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WO2002026747A1 - Derives de dihydroimidazo[2,1-b]thiazole et de dihydro-5h-thiazolo[3,2-a]pyrimidine possedant une affinite pour les recepteurs 5-ht - Google Patents

Derives de dihydroimidazo[2,1-b]thiazole et de dihydro-5h-thiazolo[3,2-a]pyrimidine possedant une affinite pour les recepteurs 5-ht Download PDF

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Publication number
WO2002026747A1
WO2002026747A1 PCT/GB2001/004317 GB0104317W WO0226747A1 WO 2002026747 A1 WO2002026747 A1 WO 2002026747A1 GB 0104317 W GB0104317 W GB 0104317W WO 0226747 A1 WO0226747 A1 WO 0226747A1
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Prior art keywords
dihydroimidazo
carbon atoms
formula
group containing
group
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English (en)
Inventor
Paul Brough
John Paul Watts
Victor Cockroft
Frank Kerrigan
Kevin James Doyle
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Abbott GmbH and Co KG
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Knoll GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to certain novel substituted dihydroimidazo[2,1- jbjthiazole and dihydro-5r/-thiazolo[3,2-a]pyrimidine compounds which have affinity for 5-HT 1A receptors and which inhibit neuronal reuptake of 5-hydroxytryptamine and/or noradrenaline, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive- compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress, as an aid to smoking cessation and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral is
  • aryl orheteroaryl group optionally substituted by one or more substituents selected from i) halo, ii) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iii) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iv) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, g) an arylalkyl or heteroarylalkyl group in which the alkyl chain contains 1 to 3 carbon atoms and in which the aryl or heteroaryl group may optionally be substituted by one or more substituents selected from i) halo, ii) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, iii) an alkoxy group containing 1 to 3 carbon
  • A is S(O) p or O; p is 0, 1 or 2; g is 0, 1, 2, 3, or 4; n is 2 or 3;
  • R-i is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group, an alkylsulphinyl group or an alkylsulphonyl group each containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) a hydroxyalkyl group containing 1 to 3 carbon atoms, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or a carbarn oy (methyl group each optionally ⁇ /-substituted by one
  • R 2 , R 3 and R 4 independently are H or an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo;
  • R 5 is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group, an alkylsulphinyi group or an alkylsulphonyl group each containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) a hydroxyalkyl group containing 1 to 3 carbon atoms, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or a carbamoylmethyl group each optionally ⁇ /-substituted by one or two al
  • the prior art compounds generally exhibit activity as monoamine oxidase inhibitors and/or have affinity for other receptors, for example muscarinic receptors, and are therefore likely to cause undesired side effects.
  • the present invention provides compounds with unexpectedly superior selectivity and efficacy.
  • g 0, 1, 2, 3, 4 or 5;
  • n -2 or 3;
  • R-i is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group, an alkylsulphinyl group or an alkylsulphonyl group each containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) a hydroxyaikyl group containing 1 to 3 carbon atoms, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or a carbamoylmethyl group each optionally ⁇ -substituted by one or two
  • R 2 represents H, an alkyl group containing 1 to 6 carbon atoms optionally substituted by one or more halo, a hydroxyaikyl group containing 1 to 6 carbon atoms, an ⁇ - hydroxyarylmethyl group, a hydroxyalkenyi group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the double bond, a hydroxyaikynyl group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the triple bond, a hydroxycycloalkyl group containing 3 to 6 carbon atoms, an alkenyl group containing 2 to 8 carbon atoms, an arylalkenyl group containing 8 to 10 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, a C 3 ⁇ cycloalkoxyCt.
  • halo when used herein, includes fluoro, chloro, bromo and iodo. It will be understood that in alkyl groups, alkenyl groups, alkynyi groups, alkylthio groups and alkoxy groups containing more .than two carbon atoms the alkyl group may be straight or branched.
  • Aryl means phenyl optionally substituted by one or more of the following: halo, a C ⁇ _ 3 alkyl group or a C ⁇ alkoxy group.
  • R-j are methyl, ethyl, propyl, isopropyl, cyciopropyl, methoxy, ethoxy, isopropoxy, bromo, chloro, fluoro, iodo, trifluoromethyl, trifiuoromethoxy, methyithio, methylsulphinyl, methylsulphonyl, hydroxy, formyloxy, acetoxy, hydroxymethyl, 1-hydroxyethyI, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, cyano, formyl, acetyl, methoxycarbonyl, " ethoxycarbonyl, carbamoyl, carbamoylmethyl, sulphamoyl, sulphamoylmethyl, amino, methylamino, dimethylamino, ethylamino or diethylamino. More preferably R 1 is methyl, methoxy, chloro, fluoro or
  • R 2 are H, methyl, ethyl, propyl, isopropyl, cyciopropyl, butyl, methoxy, ethoxy, bromo, chloro, fluoro, iodo, trifluoromethyl, trifiuoromethoxy hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl; 1-hydroxypropyl, 1- hydroxy-2-methyIpropyl, 1-hydroxybutyl, 1-hydroxy-3-methylbutyl, 1-hydroxy ⁇ e ⁇ tyl, 1-hydroxypropenyl, 1 -hydroxy but-3-eny I, 1-hydroxy-2-methylpropenyl, 1-hydroxy-2- methylbut-3-enyl, 1-hydroxypent-4-enyl, 3-hydroxybuM-enyl, 1-hydroxypropynyl, 1- hydroxybut-2-ynyl, .
  • R 2 is H, hydroxymethyl, methyl, ethyl, isopropyl, vinyl and methylthio. Most preferably R 2 is hydroxymethyl, methyl or ethyl.
