Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics

Definitions

• the present invention relates to a class of substituted imidazo- triazine derivatives and to their use in therapy. More particularly, this invention is concerned with substituted imidazo[l,2-d][l,2,4]triazine derivatives which are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.
• GABA gamma- aminobutyric acid
• GABAA receptors which are members of the Ugand-gated ion channel superfamily
• GABAB receptors which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six ⁇ subunits, four ⁇ subunits, three ⁇ subunits, one ⁇ subunit, one ⁇ subunit and two p subunits.
• Receptor subtype assemblies which do exist include, amongst many others, ⁇ l ⁇ 2 ⁇ 2, ⁇ 2 ⁇ 2/3 ⁇ 2, ⁇ 3 ⁇ 2/3, ⁇ 2 ⁇ l, ⁇ 5 ⁇ 3 ⁇ 2/3, ⁇ 6 ⁇ 2, ⁇ 6 ⁇ and ⁇ 4 ⁇ .
• 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.
• Two other major populations are the ⁇ 2 ⁇ 2 and ⁇ 3 ⁇ 2/3 subtypes.
• GABA A 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 "GABA A receptor agonists".
• GABA A 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 "GABA A 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 antagonists or inverse agonists at ⁇ l might be employed to reverse sedation or hypnosis caused by ⁇ l agonists.
• the compounds of the present invention being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system.
• disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; and disorders of circadian rhythm, e.g.
• GABAA receptors include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; and hearing loss.
• Selective ligands for GABAA receptors may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.
• the present invention provides a class of imidazo-triazine derivatives which possess desirable binding properties at various GABA A receptor subtypes.
• the compounds in accordance with the present invention have good affinity as ligands for the ⁇ 2 and/or ⁇ 3 subunit of the human GABAA receptor.
• the compounds of this invention may interact more favourably with the ⁇ 2 and/or ⁇ 3 subunit than with the ⁇ l subunit.
• the compounds of the invention will exhibit functional selectivity in terms of a selective efficacy for the ⁇ 2 and/or ⁇ 3 subunit relative to the ⁇ l subunit.
• the compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the ⁇ 2 and/or ⁇ 3 subunit, as measured in the assay described hereinbelow, of 100 nM or less, typically of 50 nM or less, and ideally of 10 nM or less.
• the compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the ⁇ 2 and/or ⁇ 3 subunit relative to the ⁇ l subunit.
• Y represents hydrogen, Ci- ⁇ alkyl or C3-7 cycloalkyl
• Z represents C1-6 alkyl, C3-7 cycloalkyl, C - 7 cycloalkenyl, C G - 8 bicycloalkyl, aryl, C3-7 heterocycloalkyl, heteroaryl or di(C 1 -6)alkylamino, any of which groups may be optionally substituted;
• R 1 represents C3-7 cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any of which groups may be optionally substituted;
• R 2 represents C3-7 cycloalkyl(Ci-6)alkyl, aryl(Ci-6)alkyl or heteroaryl(C ⁇ -6)alkyl, any of which groups may be optionally substituted.
• the present invention also provides a compound of formula I as depicted above, or a salt or prodrug thereof, wherein Y represents hydrogen or Ci- ⁇ alkyl; and Z, R 1 and R 2 are as defined above.
• the groups Z, R 1 and R 2 may be unsubstituted, or substituted by one or more, suitably by one or two, substituents. In general, the groups Z, R 1 and R 2 will be unsubstituted or monosubstituted.
• Examples of optional substituents on the groups Z, R 1 and R 2 include Ci-G alkyl, aryl(C ⁇ -6)alkyl, pyridyl(C ⁇ -6)alkyl, halogen, halo(C 1 .G)alkyl, cyano, cyano(C ⁇ -G)alkyl, hydroxy, hydroxymethyl, C1-6 alkoxy, C3-7 cycloalkyl(C ⁇ -6)alkoxy, C3-7 cycloalkoxy, amino(C 1 -6)alkyl, di(C 1 -6)alkylamino(C 1 -G)alkyl, di(C 1 .G)alkylaminocarbonyl(C 1 -G)alkyl, N-(C 1 -G)alkylpiperidinyl, pyrrolidinyl(C 1 -6)alkyl, piperazinyl(C 1 - G )alkyl, morpholinyl(C 1 -6)alkyl
• substituents include Ci-e alkyl, aryl(Ci-6)alkyl, halogen, cyano, hydroxy, hydroxymethyl, Ci-e alkoxy and C3-7 cycloalkyl(C ⁇ -e)alkoxy.
• Particular substituents include C 1 - ⁇ alkyl and halogen, specifically methyl, ethyl, fluoro or chloro, and especially methyl, fluoro or chloro.
• Ci- ⁇ alkyl includes methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, . -propyl, isopropyl, tert -butyl and 1,1-dimethylpropyl. Derived expressions such as "Ci-G alkoxy" are to be construed accordingly.
• C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• the expression "C3-7 cycloalkyl(C 1 -G)alkyl” as used herein includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cy clohexy lmethy 1.
• Typical C -7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl and cyclohexenyl.
• Typical CG-8 bicycloalkyl groups include bicyclo[2.1.1]hexyl and bicyclo[2.2.1]heptyl.
• Typical aryl groups include phenyl and naphthyl, preferably phenyl.
