WO2003087099A1 - Derives d'imidazo-pyridine tenant lieu de ligands pour les recepteurs gaba - Google Patents

Derives d'imidazo-pyridine tenant lieu de ligands pour les recepteurs gaba Download PDF

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WO2003087099A1
WO2003087099A1 PCT/GB2003/001454 GB0301454W WO03087099A1 WO 2003087099 A1 WO2003087099 A1 WO 2003087099A1 GB 0301454 W GB0301454 W GB 0301454W WO 03087099 A1 WO03087099 A1 WO 03087099A1
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alkyl
formula
compound
represents hydrogen
pharmaceutically acceptable
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PCT/GB2003/001454
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Karl Richard Gibson
Simon Charles Goodacre
David James Hallett
Leslie Joseph Street
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Merck Sharp & Dohme Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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

Definitions

  • the present invention relates to the use of a class of substituted imidazo-pyridine derivatives in therapy. More particularly, this invention is concerned with the therapeutic use of imidazo[4,5-b]pyridine analogues which are substituted in the 1-position by an optionally substituted phenyl ring.
  • These compounds are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.
  • Receptors for the major inhibitory neurotransmitter, gamma- aminobutyric acid (GABA) are divided into two main classes: (1) 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.
  • 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, o ⁇ 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, BZ1 and BZ2, on the basis of radioligand binding studies.
  • the BZ1 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 GABA A 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 GABA A receptor by acting as BZ agonists are referred to hereinafter as "GABAA receptor 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 BZ1 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.
  • the compounds of use in the present invention being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system.
  • 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; neurodegeneration arising from cerebral ischemia; Tourette's syndrome; 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-
  • disorders for which selective ligands for GABA A 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 of use in the present invention may also be useful as radioligands in assays for detecting compounds capable of binding to the human GABAA receptor.
  • EP-A-0616807 describes a class of benzimidazole derivatives which are stated to possess potent benzodiazepine receptor affinity, and thus to be useful in the treatment of convulsions, anxiety, sleep disorders, memory disorders and other disorders sensitive to benzodiazepine receptor binding activity.
  • WO 98/34923 relates to a class of 1-phenylbenzimidazole derivatives, substituted at the meta position of the phenyl ring by a methylene-, carbonyl- or tbiocarbonyl-linked amine moiety, which are selective ligands for GABAA receptors and accordingly of benefit in alleviating neurological disorders including anxiety and convulsions.
  • WO 01/18000 provides a class of 3-phenylimidazo[4,5-6]pyridine derivatives, substituted at the meta position of the phenyl ring by a range of substituents, which are selective ligands for GABAA receptors and accordingly of benefit in alleviating neurological disorders including anxiety and convulsions. That publication does not, however, disclose or suggest replacing the 3-phenylimidazo[4,5-6]pyridine derivatives disclosed therein with the l-phenylimidazo[4,5-b]pyridine substitution pattern.
  • EP-A-0563001 describes a class of fused imidazole derivatives which are stated to possess activity as calcium channel blockers.
  • the present invention provides the use of a class of imidazo- pyridine derivatives which possess desirable binding properties at various GABA A receptor subtypes.
  • the compounds of use in the present invention have good affinity as ligands for the ⁇ 2 and/or ⁇ 3 and/or ⁇ 5 subunit of the human GABA A receptor.
  • the compounds of use in 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 use in the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the ⁇ 2 and/or ⁇ 3 and/or ⁇ 5 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 of use in 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.
  • the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof:
  • X 1 represents hydrogen, halogen, Ci-6 alkyl, trifluoromethyl or Ci-e alkoxy
  • X 2 represents hydrogen or halogen
  • Z represents hydrogen, or an optionally substituted aryl or heteroaryl group
  • R a and R b independently represent hydrogen, hydrocarbon or a heterocyclic group; for the manufacture of a medicament for the treatment and/or prevention of conditions for which the administration of a GABA A receptor ligand is indicated.
  • the present invention also provides a method for the treatment and/or prevention of conditions for which the administration of a GABA A receptor ligand is indicated, 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 aryl or heteroaryl 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.
