxy, ethoxy, isopropoxy, tertrbutoxy, methyltriazolyl-methox , methylthio, ethylthio, methanesulphonyl, acetyl, fert butylamino, dimethylamino, acetylamin
  • One typical substituent which may be attached to the group W is trifluoromethyl. Another typical substituent which may be attached to the group W is (cyano) (fluorophenyl. An additional typical substituent which may be attached to the group W is difluorophenyl.
  • W represents trifluoromethyl-pyridinyl.
  • W represents trifluoromethyl-pyrimidinyl.
  • W represents (cyano)(fluoro)phenyl- pyridinyl. In a further embodiment, W represents difluorophenyl-pyrimidinyl.
  • Suitable values for the X 1 substituent include hydrogen, fluoro, chloro, methyl, trifluoromethyl and methoxyJ in particular hydrogen or fluoro; and especially fluoro.
  • Typical values of X 1 include fluoro, chloro, methyl, trifluoromethyl and methoxy, especially fluoro.
  • Typical values of X 2 include hydrogen and fluoro, especially hydrogen.
  • Y represents a chemical bond
  • Y represents an oxygen atom. In a further embodiment, Y represents a -NH- linkage.
  • Selected values for the substituent Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl and pyridin-2-on-l-yl, any of which groups may be optionally substituted by one or more substituents.
  • Z represents an optionally substituted phenyl group, in particular monosubstituted or disubstituted phenyl.
  • Z represents optionally substituted pyridinyl, especially unsubstituted, monosubstituted or disubstituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.
  • Z represents unsubstituted or substituted pyridin-2-on-l-yl.
  • substituents on the group Z include fluoro and cyano.
  • Z include cyanophenyl, (cyano) (fluorophenyl, pyridinyl, difluoro-pyridinyl, cyano-pyridinyl and pyridin-2-on-l-yl.
  • Z represents 2-cyanophenyl
  • Z represents 2-cyano-4-fluorophenyl. In an additional embodiment, Z represents 2-cyano-6-fluorophenyl.
  • Z represents pyridin-2-on-l-yl.
  • Typical values of R a include hydrogen and Ci- ⁇ alkyl.
  • R a represents hydrogen or methyl.
  • Typical values of R b include hydrogen, Ci- ⁇ alkyl, hydroxy(C ⁇ -6)alkyl and di(C ⁇ - ⁇ )alkylamino(C ⁇ -6)alkyl.
  • R b represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl.
  • Particular values of R b include hydrogen, hydroxyethyl and dimethylaminoethyl, especially hydrogen or dimethylaminoethyl.
  • Itemised values of R 1 when W is not phenyl include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially 1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxy ethyl (especially 1,1-dimethoxy ethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially 2-fh ⁇ oroprop-2-yl), cyanopropyl (especially 2-cyanoprop-2-yl), ter butyl, cyclopropyl, cyclobutyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazoly
  • R 1 when W is not phenyl include hydrogen, hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially 2- fluoroprop-2-yl) and trifluoromethyl.
  • R 1 when W is not phenyl is 2-hydroxyprop-2-yl.
  • R 1 when W is phenyl include hydrogen, halo(C ⁇ - ⁇ )alkyl, hydroxy(C ⁇ - ⁇ ) alkyl, halogen and trifluoromethyl.
  • R 1 when W is phenyl include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1 -hydroxyethyl), fluoroethyl (especially 1 -fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1 -dimethox ethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), dihydroxypropyl (especially 1,2- dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), cyanopropyl (especially 2-cyanoprop-2-yl), methoxycarbonylpropyl (especially 2-methoxycarbonylprop-2-yl), ⁇ ertrhutyl, hydroxybutyl (especially l-hydroxy-2-methylprop-2-yl),
  • R 2 is hydrogen
  • R 3 represents hydrogen or dimethylaminoethyl, especially hydrogen.