• the expression as used herein includes 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, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazol l, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
• heteroaryl(C 1 -6)alkyl as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl
• 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.
• the present invention includes within its scope prodrugs of the compounds of formula I above.
• prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in ⁇ i ⁇ o into the required compound of formula I.
• Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
• 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.
• Typical values for the substituent Y include hydrogen, methyl, ethyl and cyclopropyl, especially hydrogen or methyl.
• Y represents hydrogen.
• Y represents methyl.
• Y represents ethyl.
• Y represents cyclopropyl.
• substituent Z examples include methyl, ethyl, isopropyl, tert -butyl, 1,1-dimethylpropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl, bicyclo[2.1.1]hex-l-yl, bicyclo[2.2.1]hept-l-yl, phenyl, fluorophenyl, chlorophenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl and diethylamino.
• Z examples include cyclobutyl, cyclopentyl, cyclohexyl, phenyl, fluorophenyl, chlorophenyl and thienyl.
• Z include cyclobutyl, cyclopentyl, phenyl and chlorophenyl.
• the substituent Z represents C 3 . 7 cycloalkyl, either unsubstituted or substituted by CI-G alkyl, especially methyl.
• Z represents cyclobutyl, cyclopentyl or cyclohexyl, specifically cyclobutyl or cyclopentyl, especially cyclobutyl.
• Z represents tert -butyl.
• Z represents phenyl.
• Z represents fluorophenyl, especially 2-fluorophenyl.
• Z represents chlorophenyl, especially 3-chlorophenyl. In one more embodiment, Z represents thienyl, especially thien-2-yl.
• Examples of typical optional substituents on the group R 1 include methyl, fluoro and methoxy, especially fluoro.
• R 1 include cyclopropyl, phenyl, methylphenyl, fluorophenyl, difluorophenyl, methoxyphenyl, furyl, thienyl, methyl-thienyl and pyridinyl. More particularly, R 1 may represent unsubstituted, monosubstituted or disubstituted phenyl. Most particularly, R 1 represents phenyl, fluorophenyl or difluorophenyl.
• R 2 represents aryl(C ⁇ -G) alkyl or heteroaryl(C ⁇ .6)alkyl, either of which groups may be optionally substituted.
• Suitable values for the substituent R 2 in the compounds according to the invention include cyclohexylmethyl, benzyl, pyrazolylmethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, benzimidazolylmethyl, oxadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl, any of which groups may be optionally substituted by one or more substituents.
• R 2 represents an optionally substituted triazolylmethyl group.
• suitable optional substituents on the group R 2 include
• substituents on the group R 2 include methyl, ethyl, 7i-propyl, benzyl, pyridinylmethyl, chloro, chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl, morpholinylmethyl and dimethylmorpholinylmethyl, particularly methyl or ethyl, especially methyl.
• R 2 Representative values of R 2 include hydroxymethyl- cyclohexylmethyl, cyanobenzyl, hydroxymethyl-benzyl, pyrazolylmethyl, dimethyl-pyrazol lmethyl, methyl-isoxazolylmethyl, thiazolylmethyl, methyl-thiazolylmethyl, ethyl-thiazolylmethyl, methyl-thiazolylethyl, imidazolylmethyl, methyl-imidazolylmethyl, ethyl-imidazolylmethyl, benzyl-imidazolylmethyl, benzimidazolylmethyl, methyl- oxadiazolylmethyl, triazolylmethyl, methyl-triazolylmethyl, ethyl- triazolylmethyl, propyl-triazolylmethyl, benzyl-triazolylmethyl, pyridinylmethyl-triazolylmethyl, cyanomethyl-triazolylmethyl, dimethylaminomethyl-triazolylmethyl, aminoe
• a favoured value of R 2 is methyl-triazolylmethyl.
• Another favoured value of R 2 is ethyl-triazolylmethyl.
• a particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs thereof:
• Y, Z and R 1 are as defined with reference to formula I above; m is 1 or 2, preferably 1; and
• R 12 represents aryl or heteroaryl, either of which groups may be optionally substituted.
• R 12 represents phenyl, pyrazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl or quinoxalinyl, any of which groups may be optionally substituted by one or more substituents.
• R 12 is optionally substituted triazolyl.
• Examples of typical substituents on the group R 12 include CI- G alkyl, aryl(C 1.6) alkyl, pyridyl(Ci-6)alkyl, halogen, cyano, cyano(C 1-6 )alkyl, hydroxymethyl, C ⁇ -6 alkoxy, C3-7 cycloalkyl(C 1 -6)alkoxy, di(C 1 - 6 )alkylamino(C 1- 6)alkyl, amino(Ci-G)alkyl, di(C 1 -6)alkylaminocarbonyl(C 1 -G)alkyl, pyrrolidinyl(C 1 -6)alkyl, piperazinyl(C ⁇ -6) alkyl and morpholinyl(C 1 .
• substituents on the group R 12 include methyl, ethyl, ? ⁇ -propyl, benzyl, pyridinylmethyl, chloro, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl and morpholinylmethyl, particularly methyl or ethyl, especially methyl.