  • g 0, 1 or 2;
  • n 2 or 3;
  • Ri is halo, an alkyl group containing 1 to 3 carbon atoms, an alkoxy group containing 1 to 3 carbon atoms or hydroxy;
  • R 2 represents H, an alkyl group containing 1 to 3 carbon atoms, an alkenyl group containing 2 to 3 carbon atoms, a hydroxyaikyl group containing 1 to 6 carbon atoms, or a C ⁇ alkylthio group.
  • g is 0 or 1 , for example 0. More preferably n is 2.
  • a second preferred group of compounds of Formula I is represented by Formula II
  • R-i, R 2 , n and g are as initially defined.
  • a fourth preferred group of compounds of Formula I is represented by Formula IV.
  • R 1 f R 2l n and g are as initially defined.
  • a fifth preferred group of compounds of Formula I is represented by Formula V
  • g 0, 1 or 2;
  • n 2 or 3;
  • Ri is halo, an alkyl group containing 1 to 3 carbon atoms, an alkoxy group containing 1 to 3 carbon atoms or hydroxy;
  • R 2 represents H, an alkyl group containing 1 to 3 carbon atoms, an alkenyl group containing 2 to 3 carbon atoms, a hydroxyaikyl group containing 1 to 6 carbon atoms, or a G,. 3 alkylthio group. More preferably n is 2.
  • R 2 represents H, an alkyl group containing 1 to 3 carbon atoms, an alkenyl group containing 2 to 3 carbon atoms, a hydroxyaikyl group containing 1 to 6 carbon atoms, or a C ⁇ alkylthio group.
  • R 2 is methyl, ethyl, isopropyl, vinyl, hydroxymethyl or methylthio.
  • R 2 represents an alkyl group containing 1 to 3 carbon atoms, an alkenyl group containing 2 to 3 carbon atoms, a hydroxyaikyl group containing 1 to 6 carbon atoms, or a Ci. 3 alkylt.hi0 group.
  • R 2 is methyl, ethyl, isopropyl, vinyl, hydroxymethyl or methylthio.
  • g is 0 or 1
  • n is 2
  • R 2 represents H, an alkyl group containing 1 to 3 carbon atoms, an alkenyl group containing 2 to 3 carbon atoms, a hydroxyaikyl group containing 1 to 6 carbon atoms, or a C 1-3 alkylthio group.
  • R 2 is methyl, ethyl, isopropyl, vinyl, hydroxymethyl or methylthio.
  • R 2 represents H, an alkyl group containing 1 to 3 carbon atoms, an alkenyl group containing 2 to 3 carbon atoms, a hydroxyaikyl group containing 1 to 6 carbon atoms, or a C ⁇ alkylthio group.
  • R 2 is methyl, ethyl, isopropyl, vinyl, hydroxymethyl or methylthio.
  • Compounds of Formula I may exist as salts with pharmaceutically acceptable acids.
  • the present invention includes all such salts.
  • Examples of such salts include hydrochlorides, hydrobromides, sulphates, methanesuiphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [eg (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid.
  • Certain compounds of Formula I may exist in differenttautomeric forms or as different geometric isomers, and the present invention includes eachtautomer and/or geometric isomer of compounds of Formula I and mixtures thereof.
  • Certain compounds of Formula I may exist in different stable conformationa! forms which may be separable. For example, if R 2 is a bulky group there may be restricted rotation about one or more single bond or bonds due tosteric hindrance. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of compounds of Formula I and mixtures thereof.
  • Certain compounds of Formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. Certain compounds of Formula I and their salts may also exist in the form of soivates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • Certain compounds of Formula I contain one or morechiral centres, and exist in different optically active forms. When compounds of Formula I contain onechiral centre, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereois ⁇ meric salts which may be separated, for example, by crystallisation; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; or gas-liquid or liquid chromatography in a chiral environment, for example on a chirai support for example silica with a bound chiral ligand or in the presence of a chiral solvent, it will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form.
  • specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of Formula I When a compound of Formula I contains more than one chiral centre it may exist in diastereoisomeric forms.
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallisation and the individual enantiomers within each pair may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of Formula I and mixtures thereof.
  • a preferred group of compounds of Formula I are compounds, including pharmaceutically acceptable salts thereof, in which
  • g is 0, 1 or 2, preferably 0 or 1
  • n 2
  • Ri is a) halo, b) an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group, an alkylsulphinyl group or an alkylsulphonyl group each containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) a hydroxyaikyl group containing 1 to 3 carbon atoms, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or a carbamoylmethyl group each optionally N-substituted by one or two alkyl
  • R 2 represents H or an alkyl group containing 1 to 6 carbon atoms, an alkyl group containing 1 to 6 carbon atoms optionally substituted by one or more halo, a hydroxyaikyl group containing 1 to 6 carbon atoms, an ⁇ -hydroxyarylmethyl group, a hydroxyalkenyl group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the double bond, a hydroxyalkynyl group containing 3 to 6 carbon atoms in which hydroxy is not attached directly to either carbon of the triple bond, a hydroxycycloalkyl group containing 3 to 6 carbon atoms, an alkenyl group containing 2 to 8 carbon atoms, anarylalkenyl group containing 8 to 10 carbon atoms, a cycloalkyl group containing 3 to 6 carbon atoms, a C 3 .
  • condensed thiazoie ring may be attached at the 4 or 7-position of the benzofuran ring.
  • Particularly preferred compounds are the following:
  • the present invention also includes pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I or a salt thereof together with a pharmaceutically acceptable diluent or carrier.
  • active compound denotes a compound of Formula I or a salt thereof.
  • the active compound may be administered orally, rectally, parenterally or topically, preferably orally.
  • the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy.
  • the compositions of the invention may contain 0.1-99% by weight of active compound.
  • the compositions of the invention are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is 1-500 mg.
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
  • compositions for oral administration are the preferred compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oil suspensions.
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
  • Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the mixture by known methods.
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
  • Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner.
  • the tablets and capsules may conveniently each contain 1 to 500 mg of the active compound.
  • Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
  • compositions of the invention are administered orally in the known pharmaceutical forms for such administration.
  • Dosage forms suitable for oral administration may comprise tablets, pills, capsules, caplets, multiparticulates including: granules, beads, pellets and micro-encapsulated particles; powders, elixirs, syrups, suspensions and solutions.
  • Solid oral dosage forms for example tablets, may be prepared by mixing the pharmaceutical composition of the present invention with one or more of the following ingredients or mixtures thereof: inert diluents, for example calcium carbonate, calcium sulphate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate; disintegrating agents, for example alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, methylcellulose,
  • Solid oral dosage forms may be formulated in a manner known to those skilled in the art so as to- give a sustained release of the active compound.
  • Film coated, solid oral dosage forms comprising compositions of the present invention may be advantageous, depending on the nature of the active compound.
  • Various materials for example shellac and/or sugar, may be present as coatings, or to otherwise modify the physical form of the oral dosage form.
  • tablets or pills may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate and/or hydroxy propyl methylcellulose phthalate.
  • Capsules and/or caplets for example hard or soft gelatin capsules
  • the active compound with or without added excipients such as a fatty oil
  • the contents of the capsule and/or caplet may be formulated using known methods to give sustained release of the active compound.
  • Liquid oral dosage forms comprising compositions of the present invention may be an elixir, suspension and/or syrup (for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non- toxic suspending agent [such as sodium carboxymethylcellulose! and/or oily suspensions containing the active compound in a suitable vegetable oil [such as arachis oil and/or sunflower oil]).
  • Liquid oral dosage forms may also comprise one or more sweetening agent, flavouring agent, preservatives and/or mixtures thereof.
  • the active compound may be formulated into granules with or without additional excipients.
  • the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion.
  • the granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
  • each of the above oral dosage forms may contain from about 1 mg to about 1000 mg, more preferably from about 5 mg to about 500 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, or 400 mg) of the active compound.
  • compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with hard fat, semi-synthetic glyceride, cocoa butter and/or polyethylene glycol bases.
  • compositions may also be administered parenterally (for example subcutaneously, intramuscularly, intradermally and/or intravenously [such as by injection and/or infusionj in the known pharmaceutical dosage forms for parenteral administration (for example sterile suspensions in aqueous and/or oily media and/or sterile solutions in suitable solvents, preferably isotonic with the blood of the intended patient).
  • parenteral dosage forms may be sterilised (for example by micro-filtration and/or using suitable sterilising agents [such as ethylene oxide3).
  • suitable sterilising agents such as ethylene oxide3
  • one or more of the following pharmaceutically acceptable adjuvants suitable for parenteral administration may be added to parenteral dosage forms: local anaesthethetics, preservatives, buffering agents and/or mixtures thereof.
  • Parenteral dosage forms may be stored in suitable sterile sealed containers (for example ampoules and/or vials) until use. To enhance stability during storage the parenteral dosage form may be frozen after filling the container and fluid (for example water) may be removed under reduced pressure.
  • fluid for example water
  • compositions may be administered nasally in known pharmaceutical forms for such administration (for example sprays, aerosols, nebulised solutions and/or powders).
  • Metered dose systems known to those skilled in the art (for example aerosols and/or inhalers) may be used.
  • compositions may be administered to the buccal cavity (for example sub-linguaily) in known pharmaceutical forms for such administration (for example slow dissolving tablets, chewing gums, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and/or powders).
  • compositions for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
  • a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, for example paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
  • the active compounds may be dispersed in a pharmaceutically acceptable cream or ointment base.
  • the amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
  • the compounds of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
  • Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as a suspension or solution in a pharmaceutically acceptable oil of the compound to be infused for example in the.form of a very sparingly water-soluble derivative such as a dodecanoate salt or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused.
  • the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
  • the amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the present invention also comprises a compound of Formula I for use as a medicament.
  • the pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I may be used to treat depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia, stress in mammals particularly humans, as an aid to smoking cessation in human beings and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage.
  • the amount of active compound administered in such treatment is in the range 1 to 1000 mg preferably 5 to 500 mg given in single or divided doses at one or more times during the day.
  • the present invention provides the use of a compound of Formula I in the manufacture of a medicament for use in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia, stress, as an aid to smoking cessation and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage.
  • schizophrenia for example schizophrenia
  • tardive dyskinesia obesity
  • drug addiction drug addiction
  • cognitive disorders Alzheimer's disease
  • obsessive-compulsive behaviour panic attacks
  • social phobias eating disorders
  • eating disorders such as bulimia,
  • the present invention also provides a method of treating depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperiipidaemia, stress and seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
  • psychoses for example schizophrenia
  • tardive dyskinesia obesity
  • drug addiction drug addiction
  • cognitive disorders Alzheimer's disease
  • obsessive-compulsive behaviour panic attacks
  • social phobias eating disorders
  • eating disorders such as bulimia, anorexia, snacking and binge eating
  • the present invention also provides a method of reducing the craving to smoke in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula 1 to a patient in need thereof.
  • the present invention also provides a method of reducing weight gain after smoking cessation in human beings which comprises the administration of a therapeutically effective amount of a compound of Formula I to a patient in need thereof.
  • the compounds of the present invention may be useful in the treatment or prevention of metabolic diseases and conditions arising therefrom, for example non exercise activity thermogenesis and increased metabolic rate, sexual dysfunction, sleep apnoea, premenstrual syndrome, urinary incontinence, hyperactivity disorders, hiatial hernia and reflux esophagitis, pain, especially neuropathic pain, weight gain associated with drug treatment, chronic fatigue syndrome, osteoarthritis and gout, cancers associated with weight gain, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension.