  • 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 of use in the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of use in 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(C ⁇ -6)alkyl, indanyl, aryl and aryl(C 1 -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 ⁇ -6)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, -propyl, isopropyl, isobutyl, teri-butyl and 2,2-dimethylpropyl. Derived expressions such as "C1-6 alkoxy”, “Ci-e alkylamino" and "CI-G 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. Typical examples of C3-7 cycloalkyl(Ci-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 ⁇ -6) 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, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, 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.
  • the hydrocarbon and heterocyclic groups may in turn be optionally substituted by one or more groups selected from Ci-e alkyl, adamantyl, phenyl, halogen, C ⁇ -6 haloalkyl, C ⁇ -6 aminoalkyl, trifluoromethyl, hydroxy, Ci-e 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-e alkylthio, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, arylsulphonyl, -NR V R W , -NR v COR w -NR ⁇ C0 2 R w , -NR v S0 2
  • the compounds of use in the invention may accordingly exist as enantiomers. Where the compounds of use in the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that the use of all such isomers and mixtures thereof in any proportion is encompassed within the scope of the present invention.
  • Suitable values for the X 1 substituent include hydrogen, fluoro, chloro, methyl, trifluoromethyl and methoxy; especially hydrogen or fluoro; and more especially hydrogen.
  • Typical values of X 2 include hydrogen and fluoro, especially hydrogen.
  • Z is hydrogen.
  • Z represents an optionally substituted aryl or heteroaryl group.
  • Selected values for the substituent Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl, 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 or monosubstituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.
  • substituents on the group Z include fluoro, chloro, cyano, methyl, hydroxy, methoxy, oxy, methanesulphonyl and aminocarbonyl.
  • substituents on the group Z include fluoro, cyano and methyl; especially fluoro or cyano; and more especially cyano.
  • Z represents 2-cyano-4-fluorophenyl.
  • Z represents pyridin-3-yl.
  • R a examples include hydrogen and Ci- ⁇ alkyl.
  • R represents hydrogen or methyl.
  • R b examples include hydrogen, Ci-e alkyl, hydroxy(C ⁇ -e) alkyl and di(C ⁇ -6)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.
  • R 1 Individual values of R 1 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 l,2-dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), cyanopropyl (especially 2- cyanoprop-2-yl), methoxycarbonylpropyl (especially 2- methoxycarbonylprop-2-yl), tert-butyi, hydroxybutyl (especially 1-hydroxy- 2-methylprop-2-yl), pyridinyl, furyl,
  • R 1 represents 2-hydroxyprop-2-yl. In another favoured embodiment, R 1 represents trifluoromethyl. In a further embodiment, R 1 represents methyl.
  • R 2 is hydrogen
  • R 3 represents hydrogen or dimethylaminoethyl, especially hydrogen.
  • the present invention provides a sub-class of novel compounds represented by formula II, and pharmaceutically acceptable salts thereof:
  • X 11 represents hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy
  • X 12 represents hydrogen or fluoro
  • R 4 represents hydrogen, fluoro, cyano or methyl
  • R 5 represents hydrogen or C 1 -6 alkyl
  • R e represents hydrogen, Ci- ⁇ alkyl, hydroxy(C ⁇ -6)alkyl or di(C 1 .e)alkylamino(C ⁇ .6)alkyl.
  • X 11 include hydrogen and fluoro, suitably hydrogen.
  • X 12 represents hydrogen. In another embodiment, X 12 represents fluoro. Suitably, R 4 represents hydrogen or cyano.
  • R 4 is hydrogen
  • R 4 is fluoro
  • R 4 is cyano
  • R 4 is methyl.
  • R 5 represents hydrogen or methyl, especially hydrogen.
  • R 6 represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of R 6 include hydrogen, hydroxyethyl and dimethylaminoethyl. Typically, R 6 represents hydrogen or dimethylaminoethyl, especially hydrogen. Where 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 u represents he teroaryl(C ⁇ -e) alkyl
  • this group is suitably imidazolylmethyl or triazolylmethyl.
  • Individual values of R 11 include hydrogen, methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1 -hydroxyethyl), fluoroethyl (especially
  • 1-fl.uoroethyl difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially
  • R 11 represents 2-hydroxyprop-2-yl. In another favoured embodiment, R 11 represents trifluoromethyl. In a further embodiment, R 11 represents methyl.
  • the present invention provides a specific novel compound selected from:
  • 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 of use in 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 use in the invention is ideally 50 nM or less, preferably 10 nM or less, and more preferably 5 nM or less.