• R 12 Particular values of R 12 include cyanophenyl, hydroxymethyl- phenyl, pyrazolyl, dimethyl-pyrazolyl, methyl-isoxazolyl, thiazolyl, methyl- thiazolyl, ethyl-thiazolyl, imidazolyl, methyl-imidazolyl, ethyl-imidazolyl, benzyl-imidazolyl, benzimidazolyl, methyl-oxadiazolyl, triazolyl, methyl- triazolyl, ethyl-triazolyl, propyl-triazolyl, benzyl-triazolyl, pyridinylmethyl-triazolyl, cyanomethyl-triazolyl, dimethylaminomethyl- triazolyl, aminoethyl-triazolyl, dimethylaminoethyl-triazolyl, dimethylaminocarbonylmethyl-triazolyl, N-methylpiperid
• a favoured value of R 12 is methyl-triazolyl.
• Another favoured value of R 12 is ethyl-triazolyl.
• a particular subset of the compounds of formula IIA above is represented by the compounds of formula IIB, and pharmaceutically acceptable salts thereof:
• Y and R 1 are as defined with reference to formula I above;
• Q represents the residue of a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or thienyl ring;
• R 3 represents hydrogen, methyl, fluoro or chloro;
• R 4 represents hydrogen, methyl or ethyl.
• the present invention also provides a compound of formula IIB as depicted above, or a pharmaceutically acceptable salt thereof, wherein Q represents the residue of a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl ring; and Y, R 1 , R 3 and R 4 are as defined above.
• R 1 suitably represents phenyl, fluorophenyl or difluorophenyl.
• Q suitably represents the residue of a cyclobutyl ring.
• Q represents the residue of a cyclopentyl ring.
• Q represents the residue of a cyclohexyl ring.
• Q represents the residue of a phenyl ring.
• Q represents the residue of a thienyl ring.
• R 3 represents hydrogen, fluoro or chloro, particularly hydrogen or chloro, especially hydrogen.
• R 4 represents methyl or ethyl, especially methyl.
• Y and R 1 are as defined with reference to formula I above; and Q, R 3 and R 4 are as defined with reference to formula IIB above.
• 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 compounds of the invention is ideally 10 nM or less, preferably 2 nM or less, and more preferably 1 nM or less.
• the compounds according to the present invention will ideally elicit at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the ⁇ 3 subunit of the human GABAA receptor. Moreover, the compounds of the invention will ideally elicit at most a 30%, preferably at most a 20%, and more preferably at most a 10%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the ⁇ l subunit of the human GABAA receptor.
• the potentiation of the GABA EC20 response in stably transfected cell lines expressing the ⁇ 3 and ⁇ l subunits of the human GABA A receptor can conveniently be measured by procedures analogous to the protocol described in Wafford et al., Mol. Pharmacol., 1996, 50, 670-678.
• the procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltk- fibroblast cells.
• the compounds according to the present invention exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are substantially non-sedating, as may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al, J. Psychopharmacol., 1996, 10, 206-213).
• the compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501.
• the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called "blood-brain barrier".
• the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.
• compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
• these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
• a pharmaceutical carrier e.g.
• a solid pre formulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
• preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
• This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
• Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient.
• the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
• a variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
• the liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
• Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
• a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day.
• the compounds may be administered on a regimen of 1 to 4 times per day.
• the compounds of formula I as defined above 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.
• the leaving group L 1 is suitably a halogen atom, typically chloro.
• reaction between compounds III and IV is conveniently effected by stirring the reactants in a suitable solvent, typically N,N- dimethylformamide, in the presence of a base such as sodium hydride or potassium carbonate.
• a suitable solvent typically N,N- dimethylformamide
• a base such as sodium hydride or potassium carbonate.
• the compounds of formula I as defined above may be prepared by a process which comprises reacting a compound of formula III as defined above with a compound of formula V:
• the reaction is conveniently effected at a temperature in the region of 0°C, typically in an inert solvent such as tetrahydrofuran.
• L 2 represents a suitable leaving group
• X represents a halogen atom, preferably chloro.
• the leaving group L 2 is suitably a halogen atom, e.g. chloro or bromo.