  • metabolic diseases and conditions for example non exercise activity thermogenesis and increased metabolic rate, sexual dysfunction, sleep apnoea, premenstrual syndrome, urinary incontinence, hyperactivity disorders, hiatial hernia and reflux esophagitis, pain, especially neuropathic pain, weight gain associated with drug treatment, chronic fatigue syndrome, osteoarthritis and gout, cancers associated with weight gain, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension.
  • the compounds of the present invention may be useful in preventing cardiovascular disease, and in reducing platelet adhesiveness, in aiding weight loss after pregnancy and in aiding weight loss after smoking cessation.
  • Processes for the preparation of compounds of Formula I will now be described.
  • the processes may be performed on an individual basis, or by multiple parallel synthesis, also known as High Speed Analoguing.
  • the processes are preferably carried out at atmospheric pressure.
  • R ⁇ ,R 2 , g and n are as hereinbefore defined, optionally in the presence of an acid, for example acetic or sulphuric acid, and optionally in the presence of a second dehydrating agent, for example acetic anhydride, at a temperature in the range 0- 200°C; preferably in the range 20-150°C.
  • an acid for example acetic or sulphuric acid
  • a second dehydrating agent for example acetic anhydride
  • Z is a leaving group, for example a halo such as bromo, and R ⁇ ,R 2 and g are as hereinbefore defined, at a temperature in the range 0-200°C, in the presence of a solvent, for example ethanol and optionally in the presence of an acid, for example acetic acid preferably by heating at a temperature in the range 20°C to the boiling point of the solvent used.
  • a solvent for example ethanol
  • an acid for example acetic acid
  • Compounds of Formula I may also be prepared directly by reacting a compound of Formula VII with a compound of Formula VIII at a temperature in the range of 0-200°C, optionally in the presence of an acid, for example acetic acid, and optionally in the presence of a solvent, for example ethanol, without isolation of the intermediate of Formula VI; preferably by heating at a temperature in the range 20-150°C.
  • R ⁇ , R 2 and g are as hereinbefore defined, with a halogenating agent, for example a brominating agent such as phenyltrimethylammonium tribromide or copper(ll) bromide, at a temperature in the range 0-200°C in the presence of a solvent, for example tetrahydrofuran; preferably at a temperature in the range 20- 150°C.
  • a halogenating agent for example a brominating agent such as phenyltrimethylammonium tribromide or copper(ll) bromide
  • ⁇ and g are as hereinbefore defined with an organometallic reagent, for example a compound of formula R 2 CH 2 MgX in which R 2 is as hereinbefore defined and X is halo, for example bromo, in the presence of a solvent, for example tetrahydrofuran or ether, at a temperature in the range of -50°C to the boiling point of the solvent used, followed by hydrolysis of the intermediate imine salt optionally in the presence of an acid catalyst, for example hydrochloric acid.
  • organometallic reagent for example a compound of formula R 2 CH 2 MgX in which R 2 is as hereinbefore defined and X is halo, for example bromo
  • a solvent for example tetrahydrofuran or ether
  • Ri and g are as hereinbefore defined with an oxidising agent such as 2,3- dichioro-5,6-dicyano-1,4-benzoquinone, in the presence of a solvent, for example toluene, at a temperature in the range of 0°C to the boiling point of the solvent used.
  • an oxidising agent such as 2,3- dichioro-5,6-dicyano-1,4-benzoquinone
  • R-i and g are as hereinbefore defined with a source of cyanide, for example trimethylsilyl cyanide, optionally in the presence of an acid, for example a Lewis acid such as boron trifluoride etherate, and optionally in the presence a solvent, for example toluene, at a temperature in the range of 0-250°C, followed by reaction with a reagent capable of generating a double bond, for example phosphorous oxychloride, or an acid, such as 4-toluenesulphonic acid, optionally in the presence of a solvent, for example toluene, at a temperature in the range of 0-250°C.
  • a source of cyanide for example trimethylsilyl cyanide
  • an acid for example a Lewis acid such as boron trifluoride etherate
  • solvent for example toluene
  • Ri and g are as hereinbefore defined in which the cyano- group is attached at the 4- position of benzo[bjfuran may be used to prepare compounds of Formula X in which the cyano- group is attached at the 5-, 6- or 7-position by starting from the appropriate dihydrobenzofbjfuranone having the Formula XIII, XIV or XV
  • R-t, n and g are as hereinbefore defined, with a halogenating agent for example bromine, phenyltrimethylammonium tribromide or benzyltrimethyl- ammonium tetrachloroiodate at a temperature in the range -50-200°C optionally in the presence of a solvent, for example dichloromethane, tetrahydrofuran or acetone.
  • a halogenating agent for example bromine, phenyltrimethylammonium tribromide or benzyltrimethyl- ammonium tetrachloroiodate at a temperature in the range -50-200°C
  • a solvent for example dichloromethane, tetrahydrofuran or acetone.
  • R 2 represents a group of Formula -CH(OH)R x in which R x is a C 1-5 alkyl group, an alkenyl group containing 2-5 carbon atoms, an alkynyl group containing 2-5 carbon atoms or an aryl group
  • R x is a C 1-5 alkyl group, an alkenyl group containing 2-5 carbon atoms, an alkynyl group containing 2-5 carbon atoms or an aryl group
  • R-i, n and g are as hereinbefore defined and R y is H with an organometallic reagent, for example a compound of formula R x MgX or R x Li in which R x is as hereinbefore defined and X is halo, for example bromo, in the presence of a solvent, for example tetrahydrofuran or ether, at a temperature in the range of -50°C to the boiling point of the solvent used.
  • organometallic reagent for example a compound of formula R x MgX or R x Li in which R x is as hereinbefore defined and X is halo, for example bromo, in the presence of a solvent, for example tetrahydrofuran or ether, at a temperature in the range of -50°C to the boiling point of the solvent used.