  • a particular sub-class of compounds according to the invention is represented by the compounds of formula HA, and pharmaceutically acceptable salts thereof
  • W is as defined above;
  • X 1 represents hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy;
  • X 2 represents hydrogen or fluoro
  • R 4 represents hydrogen or Ci- ⁇ alkyl
  • R 5 represents hydrogen, Ci- ⁇ alkyl, hydroxy(C ⁇ - ⁇ )alkyl or di(C ⁇ -6)alkylamino(C ⁇ -6)alkyl.
  • Suitable values of X 1 include hydrogen and fluoro, especially fluoro.
  • Typical values of X 1 include fluoro, chloro, methyl, trifluoromethyl and methoxy. A particular value of X 1 is fluoro.
  • X 2 represents hydrogen. In another embodiment, X 2 represents fluoro.
  • R 4 represents hydrogen or methyl, especially hydrogen.
  • R 5 represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of R 5 include hydrogen, hydroxyethyl and dimethylaminoethyl. Typically, R 5 represents hydrogen or dimethylaminoethyl, especially hydrogen.
  • R 11 represents heteroaryl, this group is suitably pyridinyl, furyl, thienyl or oxazolyl.
  • R 11 represents Ci- ⁇ alkyl-heteroaryl, this group is suitably methylthiazolyl (e.g. 2-methylthiazol"5-yl) or methyloxadiazolyl (e.g. 3- methyl- [l,2,4]oxadiazol-5-yl).
  • R 11 represents heteroaryl(C ⁇ - ⁇ )alkyl
  • this group is suitably imidazolylmethyl or triazolylmethyl.
  • Itemised values of R 11 when W is not phenyl include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially 1 -fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), cyanopropyl (especially 2-cyanoprop-2-yl), tertrbutyl, cyclopropyl, cyclobutyl, pyridinyl, furyl, thi
  • R 11 when W is not phenyl include hydrogen, hydroxypropyl (especially 2-hydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl) and trifluoromethyl.
  • R 11 when W is phenyl include hydrogen, hydroxy(C ⁇ - ⁇ )alkyl, fluoro(C ⁇ - ⁇ )alkyl, halogen and trifluoromethyl.
  • Individual values of R 11 when W is phenyl include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially 1 -fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), dihydroxypropyl (especially 1,2- dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), cyanopropyl (especially 2-cyanoprop-2-yl), methoxycarbonylpropy
  • R 11 represents 2-hydroxyprop-2-yl. In another embodiment when W is phenyl, R 11 represents 2-fluoroprop-2-yl. In an additional embodiment when W is phenyl, R 11 represents trifluoromethyl.
  • T represents CH and V represents N;
  • T represents N and V represents CH or N;
  • R 6 represents hydrogen, halogen, cyano, trifluoromethyl, Ci- ⁇ alkyl, halo(C ⁇ - ⁇ )alkyl, dihalo(C ⁇ - ⁇ )alkyl, hydroxy(C ⁇ - ⁇ )alkyl, Ci- ⁇ alkoxy(C ⁇ - ⁇ )alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, benzyl-tetrahydropyridinyl, Ci- ⁇ alkoxy, methyltriazolyl(C ⁇ - ⁇ )alkoxy, Ci- ⁇ alkylthio, Ci- ⁇ alkylsulphonyl, C2-6 alkylcarbonyl, amino, Ci- ⁇ alkylamino, di(C ⁇ - ⁇ )alkylamino, C2-6 alkylcarbonylamino, phenyl, (C ⁇ - ⁇ )alkyl-phenyl, halophenyl, dihalophenyl, trihalophenyl, (fluoro) (methyl)
  • R 6 Illustrative values of R 6 include hydrogen, fluoro, chloro, bromo, iodo, cyano, trifluoromethyl, methyl, isopropyl, ter butyl, chloromethyl, fluoropropyl (especially 2-fluoroprop-2-yl), difluoroethyl (especially 1,1- difluoroethyl), hydroxypropyl (especially 2-hydroxyprop-2-yl), methoxymethyl, cyclopentyl, pyrrolidinyl, morpholinyl, benzyl- tetrahydropyridinyl, methoxy, ethoxy, isopropoxy, ter ⁇ butoxy, methyltriazolyl-methoxy, methylthio, ethylthio, methanesulphonyl, acetyl, fert butylamino, dimethylamino, acetylamino, phenyl, methylphenyl, isopropy
  • R 6 represents (cyano)(fluoro)phenyl. In an additional embodiment, R 6 represents difluorophenyl.