• the reaction between compounds VI and VII may conveniently be accomplished by stirring the reactants in a solvent such as dichloromethane, typically in the presence of pyridine; followed by heating the product thereby obtained with sodium iodide and triethylamine in a solvent such as 1,2-dichloroethane or n-butanol.
• the reaction between compounds VI and Nil may be effected by stirring at 0°C in a suitable solvent, e.g.
• 1,2-dichloroethane typically in the presence of approximately one equivalent of an organic base such as triethylamine; followed by heating at reflux in the presence of approximately one further equivalent of triethylamine.
• an organic base such as triethylamine
• the compounds of formula I as defined above may be prepared by a process which comprises reacting a compound of formula NIII with a compound of formula IX:
• Y, Z, R 1 and R 2 are as defined above, and L 3 represents a suitable- leaving group; in the presence of a transition metal catalyst.
• the leaving group L 3 is typically a halogen atom, e.g. bromo.
• the transition metal catalyst of use in the reaction between compounds NIII and IX is suitably tris(dibenzylideneacetone)- dipalladium(O), 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-tert-butylphosphine and cesium carbonate.
• the intermediates of formula IX in which the leaving group L 3 represents bromo may be prepared by brominating a compound of formula X:
• the bromination reaction is conveniently effected by treating the appropriate compound of formula X with bromine in a suitable solvent, e.g. a mixture of carbon tetrachloride and chloroform.
• the intermediates of formula X may be prepared by reacting a compound of formula IV as defined above with a compound of formula XI:
• the intermediates of formula X may be prepared by reacting a compound of formula V as defined above with a compound of formula XI as defined above in the presence of triphenylphosphine and diethyl azodicarboxylate; under conditions analogous to those described above for the reaction between compounds III and V.
• the intermediates of formula XI may be prepared by reacting a compound of formula NI as defined above with a compound of formula XII:
• any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art.
• a compound of formula I initially obtained wherein R 2 is unsubstituted may be converted into a corresponding compound wherein R 2 is substituted, typically by standard alkylation procedures, for example by treatment with a haloalkyl derivative in the presence of sodium hydride and iV,N-dimethylformamide, or with a hydroxyalkyl derivative in the presence of triphenylphosphine and diethyl azodicarboxylate.
• a compound of formula I initially obtained wherein the R 2 substituent is substituted by a halogen atom, e.g. chloro may be converted into the corresponding compound wherein the R 2 substituent is substituted by a di(C ⁇ -G)alkylamino moiety by treatment with the appropriate di(C 1 -6)alkylamine, typically with heating in a solvent such as 1,4-dioxane in a sealed tube.
• a compound of formula I initially obtained wherein the R 2 substituent is substituted by a halogen atom, e.g. chloro may be converted into the corresponding compound wherein the R 2 substituent is substituted by a di(C ⁇ -G)alkylamino moiety by treatment with the appropriate di(C 1 -6)alkylamine, typically with heating in a solvent such as 1,4-dioxane in a sealed tube.
• 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- -toluoyl-d-tartaric acid and/or (+)-di-/?-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base.
• the novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
• any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
• the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
• the compounds in accordance with this invention potently inhibit the binding of [ 3 H]-flumazenil to the benzodiazepine binding site of human GABAA receptors containing the ⁇ 2 or ⁇ 3 subunit stably expressed in Ltk- cells.
• PBS Phosphate buffered saline
• Assay buffer 10 mM KH2PO4, 100 mM KCl, pH 7.4 at room temperature.
• Harvesting Cells Supernatant is removed from cells. PBS (approximately 20 ml) is added. 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:
• 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.
• Tris(dibenzylideneacetone)dipalladium(0) (15.5 mg, 0.017 mmol) and a 0.1M solution of tri-terf-butylphosphine in 1,4- dioxane (0.406 ml, 0.406 mmol) was added, and the mixture was further degassed with two more freeze-pump-thaw cycles before heating at 90°C under nitrogen for 17 h.
• the mixture was filtered through glass fibre paper, washed with ethyl acetate. The filtrate was washed with saturated NaCl solution, separated, dried over MgSO 4 and evaporated in vacuo.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Neurology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Steroid Compounds (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (1)