  • the anxiolytic compounds of use in 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 use in 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 of use in 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 use in 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 of use in 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.,
  • 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,
  • Cognitive disorders for which the compounds of use in 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
  • the compounds of use in 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 use in the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.
  • compositions comprising one or more novel 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.
  • a solid preformulation composition containing a homogeneous mixture of a novel 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.
  • 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 of use in the present invention may be prepared by a process which comprises reacting a compound of formula III:
  • X 1 , X 2 , Z and R 1 are as defined above; with triethyl orthoformate.
  • the reaction is conveniently effected in the presence of formic acid, typically at an elevated temperature, e.g. the reflux temperature of the solvent.
  • the intermediates of formula III may be prepared by reacting a compound of formula IN with a compound of formula N:
  • X 1 , X 2 , Z and R 1 are as defined above, and L 1 represents a suitable leaving group; followed by reduction of the nitro group.
  • the leaving group L 1 is suitably a sulfonyloxy moiety, e.g. trifluoromethanesulfonyloxy (triflyloxy); or a halogen atom, e.g. chloro.
  • reaction between compounds IN and N is conveniently carried out by heating in a solvent such as dime thy lsulfoxide.
  • Reduction of the nitro group in the compound thereby obtained is conveniently effected by treatment with a reducing agent such as sodium sulphide nonahydrate, in which case the reaction is suitably carried out in methanol, typically in the presence of ammonium chloride at the reflux temperature of the solvent.
  • a reducing agent such as sodium sulphide nonahydrate
  • the compounds of use in the present invention may alternatively be prepared by a process which comprises reacting a compound of formula NI with a compound of formula Nil:
  • L 2 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; in the presence of a transition metal catalyst.
  • the leaving group L 2 is typically a halogen atom, e.g. bromo.
  • the transition metal catalyst of use in the reaction between compounds VI and Nil is suitably tetrakis(triphenylphosphine)- palladium(O).
  • the reaction is conveniently carried out at an elevated temperature in a solvent such as -ZV,AT-dimethylformamide, advantageously in the presence of potassium phosphate.
  • the compounds of use in the present invention may be prepared by a process which comprises reacting a compound of formula NIII with a compound of formula IX:
  • L 3 represents a suitable leaving group; in the presence of a transition metal catalyst.
  • the leaving group L 3 is typically triflyloxy.
  • the transition metal catalyst of use in the reaction between compounds NIII and IX is suitably tris(dibenzylideneacetone)- dipalladium(O).
  • the reaction is conveniently carried out at an elevated temperature in a solvent such as A ⁇ A ⁇ -dimethylacetamide, typically in the presence of 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl and potassium phosphate.
  • M 1 in the intermediates of formula NI above represents a cyclic ester of a boronic acid moiety -B(OH)2 formed with pinacol
  • the relevant compound NI may be prepared by reacting bis(pinacolato)diboron with a compound of formula NIII as defined above; in the presence of a transition metal catalyst.
  • the transition metal catalyst of use in the reaction between bis(pinacolato)diboron and compound NIII is suitably dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II).
  • the reaction is conveniently carried out at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of l,l'-bis(diphenylphosphino)- ferrocene and potassium acetate.
  • the compounds of use in the present invention may be prepared by a process which comprises reacting a compound of formula X with a compound of formula XI:
  • X 1 , X 2 , Z and R 1 are as defined above, and L 4 represents a suitable leaving group; in the presence of a transition metal catalyst.
  • the leaving group L 4 is typically a halogen atom, e.g. bromo.
  • the transition metal catalyst of use in the reaction between compounds X and XI is suitably tetrakis(triphenylphosphine)- palladium(O), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as iV,iV-dimethylformamide or a mixture of 1,3-propanediol and 1,2-dimethoxyethane, typically in the presence of potassium phosphate or sodium carbonate.
  • L 4 in the compounds of formula XI above represents a halogen atom
  • these compounds correspond to compounds of formula I as defined above wherein R 3 represents halogen, and they may therefore be prepared by any method analogous to those described above for the preparation of the compounds of use in the invention.
  • X 1 , X 2 and R 1 are as defined above; with triflic anhydride, typically in the presence of pyridine.