  • T and V are as defined above or T is CX 2 and V is CX 1 where X 1 and X 2 are as defined for formula IIA above; R 11 is as defined above; and R 6 represents hydrogen or fluoro.
  • R 6 is hydrogen.
  • R 6 is fluoro, in which case the fluorine atom R 6 is favourably attached to the phenyl ring at the 4-, 5- or 6-position (relative to the cyano group at position 2).
  • X is CH and Y is N.
  • X is N and Y is CH.
  • X and Y are both N.
  • R 7 represents hydrogen, fluoro, cyano or methyl.
  • R 7 is hydrogen
  • R 7 is fluoro
  • R 7 is cyano
  • R 7 is methyl.
  • R 8 represents hydrogen or fluoro.
  • R 8 represents hydrogen. In another embodiment, R 8 represents fluoro.
  • 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 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.
  • 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 anxiolytic compounds of the invention is ideally 50 nM or less, preferably 10 nM or less, and more preferably 5 nM or less.
  • the anxiolytic 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 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 may 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 likely to be 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 present invention provides a method for the treatment and/or prevention of cognitive disorders, including dementing conditions such as Alzheimer's disease, 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.
  • Cognition enhancement can be shown by testing the compounds in the Morris watermaze as reported by McNamara and Skelton, Psychobiology, 1993, 21, 101-108. Further details of relevant methodology are described in WO 96/25948.
  • Cognitive disorders for which the compounds of the present invention may be of benefit include delirium, dementia, amnestic disorders, and cognition deficits, including age-related memory deficits, due to traumatic injury, stroke, Parkinson's disease and Down Syndrome.
  • dementia any of these conditions may be attributable to substance abuse or withdrawal.
  • dementia include dementia of the Alzheimer's type with early or late onset, and vascular dementia, any of which may be uncomplicated or accompanied by delirium, delusions or depressed mood; and dementia due to HIV disease, head trauma, Parkinson's disease or Creutzfeld- Jakob disease.
  • 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 reacting a compound of formula III with a compound of formula IV:
  • L 1 represents a suitable leaving group
  • M 1 represents a boronic acid moiety -B(OH)2 or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol, or M 1 represents -Sn(Alk)3 in which Alk represents a C ⁇ - ⁇ alkyl group, typically /rbutyl; in the presence of a transition metal catalyst.
  • the leaving group L 1 is typically a halogen atom, e.g. bromo.
  • the transition metal catalyst of use in the reaction between compounds III and IV is suitably tetrakis(triphenylphosphine)- palladium( ⁇ ).
  • the reaction is conveniently carried out at an elevated temperature in a solvent such as 1,2-dimethoxyethane, N,N- dimethylacetamide, 1,4-dioxane or tetrahydrofuran, advantageously in the presence of sodium hydrogencarbonate, potassium phosphate, copperCO iodide, sodium carbonate or cesium carbonate.
  • the transition metal catalyst employed may be dichloro[l,l'-bis(diphenyl- phosphino)ferrocene]palladium(II), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as NN- dimethylformamide, advantageously in the presence of potassium phosphate.
  • the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula V with a compound of formula I:
  • the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula VII with a compound of formula VIII :
  • X 1 , X 2 , Z, R 1 , L 1 and M 1 are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.
  • the leaving group L 1 is typically trifluoromethanesulfonyloxy (triflyloxy); or a halogen atom, e.g. bromo.
  • the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula IX with a compound of formula X:
  • the compounds according to the present invention in which Y represents an oxygen atom may be prepared by a process which comprises reacting a compound of formula X as defined above with a compound of formula XI:
  • reaction is conveniently carried out under basic conditions, e.g. using sodium hydride in a solvent such as ⁇ A ⁇ -dimethylformamide, typically at an elevated temperature which may be in the region of 120°C.