Family

ID=10859670

Family Applications (1)

Country Status (10)

Cited By (6)

Families Citing this family (11)

Citations (3)

• 1999
  • 1999-08-23 GB GBGB9919957.2A patent/GB9919957D0/en not_active Ceased
• 2000
  • 2000-08-17 CA CA002380452A patent/CA2380452C/en not_active Expired - Fee Related
  • 2000-08-17 WO PCT/GB2000/003199 patent/WO2001014377A1/en not_active Ceased
  • 2000-08-17 AU AU67077/00A patent/AU775008B2/en not_active Ceased
  • 2000-08-17 US US10/069,437 patent/US6608062B1/en not_active Expired - Fee Related
  • 2000-08-17 DE DE60006260T patent/DE60006260T2/de not_active Expired - Lifetime
  • 2000-08-17 AT AT00954717T patent/ATE253066T1/de not_active IP Right Cessation
  • 2000-08-17 ES ES00954717T patent/ES2208404T3/es not_active Expired - Lifetime
  • 2000-08-17 JP JP2001518708A patent/JP2003507479A/ja not_active Withdrawn
  • 2000-08-17 EP EP00954717A patent/EP1212324B1/en not_active Expired - Lifetime

Patent Citations (3)

Also Published As

Similar Documents

Legal Events