  • the intermediates of formula XII above may suitably be prepared by reacting a compound of formula X as defined above with a compound of formula XIII:
  • X 1 , X 2 and L 4 are as defined above; by treatment with hydrobromic acid, typically in acetic acid at an elevated temperature.
  • X 1 , X 2 and L 4 are as defined above; with triethyl orthoformate; under conditions analogous to those described above for the reaction between compound III and triethyl orthoformate.
  • the intermediates of formula XV above may suitably be prepared by reacting a compound of formula XVI with a compound of formula XVII:
  • the compounds of use in the present invention may be prepared by a process which comprises reacting a compound of formula XVIII with a compound of formula XIX:
  • L 5 represents a suitable leaving group.
  • the leaving group L 5 is suitably a halogen atom, e.g. bromo; or trimethoxysilyl.
  • L 5 represents halogen
  • the reaction is conveniently effected by heating in xylene, typically in the presence of copper triflate benzene complex, phenanthroline, dibenzylidene acetone and cesium carbonate.
  • LHMDS lithium hexamethyldisilazide
  • solvent such as tetrahydrofuran.
  • L 5 represents trimethoxysilyl
  • the reaction is conveniently effected in a solvent such as AT,iV-dimethylformamide, typically in the presence of copper(II) acetate and tetra-. ⁇ -butylammonium fluoride.
  • R 1 is as defined above; with a reducing agent, e.g. 10% palladium on charcoal, in the presence of formic acid, typically at the reflux temperature.
  • a reducing agent e.g. 10% palladium on charcoal
  • the intermediates of formula XIX above may, for example, be prepared by methods analogous to those described in WO 01/18000 and WO 01/90108.
  • Ci-6 alkyl 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 hydroxymethyl may be oxidised to the corresponding compound of formula I wherein R 1 represents formyl by treatment with manganese dioxide.
  • the formyl derivative thereby obtained may be condensed with a hydroxylamine derivative of formula H 2 N-OR b to provide a compound of formula I wherein R 1 represents
  • 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 diethylaminosulfur 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 -CF2R 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(I) 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 lH-[l,2,4]triazole to provide a compound of formula I wherein R 1 represents imidazol-1-ylmethyl or [l,2,4]triazol-l-ylmethyl respectively; or with the sodium salt of 1H- [l,2,3]triazole to provide a mixture of compounds of formula I wherein R 1 represents [l,2,3]triazol-l-ylmethyl and [l,2,3]triazol-2-ylmethyl; or with morpholine to provide a compound of formula I wherein R 1 represents morpholin-4-ylmethyl.
  • a compound of formula I wherein Z is substituted with methoxy may be converted to the corresponding compound wherein Z is substituted with
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative ⁇ PLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • preparative ⁇ PLC or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base.
  • optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base.
  • optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the compounds of use in this invention potently inhibit the binding of [ 3 H]-flumazenil to the benzodiazepine binding site of human GABAA 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 KC1, pH 7.4 at room temperature.
  • [ 3 H]-Flumazenil (18 nM for ⁇ l ⁇ 3 ⁇ 2 cells; 18 nM for ⁇ 2 ⁇ 3 ⁇ 2 ceUs; 10 nM for ⁇ 3 ⁇ 3 ⁇ 2 cells; 10 nM for ⁇ 5 ⁇ 3 ⁇ 2 cells) in assay buffer.
  • Supernatant is removed from cells.
  • PBS approximately 20 ml
  • the cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed.
  • the cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cm x 25 cm) of cells.
  • Assay Can be carried out in deep 96-well plates or in tubes. Each tube contains:
  • Assays are incubated for 1 hour at 40°C, then filtered using either a Tomtec or Brandel cell harvester onto GF/B filters followed by 3 x 3 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. 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.
  • Trifluoromethanesulfonic acid 6-methyl-2-nitropyridin-3-yl ester 50 mg, 0.17 mmol
  • 3-(pyridin-3-yl)aniline 30 mg, 0.17 mmol
  • the reaction was partitioned between water (20 ml) and ethyl acetate (20 ml).
  • A/-Benzyl-N-(3-nitro-6-trifluoromethylpyridin-2-yl)amine (110 mg, 0.37 mmol) was dissolved in formic acid (25 ml) and 10% Pd/C (25 mg) was added as a slurry in water. The reaction was heated at reflux for 24 h. The reaction was allowed to cool, filtered through celite and evaporated before azeotroping with toluene (2 x 10 ml) to afford a white solid. The solid was partitioned between ethyl acetate and Na ⁇ C ⁇ 3 solution (sat. aq.).
  • the reaction was dissolved in methanol and partitioned between water (150 ml) and ethyl acetate (150 ml), the layers were separated and the aqueous extracted with ethyl acetate (2 x 50 ml), the combined organic extracts were washed with brine (50 ml), dried (Na 2 S0 4 ) and evaporated.
  • the reaction was purified by preparative thin layer chromatography (5% 2M NH3 in methanol/ethyl acetate) to afford the title product (3.6 mg, 1%).