  • the compounds according to the present invention in which Y represents a -NH- linkage may be prepared by a process which comprises reacting a compound of formula X as defined above with a compound of formula XII:
  • the leaving group L 1 in the compounds of formula X may suitably represent fluoro.
  • the reaction between compounds X and XII is conveniently carried out by heating the reactants, typically at a temperature in the region of 120°C, in a solvent such as ⁇ dimethylformamide.
  • M 1 in the intermediates of formula IV and IX above represents a boronic acid moiety -B(OH)2 or a cyclic ester thereof formed with pinacol or neopentyl glycol
  • the relevant compound IV or IX may be prepared by reacting bis(pinacolato)diboron or bis(neopentyl glycolato)diborane respectively with a compound of formula VI or VII as defined above; in the presence of a transition metal catalyst.
  • the transition metal catalyst of use in the reaction between bis(pinacolato)diboron or bis(neopentyl glycolato)diborane and compound VI or VII is suitably dichloro[l,l'-bis(diphenylphosphino)ferrocene]- palladiumdl).
  • the reaction is conveniently carried out at an elevated temperature in a solvent such as 1,4-dioxane, optionally in admixture with dimethylsulf oxide, typically in the presence of 1,1' - bis(diphenylphosphino)ferrocene and/or potassium acetate.
  • the relevant compound VII may be prepared by reacting the appropriate compound of formula XI as defined above with triflic anhydride, typically in the presence of pyridine. Analogous conditions may be utilised of preparing a compound of formula VI wherein L 1 represents triflyloxy from the corresponding hydroxy precursor.
  • X 1 , X 2 and R 1 are as defined above, * by treatment with boron tribromide, typically in chloroform or dichloromethane! or with hydrogen bromide, typically in acetic acid at reflux.
  • X 1 , X 2 and M 1 are as defined above, and Y 1 represents amino or methoxy; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.
  • the transition metal catalyst of use in the reaction between compounds III and XTV is suitably tetrakis(triphenylphosphine)- palladium( ⁇ ), in which case the reaction is conveniently carried out at an elevated temperature in a solvent such as aqueous 1, 2 -dimethoxy ethane, advantageously in the presence of sodium carbonate.
  • M 1 in the intermediates of formula V above represents
  • this compound may be prepared by reacting a compound of formula III as defined above with a reagent of formula (Alk)3Sn-Hal, in which Hal represents a halogen atom, typically chloro.
  • a reagent of formula (Alk)3Sn-Hal in which Hal represents a halogen atom, typically chloro.
  • the reaction is conveniently effected by treating compound III with isopropylmagnesium chloride, typically in a solvent such as tetrahydrofuran, with subsequent addition of the stannyl reagent (Alk) 3 Sn-Hal.
  • R 1 is as defined above; typically by treatment with bromine in acetic acid or methanol, in the presence of sodium acetate and optionally also potassium bromide.
  • the intermediates of formula XV may be prepared by reacting chloroacetaldehyde or bromoacetaldehyde, or an acetal derivative thereof, e.g. the dimethyl or diethyl acetal thereof, with the requisite compound of formula XVI:
  • R 1 is as defined above.
  • chloroacetaldehyde or bromoacetaldehyde is utilised as one of the reactants
  • the reaction is conveniently carried out by heating the reactants under basic conditions in a suitable solvent, e.g. sodium methoxide or sodium hydrogencarbonate in a lower alkanol such as methanol, ethanol or isopropanol.
  • a suitable solvent e.g. sodium methoxide or sodium hydrogencarbonate in a lower alkanol such as methanol, ethanol or isopropanol.
  • an acetal derivative of chloroacetaldehyde or bromoacetaldehyde, e.g. the dimethyl or diethyl acetal thereof is utilised as one of the reactants
  • the aldehyde is conveniently generated in situ by heating the acetal under acidic conditions, e.g. in aqueous hydrobromic acid.