  • R 2 represents a group of Formula -CH(OH)R y in which R y is a C 1-5 alkyl group, an alkenyl group containing 2-5 carbon atoms, an alkynyl group containing 2-5 carbon atoms or an aryl group
  • R y is a C 5 alkyl group, an alkenyl group containing 2-5 carbon atoms, an alkynyl group containing 2-5 carbon atoms or an aryl group with a reducing agent, for example sodium borohydride, in the presence of a solvent, for example ethanol, at a temperature in the range of 0°C to the boiling point of the solvent used.
  • a reducing agent for example sodium borohydride
  • Compounds of Formula I in which R 2 is hydroxymethyl may be prepared by reacting a compound of Formula XVII in which R ⁇ n and g are as hereinbefore defined and R y is H with a reducing agent, for example sodium borohydride, in a solvent, for example methanol, at a temperature in the range of-50°C to the boiling point of the solvent used.
  • a reducing agent for example sodium borohydride
  • Compounds of Formula I in which R 2 represents a group of Formula -CH 2 R X in which R x is H or a C 1-5 alkyl group may be prepared by reacting a compound of Formula XVII in which R-), n and g are as hereinbefore defined and R y is H or a C 1-5 alkyl group with a reducing agent, for example borane-dimethyiamine complex, in the presence of a Lewis acid catalyst, for example aluminium chloride, and a solvent, for example dichloromethane, at a temperature in the range of -50°C to the boiling point of the solvent used.
  • a reducing agent for example borane-dimethyiamine complex
  • Compounds of Formula I in which R 2 is hydroxyiminomethyl may be prepared by reacting a compound of Formula XVII in which Ri, n and g are as hereinbefore defined and R y is H with hydroxylamine or a salt thereof optionally in the presence of a solvent, for example an alcohol, eg ethanol, at a temperature in the range of 0-
  • R 2 Is cyano may be prepared by reacting a compound of Formula XVII in which R ⁇ n and g are as hereinbefore defined and R y is H with hydroxylamine or a salt thereof in the presence of formic acid at a temperature in the range of 0-250°C.
  • R 2 represents a group
  • R y represents hydrogen
  • R a represents a C ⁇ alkyl group optionally in the presence of a solvent, for example an alcohol e.g. ethanol, optionally in the presence of an acid catalyst for example, acetic acid, at a temperature in the range 0-250°C.
  • Compounds of Formula I in which R 2 represents a group may be prepared by reacting a compound of Formula I in which R 2 represents a C ⁇ alkyliminomethylene group with a reducing agent, for example sodium borohydride, in the presence of a solvent, for example an alcohol e.g. ethanol, at a temperature in the range 0°C to the boiling point of the solvent used.
  • a reducing agent for example sodium borohydride
  • a solvent for example an alcohol e.g. ethanol
  • R represents a C ⁇ aikylaminomethylene group
  • R y represents hydrogen by reaction with an amine of formula R a NH 2 wherein R a represents a C ⁇ alkyl group and a reducing agent, for example sodium triacetoxyborohydride, in the presence of a solvent, for example tetrahydrofuran, at a temperature in the range 0°C to the boiling point of the solvent used.
  • a solvent for example tetrahydrofuran
  • R 2 represents a group of formula -C(OH)R x R y in which R x and R y are each independently a C 1-5 alkyl group
  • R x and R y are each independently a C 1-5 alkyl group
  • an organometallic reagent for example a compound of formula R x MgX or R x Li in which R x is as hereinbefore defined and X is halo, for example bromo, in the presence of a solvent, for example tetrahydrofuran or ether, at a temperature in the range of -50°C to the boiling point of the solvent used.
  • a solvent for example tetrahydrofuran or ether
  • R 2 represents a group of formula -C(OH)R x R y in which R x and R y are the same C ⁇ -2 alkyl group
  • R y is OR z in which R z is a C 1-6 alkyl group
  • an organometallic reagent for example a compound of formula R x MgX or R x Li in which R x is as hereinbefore defined and X is halo, for example bromo, in the presence of a solvent, for exampletetrahydrofuran or ether, at a temperature in the range of -50°C to the boiling point of the solvent used.
  • Compounds of Formula I in which R 2 represents a C 2 _ 6 alkenyl group in which the double bond is attached to the carbon alpha to the thiazoie ring or a styryi group may be prepared by reacting compounds of Formula XVII, in which R y represents hydrogen or a C- alkyl group, with a phosphonium salt of formula R z Ph 3 P+Br- or a phosphonate of formula R z PO(OEt) 2 in which Rz represents a C 1 . 5 alkyl group or a benzyl group in the presence of a base, for example ⁇ -butyllithium or sodium hydride, in a solvent, for example an ether, e.g. tetrahydrofuran, at a temperature in the range -78°C to the boiling point of the solvent used.
  • a base for example ⁇ -butyllithium or sodium hydride
  • a solvent for example an ether, e.g.
  • Compounds of Formula I in which R 2 represents a C 2 _g alkanoyl group may be prepared by reacting a compound of Formula I in which R 2 represents halo, for example bromo or chloro, or a compound of Formula XVI, with a metallating agent for example a compound of formula R b MgX or R b Li in which R b is a C ⁇ alkyl group and X is halo, for example bromo or chloro, in the presence of a solvent, for example an ether, eg diethyl ether or tetrahydrofuran, at a temperature in the range -78°C to the boiling point of the solvent used, and then reacting the product obtained with an acylating agent for example a compound of Formula R c CON(CH 3 )OCH 3 in which R c represents a C ⁇ s alkyl group in a solvent, for example an ether e.g. tetrahydrofuran, at a temperature in the range
  • Compounds of Formula I in which R 2 represents a C ⁇ _ 3 a!koxyC ⁇ _ 3 alkyl group may be prepared by reacting a compound of Formula I in which R 2 represents a hydroxyC ⁇ _ 3 alkyl group with a C ⁇ alkylating agent, for example a C ⁇ alkyl halide e.g. a C ⁇ _ 3 alkyl iodide, in the presence of a base, for example sodium hydride, in a solvent, for example ⁇ /, ⁇ /-dimethylformamide, at a temperature in the range of -50 to 150°C.