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Abstract

L'invention concerne une classe de dérivés de 1-phénylimidazo[4,5-b]pyridine, éventuellement substitués en position méta du cycle phényle par un groupe aryle ou heteroaryle éventuellement substitué. Ces dérivés tiennent lieu de ligands sélectifs pour les récepteurs GABAA. En particulier, ils présentent une grande affinité de liaison avec la sous-unité α2 et/ou α3 et/ou α5 de ces récepteurs, et ils sont donc utiles dans le traitement et/ou la prévention des troubles du système nerveux central, y compris l'anxiété, les convulsions et les troubles cognitifs.
PCT/GB2003/001454 2002-04-11 2003-04-03 Derives d'imidazo-pyridine tenant lieu de ligands pour les recepteurs gaba WO2003087099A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7442709B2 (en) * 2003-08-21 2008-10-28 Osi Pharmaceuticals, Inc. N3-substituted imidazopyridine c-Kit inhibitors
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
WO2020053377A1 (fr) 2018-09-13 2020-03-19 Saniona A/S Ligand de récepteur gaba a

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US4654350A (en) * 1981-12-19 1987-03-31 Merck Patent Gesellschaft Mit Beschrankter Haftung Gaba-agonistic imidazo(4,5-c)pyridines useful as pharmaceuticals
EP0563001A1 (fr) * 1992-03-26 1993-09-29 Neurosearch A/S Dérivés de l'imidazole, leur préparation et leur utilisation
WO2001018000A1 (fr) * 1999-09-07 2001-03-15 Merck Sharp & Dohme Limited Derives d'imidazo-pyridine en tant que ligands destines aux recepteurs gaba

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US4654350A (en) * 1981-12-19 1987-03-31 Merck Patent Gesellschaft Mit Beschrankter Haftung Gaba-agonistic imidazo(4,5-c)pyridines useful as pharmaceuticals
EP0563001A1 (fr) * 1992-03-26 1993-09-29 Neurosearch A/S Dérivés de l'imidazole, leur préparation et leur utilisation
WO2001018000A1 (fr) * 1999-09-07 2001-03-15 Merck Sharp & Dohme Limited Derives d'imidazo-pyridine en tant que ligands destines aux recepteurs gaba

Non-Patent Citations (2)

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Title
KROGSGAARD-LARSEN ET AL: "GABA Receptor Agonists, Partial Agonists, and Antagonists. Design and Therapeutic Prospects", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 37, no. 16, 5 August 1994 (1994-08-05), pages 2489 - 2505, XP002080824, ISSN: 0022-2623 *
MARTIN I L ET AL: "BENZODIAZEPINE RECOGNITION SITE LIGANDS AND GABAA RECEPTORS", EXPERT OPINION ON THERAPEUTIC PATENTS, ASHLEY PUBLICATIONS, GB, vol. 9, no. 10, 1999, pages 1347 - 1358, XP001007805, ISSN: 1354-3776 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7442709B2 (en) * 2003-08-21 2008-10-28 Osi Pharmaceuticals, Inc. N3-substituted imidazopyridine c-Kit inhibitors
US7767673B2 (en) 2003-08-21 2010-08-03 Osi Pharmaceuticals, Inc. N-substituted imidazopyridine c-Kit inhibitors
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
WO2020053377A1 (fr) 2018-09-13 2020-03-19 Saniona A/S Ligand de récepteur gaba a
JP2022500445A (ja) * 2018-09-13 2022-01-04 サニオナ エー／エス Ｇａｂａａ受容体リガンド
US11396510B2 (en) 2018-09-13 2022-07-26 Saniona A/S GABAA receptor ligand
JP7353663B2 (ja) 2018-09-13 2023-10-02 サニオナ エー／エス Ｇａｂａａ受容体リガンド

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