  • the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula XVI as defined above with a compound of formula XVII:
  • X 1 , X 2 , Y and Z are as defined above, and L 2 represents a suitable leaving group; under conditions analogous to those described above for the reaction between chloroacetaldehyde or bromoacetaldehyde, or an acetal derivative thereof, and compound XVI.
  • the leaving group L 2 is suitably a halogen atom, e.g. bromo.
  • the compounds according to the present invention wherein R 1 represents an aryl or heteroaryl moiety may be prepared by a process which comprises reacting a compound of formula XVIII with a compound of formula XIX:
  • R la represents an aryl or heteroaryl moiety
  • L 3 represents a suitable leaving group
  • the leaving group L 3 is typically a halogen atom, e.g. chloro.
  • the transition metal catalyst of use in the reaction between compounds XVIII and XIX is suitably tetrakis(triphenylphosphine)- palladium( ⁇ ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as ⁇ A-dimethylacetamide, typically in the presence of potassium phosphate or in the presence of lithium chloride and copperd) iodide.
  • the transition metal catalyst may suitably be tris(dibenzylideneacetone)dipalladium( ⁇ ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of tri- tertr-butylphosphine and cesium carbonate.
  • L 3 in the compounds of formula XIX above represents a halogen atom
  • these compounds correspond to compounds of formula I as defined above wherein R 1 represents halogen, and they may therefore be prepared by any of the methods described above for the preparation of the compounds according to the invention.
  • the compounds according to the invention in which Y represents a chemical bond and Z represents pyrrol- 1-yl may be prepared by reacting a compound of formula XII as defined above with 2,5-dimethoxy- tetrahydrofuran. The reaction is conveniently accomplished at an elevated temperature in a solvent such as acetic acid.
  • the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula VI as defined above with a compound of formula XV as defined above in the presence of a transition metal catalyst.
  • the transition metal catalyst of use in the reaction between compounds VI and XV is suitably palladium(II) acetate, in which case the reaction is conveniently effected at an elevated temperature in the presence of triphenylphosphine in a solvent such as aqueous N, N- dimethylacetamide, typically in the presence of potassium acetate.
  • the transition metal catalyst employed in the reaction between compounds VI and XV may suitably be t ⁇ trakis(triphenyl- phosphine)palladium( ⁇ ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of cesium carbonate.
  • the starting materials of formula VI, VIII, X, XTV, XVI, XVII and XVIII may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
  • a compound of formula I initially obtained wherein the moiety W is not phenyl and is substituted by a halogen atom, e.g. bromo, may be converted into the corresponding compound wherein the moiety W is not phenyl and is substituted by an aryl or heteroaryl group, e.g. 2- cyanophenyl, 2-cyano-6-fluorophenyl or pyridin-3-yl, by treatment with the requisite aryl or heteroaryl boronic acid or cyclic ester thereof formed with an organic diol, e.g.
  • 2-cyanophenylboronic acid 3-fluoro-2-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)benzonitrile or pyridine-3-boronic acid"l,3-propanediol cyclic ester, in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium( ⁇ ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as A A 1 dimethylacetamide, aqueous 1,2-dimethoxyethane, aqueous 1,4-dioxane or aqueous tetrahydrofuran, typically in the presence of potassium phosphate, sodium carbonate or cesium carbonate; or by treatment with the appropriate stannyl reagent, e.g.
  • 2- tributylstannylbenzonitrile in the presence of a transition metal catalyst such as dichloro[l,l'-bis(diphenylphosphino)ferrocene]palladium(lI), in which case the reaction is conveniently effected at a elevated temperature in a solvent such as N, ⁇ -dimethylacetamide, typically in the presence of lithium chloride and copperd) chloride; or by treatment with the appropriate stannyl reagent in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium( ⁇ ), in which case the reaction is conveniently accomplished at an elevated temperature in a solvent such as tetrahydrofuran or 1,4-dioxane, typically in the presence of copperd) iodide; or, where the moiety W is not phenyl and in the desired compound of formula I is substituted by imidazoM-yl, simply by treatment with imidazole in the presence of a strong base such as
  • a compound of formula I wherein the moiety W is not phenyl and is substituted by pyridinyl may be converted into the corresponding compound wherein W is not phenyl and is substituted by ⁇ oxypyridinyl by treatment with znef ⁇ -chloroperbenzoic acid.