  • a C ⁇ alkylating agent for example a C ⁇ alkyl halide e.g. a C ⁇ _ 3 alkyl iodide
  • a base for example sodium hydride
  • solvent for example ⁇ /, ⁇ /-dimethylformamide
  • Compounds of FormuIa I in which R 2 represents a C 3 ⁇ cycloalkoxyC 1 . 3 alkyl group may be prepared by reacting a compound of Formula I in which R 2 represents a hydroxyC-j. 3 alkyl group with a C 3 ⁇ cycloalkylating agent, for example a C 3 _ ⁇ cycloalkyl halide e.g. a C- 3 _ 6 cycIoalkyl iodide, in the presence of a base, for example sodium hydride, in a solvent, for example ⁇ /,N-dimethylformamide, at a temperature in the range of -50 to 150°C.
  • a base for example sodium hydride
  • solvent for example ⁇ /,N-dimethylformamide
  • 7 cydoalkyIalkoxyC 1-3 alkyl group may be prepared by reacting a compound of Formula I in which R 2 represents a hydroxyC ⁇ alkyl group with a C4-7 cycloaikylalkylating agent, for example a C ⁇ cycloalkylalkyf halide e.g. a C4-7 cycloalkylalkyl iodide in the presence of a base, for example sodium hydride, in a solvent, for example N, -dimethylforrnamide, at a temperature in the range of -50 to 150°C.
  • a C4-7 cycloaikylalkylating agent for example a C ⁇ cycloalkylalkyf halide e.g. a C4-7 cycloalkylalkyl iodide
  • a base for example sodium hydride
  • a solvent for example N, -dimethylforrnamide
  • Compounds of Formula I in which R 2 represents a C 3 . 7 alkynylalkoxyC 1 ⁇ alkyl group may be prepared by reacting a compound of Formula I in which R 2 represents a hydroxyCi_ 3 alkyl group with a C 3 . 7 alkynylalkylating agent, for example a C 3 . 7 alkynylalkyl halide e.g. a C 3 . 7 alkynylalkyl iodide in the presence of a base, for example sodium hydride, in a solvent, for example N,N-dimethylformamide, at a temperature in the range of -50 to 150°C.
  • a base for example sodium hydride
  • Compounds of Formula I in which R 2 represents a C 1 . 3 alkylthioC 1 . 3 alkyl group may be prepared by reacting a compound of Formula I in which R 2 represents a mercaptoC ⁇ _ 3 alkyl group with a C ⁇ alkylating agent, for example a C 1-3 alkyl halide e.g. a C ⁇ alkyl iodide in the presence of a base, for example sodium hydride or sodium hydroxide, in a solvent, for example N,N-dimethyiformamide, at a temperature in the range of -50 to 150°C.
  • a C ⁇ alkylating agent for example a C 1-3 alkyl halide e.g. a C ⁇ alkyl iodide
  • a base for example sodium hydride or sodium hydroxide
  • a solvent for example N,N-dimethyiformamide
  • Compounds of Formula I in which R 2 represents a C ⁇ _ 3 alkylthio group or an arylthio group and Ri, n and g are as previously defined may be prepared by reacting a compound of Formula I in which R 2 represents halo, or a compound of Formula XVI, with a metallating agent, for example a compound of formula RMgX or RLi in which R is a C ⁇ _ 6 alkyl group and X is halo, for example chloro, bromo or iodo, in a solvent, for example an ether or a mixture of ethers, eg tetrahydrofuran or diethyl ether, at a temperature in the range of -100°C to the boiling point of the solvent used to give an intermediate complex, which is reacted with a disulphide of formula R d S-SR d in which R d is a C 1 . 3 alkyl group or an aryl group, at a temperature in the range of -
  • Compounds of Formula I in which R 2 represents a C 1 . 3 alkoxy group and Ri, n and g are as previously defined may be prepared by reacting a compound of Formula I in which R 2 represents halo, for example bromo or iodo, with a C-
  • . 3 alkoxide salt for example a sodium or potassium salt
  • a solvent for example a C ⁇ alcohol ordimethylformamide
  • a catalyst for example a copper (I) salt
  • Compounds of Formula VII are commercially available.
  • Compounds of Formula VIII, IX, XII, XIII, XIV and XV may be prepared by methods known to those skilled in the art and as specified in the individual Examples described herein.
  • the ability of compounds of Formula I to interact with 5-hydroxytryptamine (5-HT) receptors has been demonstrated for the products of Examples 1 to 3 by the following test which determines the ability of the compounds to inhibit tritiated ligand binding to 5-HT receptors in vitro and in particular to 5-HT 1A receptors.
  • Hippocampal tissue from the brains of male Sprague-Dawley rats (Charles River; weight range 150-250 g) was homogenised in ice-cold 50 mM Tris-HCl buffer (pH 7.7 when measured at 25°C, 1:40 w/v) and centrifuged at 40,000 g at 4°C for 10 minutes. The pellet was rehomogenised in the same buffer, incubated at 37°C for 10 minutes and centrifuged at 40,000 g at 4°C for 10 minutes. The final pellet was resuspended in 50 mM Tris-HCl buffer (pH 7.7) containing 4 M CaCl2, 0.1%
  • L-ascorbic acid and 10 ⁇ M pargyline hydrochloride (equivalent to 6.25 mg wet weight of tissue/ml) and used immediately in the binding assay.