  • a compound of formula I wherein W is not phenyl and is substituted by a halogen atom, e.g. iodo may be converted, by treatment with isopropylmagnesium chloride, into a Grignard reagent which may be reacted with an aldehyde such as acetaldehyde to afford a secondary alcohol, e.g.
  • the 1-hydroxyethyl derivative and this compound may in turn be treated with an oxidising agent, e.g. Dess-Martin periodinane, to afford the corresponding compound of formula I wherein W is not phenyl and is substituted by acetyl.
  • an oxidising agent e.g. Dess-Martin periodinane
  • the resulting acetyl derivative may be converted, by treatment with methylmagnesium chloride, into the corresponding compound wherein W is not phenyl is substituted by 2"hydroxyprop-2-yl; and this compound may in turn be treated with (diethylamino) sulfur trifluoride (DAST) to afford the corresponding compound of formula I wherein W is not phenyl and is substituted by 2-fluoroprop-2-yl.
  • DAST diethylamino sulfur trifluoride
  • 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 wherein R 1 represents -C(0-Alk 1 )2R a initially obtained, wherein Alk 1 is Ci- ⁇ alkyl, typically methyl or ethyl may be converted into the corresponding compound of formula I wherein R 1 represents -COR a by hydrolysis with a mineral acid, typically aqueous hydrochloric acid.
  • a compound wherein R 1 represents formyl may be reduced with sodium triacetoxyborohydride to the corresponding compound wherein R 1 represents hydroxymethyl.
  • a compound of formula I wherein R 1 represents C2-6 alkoxycarbonyl may be reduced with lithium aluminium hydride to the corresponding compound of formula I wherein R 1 represents hydroxymethyl.
  • a compound of formula I wherein R 1 represents hydroxymethyl may be oxidised to the corresponding compound of formula I wherein R 1 represents formyl by treatment with manganese dioxide.
  • the compound of formula I wherein R 1 represents formyl may be reacted with a Grignard reagent of formula R a MgBr to afford a compound of formula I wherein R 1 represents -CH(OH)R a , and this compound may in turn be oxidised using manganese dioxide to the corresponding compound of formula I wherein R 1 represents -COR a .
  • a compound of formula I wherein R 1 represents -CH(OH)R a may be converted into the corresponding compound of formula I wherein R 1 represents -CHFR a by treatment with (diethylamino) sulfur trifluoride (DAST).
  • DAST diethylamino sulfur trifluoride
  • a compound of formula I wherein R 1 represents -COR a may be converted into the corresponding compound of formula I wherein R 1 represents -CF 2 R a by treatment with DAST.
  • a compound of formula I wherein R 1 represents amino may be converted into the corresponding compound of formula I wherein R 1 represents chloro by diazotisation, using sodium nitrite, followed by treatment with copper(l) chloride.
  • a compound of formula I wherein R 1 represents -COCH3 may be treated with thioacetamide in the presence of pyridinium tribromide to furnish the corresponding compound of formula I wherein R 1 represents 2- methylthiazol-5-yl.
  • a compound of formula I wherein R 1 is formyl may be treated with (p-tolylsulfonyl)methyl isocyanide (TosMIC) in the presence of potassium carbonate to afford the corresponding compound of formula I wherein R 1 represents oxazol-5-yl.
  • a compound of formula I wherein R 1 represents hydroxymethyl may be treated with carbon tetrabromide and triphenylphosphine to afford the corresponding compound of formula I wherein R 1 represents bromomethyl, which may then be reacted (typically in situ) with the sodium salt of imidazole or 1H- [l,2,4]triazole to provide a compound of formula I wherein R 1 represents imidazol-1-ylmethyl or [l,2,4]triazoM-ylmethyl respectively; or with the sodium salt of lH-[l,2,3]triazole to provide a mixture of compounds of formula I wherein R 1 represents [l,2,3]triazol-l-ylmethyl and
  • a compound of formula I wherein Z is substituted with methoxy may be converted to the corresponding compound wherein Z is substituted with hydroxy by treatment with boron tribromide.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the 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-j.)-toluoyl-d-tartaric acid and/or (+)-di-jrtoluoyH-tartaric acid, followed by fractional crystallization and regeneration of the free base.
  • novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
  • 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 GABA A receptors containing the ⁇ 2 and/or ⁇ 3 and/or ⁇ 5 subunit stably expressed in Ltk " cells.
  • PBS Phosphate buffered saline
  • Assay buffer 10 mM KH 2 P0 4 , 100 mM KCl, 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'-
  • Residue was purified by flash column chromatography on silica, eluting with a gradient of 10-50% ethyl acetate in hexane, to give 2-(3-chloro"2,5,6-trifluoropyridin-4-yl)propan-2- ol (300 mg, 40%): ⁇ H (400 MHz, CDC1 3 ) 1.80 (6H, d, J3 ⁇ Hz), 3.02 (lH, d, J 1.6 Hz).
  • a methanolic solution (35 ml) of the above compund (1.39 g, 6.25 mmol) in a Parr hydrogenation vessel was degassed with nitrogen via an immersed syringe needle for 10 min.
  • 10% palladium on carbon (1.4 g) was introduced to the flask under a nitrogen atmosphere.
  • Degassing was resumed for 5 min followed by addition of triethylamine (1.13 ml, 8.12 mmol).
  • Reaction mixture was subjected to a hydrogen atmosphere at 50 psi for 3 h at room temperature. Catalyst was removed by filtration under a stream of nitrogen and filtrate evaporated to dryness.
  • Residue was purified by flash column chromatography on silica, eluting with 30% ethyl acetate in hexane, to give 2-(2-amino-3,6-difluoropyridin-4-yl)propan-2-ol (1.04 g, 89%).
  • Residue was partitioned between ethyl acetate (150 ml) and aqueous sodium hydrogencarbonate solution (150 ml) and aqueous phase extracted with ethyl acetate (3 x 150 ml). Extracts were combined, dried over sodium sulphate, drying agent removed by filtration and filtrate dried under reduced pressure.
  • Residue was purified by flash column chromatography on silica, eluting with a gradient of 60-100% diethyl ether in hexane, to give 2-(5,8- difluoroimidazo[l,2-a]pyridin-7-yl)propan-2-ol (0.61 g, 75%): 6H (360 MHZ, CDCI3) 1.72 (6H, d, 0.8 Hz), 2.57 (lH, s), 6.88 (lH, dd, 5.3, 5.4 Hz), 7.63 (1H, d, ⁇ /3.0 Hz), 7.65 (lH, s); mlz (ES + ) 213 (M + +H).
  • Residue was purified by flash column chromatography on silica, eluting with 50% diethyl ether in hexane, to give 2-(3-bromo-5,8-difluoroimidazo[l,2-a]pyridin-7-yl)propan-2-ol (0.73 g, 87%): ⁇ H (360 MHz, CDCI3) 1.71 (6H, s), 2.14 (lH, s), 6.86 (lH, dd, 5.2, 7.6 Hz), 7.52 (1H, s); m/z ( ⁇ ,S + ) 291, 293 (M + +H).
  • Tetrakis(triphenylphosphine)palladium( ⁇ ) (0.022 g, 0.019 mmol) was added and the reaction mixture heated at 85°C for 16 h. Reaction was allowed to cool to room temperature and the mixture partitioned between ethyl acetate (20 ml) and water (20 ml). Organic phase was washed with IN sodium hydroxide, dried over sodium sulphate, filtered and filtrate dried under reduced pressure.
  • WO 02/074773 (0.051 g, 50%): ⁇ H (400 MHz, CDCI3) 1.73 (6H, d, J1.0 Hz), 2.16 (IH, s), 6.85 (lH, dd, Jb.l, 7.5 Hz), 7.33 (lH, t, ,78.8 Hz), 7.45 (lH, dt, e/ .3, 8.6 Hz), 7.51-7.56 (2H, m), 7.58-7.64 (lH, m); mtz (ES + ) 426 (M++H).
  • Residue was purified by flash column chromatography on silica, eluting with a gradient of 5-10% ethyl acetate in hexane, to give 2-(6-bromopyridin-2-yl)-5- fluorobenzonitrile (0.43 g, 25%): ⁇ H (360 MHz, CDCI3) 7.42 (lH, dt, J2.Q, 8.4 Hz), 7.49 (IH, dd, 2.6, 8.0 Hz), 7.56 (lH, d, 7.8 Hz), 7.70 (lH, t, J 7.7 Hz), 7.78 (IH, d, J7.6 Hz), 7.91 (lH, dd, 5.4, 8.8 Hz); mlz (ES + ) 278, 279 (M + +H).

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Abstract

La présente invention concerne un composé représenté par la formule I dans laquelle W est un noyau hétéroaromatique à cinq ou six chaînons éventuellement substitué, ou un phényle éventuellement substitué, substitué méta sur le noyau d'imidazopyridine par Y-Z, Y représentant une liaison chimique, un atome d'oxygène, ou une liaison -NH-, et Z représentant aryle, hétéroaryle ou pyridin-2-on-1-yle, n'importe lequel de ces groupes pouvant être éventuellement substitué; R1 représente hydrogène, un hydrocarbure, un groupe hétérocyclique, halogène, cyano, trifluorométhyle, nitro, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra, -CONRaRb ou -CRa=NORb, Ra et Rb représentant indépendamment hydrogène, un hydrocarbure ou un groupe hétérocyclique. L'invention concerne également des compositions pharmaceutiques contenant ledit composé, son utilisation thérapeutique, ainsi que son utilisation dans le traitement ou la prévention de l'anxiété ou de la dépression.
PCT/GB2004/000696 2003-02-26 2004-02-20 5,8-difluoroimidazo[1,2-a]pyridines constituant des ligands gaba-a ?2/?3 utilises dans le traitement de l'anxiete et/ou de la depression WO2004076452A1 (fr)

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* Cited by examiner, † Cited by third party
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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
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
WO2013120438A1 (fr) 2012-02-14 2013-08-22 中国科学院上海生命科学研究院 Substance pour le traitement ou le soulagement de la douleur

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Cited By (11)

* 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
WO2007082806A1 (fr) * 2006-01-17 2007-07-26 F. Hoffmann-La Roche Ag Derive aryl-isoxazol-4-yl-imidazo[1,2-a]pyridine utile pour le traitement de la maladie d’alzheimer via les recepteurs gaba
US7585874B2 (en) 2006-01-17 2009-09-08 Hoffmann-La Roche Inc. Aryl-isoxazol-4-yl-imidazo[1,2-a]pyridine derivatives
US8124764B2 (en) 2008-07-14 2012-02-28 Gilead Sciences, Inc. Fused heterocyclyc inhibitor compounds
US8134000B2 (en) 2008-07-14 2012-03-13 Gilead Sciences, Inc. Imidazolyl pyrimidine inhibitor compounds
US8344018B2 (en) 2008-07-14 2013-01-01 Gilead Sciences, Inc. Oxindolyl inhibitor compounds
US8088771B2 (en) 2008-07-28 2012-01-03 Gilead Sciences, Inc. Cycloalkylidene and heterocycloalkylidene inhibitor compounds
US8258316B2 (en) 2009-06-08 2012-09-04 Gilead Sciences, Inc. Alkanoylamino benzamide aniline HDAC inhibitor compounds
US8283357B2 (en) 2009-06-08 2012-10-09 Gilead Sciences, Inc. Cycloalkylcarbamate benzamide aniline HDAC inhibitor compounds
WO2013120438A1 (fr) 2012-02-14 2013-08-22 中国科学院上海生命科学研究院 Substance pour le traitement ou le soulagement de la douleur

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