  • Membranes 400 ⁇ l; equivalent to 2.5 mg wet weight of tissue/tube were incubated with 50 ⁇ l of [ 3 Hj8-hydroxy-2-(dipropylamino)tetralin ([ 3 HJ8-OH-DPAT) at a single concentration of 1 nM and 50 ⁇ l of distilled water (total binding) or 50 ⁇ l of test compound (at a single concentration of 10 "6 M or at 10 concentrations ranging from 10 "11 -10 "3 M) or 50 ⁇ l of 5-HT (10 ⁇ M, non-specific binding) at 25°C for 30 minutes. The incubation was terminated by rapid filtration under vacuum through Skatron 11734 filters using a Skatron Cell Harvester.
  • Membranes 400 ⁇ l; equivalent to 1.25 mg wet weight of tissue/tube) were incubated with 50 ⁇ l [ 3 Hjcitalopram at a single concentration of 1.3 nM and 50 ⁇ l of distilled water (total binding) or 50 ⁇ l of test compound (at a single concentration of 10 "6 M or at 10 concentrations ranging from 10 "11 -10 "3 M) or 50 ⁇ l of paroxetine (0.5 ⁇ M; non-specific binding) for 1 h at 27°C.
  • Membrane bound radioactivity was recovered by filtration under vacuum through Skatron 11734 filters presoaked in 0.5% PEI using a Skatron Cell Harvester.
  • noradrenaline (NA) reuptake sites The ability of compounds of Formula I to interact with noradrenaline (NA) reuptake sites has been demonstrated for the products of Examples 1 to 3 by the following test which determines the ability of compounds to displace the standard ligand, [ 3 H]nisoxetine, from noradrenaline reuptake sites in vitro.
  • Frontal cortical tissue from the brains of male Charles River rats weighing 150-250 g was homogenised in ice-cold 50 mM Tris-HCl, pH 7.4 (at 25°C) containing 120 mM sodium chloride and 5 mM potassium chloride (Tris buffer; 1:60 w/v) using a Kinematic polytron (speed setting 6 for 10 seconds) and centrifuged at 40,000 g for 10 minutes. The supernatant was discarded and the pellet rehomogenised in Tris buffer, 1:60 w/v, and centrifuged at 40,000 g for 10 minutes. This step was repeated twice more so that, in total, the brain tissue was homogenised and centrifuged four times.
  • the final pellet was resuspended in 50 mM Tris-HCl, pH 7.4 containing 300 mM sodium chloride and 5 mM potassium chloride (equivalent to 18.75 mg wet weight of tissue/ml) and used immediately in the binding assay. All centrifugations were performed at 4°C.
  • Membranes 400 ⁇ l; equivalent to 7.5 mg wet weight of tissue/tube) were incubated with 50 ⁇ l [ 3 HJnisoxetine at a single concentration of 0.6 nM and 50 ⁇ l of distilled water (total binding) or 50 ⁇ l of test compound (at a single concentration lO ⁇ M or at 10 concentrations ranging from 10 "11 -10 "3 M) or 50 ⁇ l of mazindol (1 ⁇ M; non-specific binding) for 4 h at 4°C. Membrane bound radioactivity was recovered by filtration under vacuum through Skatron 11734 filters using a Skatron cell harvester.
  • Frontal cortical tissue from the brains of male Charles River rats weighing 150-250 g was homogenised in ice-cold 20 mM HEPES buffer, pH 7.5 (measured at 25°C) containing 100 mM sodium chloride and 10 mM magnesium chloride (1:10 w/v) using a Polytron PT3100 (speed setting 21 ,700rpm, 3 x 5 seconds) and centrifuged at 49,500 g for 30 minutes at 4°C. The supernatant was discarded and the pellet rehomogenised in 20 mM HEPES buffer, pH 7.5 containing 100 mM sodium chloride and 10 mM magnesium chloride (equivalent to 12.5 mg wet weight of tissue/ml). Membranes were stored at -80°C until required.
  • Membranes were thawed, diluted 1:10 in ice-cold 20 mM HEPES buffer, pH 7.5 containing 100 mM sodium chloride and 10 mM magnesium chloride and homogenised using a Polytron PT3100 as above.
  • Diluted membranes 200 ⁇ l; equivalent to 0.25 mg wet weight of tissue/tube were incubated with 200 ⁇ l of 20 mM HEPES buffer, pH 7.5 containing 100 mM sodium .chloride and 10 mM magnesium chloride and 50 ⁇ l of [ 3 HJN-methylscopolamine at a single concentration of 0.15 nM and 50 ⁇ l of distilled water (total binding) or 50 ⁇ l of test compound (at a single concentration of lO ⁇ or at 10 concentrations ranging from 10 ⁇ 11 - 10 "3 M) or 50 ⁇ l of atropine sulphate (1 ⁇ M; .non-specific binding) for 30 min at 30°C.
  • Membrane bound radioactivity was recovered by filtration under vacuum through Skatron 11734 filters using a Skatron ceil harvester. Filters were rapidly washed with ice-cold 20 mM HEPES buffer, pH 7.5 (wash 1,2 at setting 5,5). The scored filter paper discs were punched out into vials, scintillation fluid added and radioactivity determined by liquid scintillation counting.
  • a (dpm) Total binding (dpm) - Non-specific binding (dpm)
  • Compounds of the present invention show reduced affinity for muscarinic receptors compared to Example 3 of WO97/02269 which has a Kj of 57nM Muscarinic affinity may cause undesired side-effects, for example dry mouth, blurred vision, sweating, palpitations, constipation and aggravation of narrow angle glaucoma (Blackwell, B. Adverse effects of antidepressant drugs. Part 1 Monoamine oxidase inhibitors and tricyclics. Drugs 21, 202-219, 1981). Obviously it is desirable for compounds to have minimal affinity for muscarinic receptors.
  • the assay was performed using the following general procedure in which the tissue source was human placenta:
  • the compounds were tested at 1 and lOmicromolar in duplicate.
  • Especially preferred compounds of the present invention may have significantly reduced MAO A inhibitory activity compared to compounds exemplified in WO97/02269.
  • Especially preferred compounds of the present invention also exhibit higher 5 ⁇ H T 1A affinity and/or greater selectivity over muscarinic activity compared to compounds of the prior art. Acute feeding studies
  • Especially preferred compounds of the present invention have superior activity in acute feeding studies compared to compounds exemplified in WO97/02269.
  • the compounds of the present invention are particularly useful in treating obesity and related co-morbid conditions, for example, diabetes, hyperglycaemia and hyperiipidaemia.
  • monoamine reuptake inhibitors which are used to treat obesity are often associated with cardiovascular side effects, for example, increased heart rate and increased blood pressure.
  • the compounds of the present invention reduce the cardiovascular side effects which might be expected to occur from the administration of a monoamine reuptake inhibitor particularly a noradrenaline reuptake inhibitor.
  • a monoamine reuptake inhibitor particularly a noradrenaline reuptake inhibitor.
  • 5-HT iA agonism in the compounds of the present invention reduces the cardiovascular side effects which might have arisen from their monoamine reuptake inhibition particularly their noradrenaline reuptake inhibition.
  • the 5 ⁇ HT ⁇ A agonism of especially preferred compounds of the present invention can be determined by electrophysiology by methods known to those skilled in the art.
  • the invention is illustrated by the following Examples which are given by way of example only.
  • the final product of each of these Examples was characterised by one or more of the following procedures: high performance liquid chromatography; elemental analysis, nuclear magnetic resonance spectroscopy, mass spectroscopy and infrared spectroscopy.
  • Phenyltrimethylammonium tribromide (4.3 g) was added in portions under nitrogen at 0 °C over 1 minute to a stirred solution of 1-(benzo[b]furan-7-yl)propa ⁇ -1- one (1.99 g; prepared in a manner similar to that described above) in tetrahydrofuran (25 ml), the mixture was stirred for 30 minutes at 0°C, then at ambient temperature for 3 hours, then it was filtered and the solvent was removed in vacuo. The residue was dissolved in ethanol (40 mi), acetic acid (20 ml) and 2-imidazolidinethione (1.16 g) were added, and the mixture was heated under reflux for 20 hours.
  • Aqueous sodium hydroxide solution (5M, 38 ml) was added to a stirred mixture of dichloromethane (500 ml), water (1250 ml) and 3-(benzo[b]furan-7-yl)-2- methyl-5,6-dihydroirnidazo[2,1 -bjthiazole hydrobromide (29.07 g; prepared in a manner similar to that described in Example 1).
  • the mixture was stirred for 30 minutes then the dichloromethane layer was separated and the aqueous phase extracted with dichloromethane (2 x 500 ml).
  • the combined dichloromethane extracts were dried (MgSO 4 ), and the solvents were removed in vacuo to give 3-
  • Trimethylsilyl cyanide (5.0 g), then boron trifluoride etherate (8 drops) were added with stirring under nitrogen to 6,7-dihydro-4(5W)benzofuranone (6.1 g). The mixture was stirred at ambient temperature for 2 hours, at 60 °C for 40 minutes and at 100 °C for 5 minutes then it was allowed to cool to ambient temperature. Pyridine (34 ml), then phosphorous oxychloride (6.6 ml) were added, then the mixture was heated to 125 °C for 1.75 hours whilst volatile materials were removed by distillation. The residual material was allowed to cool to ambient temperature then poured onto ice (150 ml). Ether (50 ml) was added then the mixture was filtered through Celite.
  • Phenyltrimethylammonium tribromide (0.30 g) was added to a stirred solution of 1-(benzo[b3furan-4-yl)propan-1-one (0.14 g) in tetrahydrofuran (4 ml), the mixture was stirred for 23 hours at ambient temperature, then resulting solids were removed by filtration. The filter cake was washed with dichloromethane (10 ml), then the combined filtrates were washed with water (30 ml). The separated water layer was extracted with dichloromethane (10 ml), then the combined organic extracts were dried (MgSO 4 ) and the solvents were removed in vacuo.
  • active compound denotes any compound of the invention but particularly any compound which is the final product of one of the preceding Examples.
  • capsules 10 parts by weight of active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into .hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound.
  • Tablets are prepared from the following ingredients.
  • the active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol.
  • the dry granulate is blended with the magnesium stearate and the rest of the starch.
  • the mixture is then compressed in atabletting machine to give tablets each containing a unit dose or a part of a unit dose of active compound.
  • Tablets are prepared by the method described in (b) above.
  • the tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dich!oromethane (1:1).
  • suppositories 100 parts by weight of active compound is incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.

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Abstract

L'invention concerne certains nouveaux composés substitués de dihydroimidazo [2,1-b]thiazole et de dihydro-5H-thiazolo[3,2-a]pyrimidine représentés par la formule (I), qui possèdent une affinité pour les récepteurs 5-HT1A et inhibent le recaptage neuronal de 5-hydroxytryptamine et/ou de noradrénaline ; des procédés de préparation de ces composés, des compositions pharmaceutiques les contenant et leur utilisation dans le traitement de la dépression, de l'anxiété, de psychoses (p. ex. schizophrénie), de la diskynésie tardive, de l'obésité, de pharmacodépendances, de toxicomanies, de troubles cognitifs, de la maladie d'Alzheimer, de troubles obsessionnels-compulsifs, d'attaques de panique, de phobies sociales, de troubles du comportement alimentaire tels que boulimie, anorexie, grignotage et frénésies alimentaires, du diabète non insulino-dépendant, de l'hyperglycémie, de l'hyperlipidémie et du stress, comme aide pour arrêter de fumer et dans le traitement et/ou la prévention de crises, de troubles neurologiques tels que l'épilepsie et/ou d'états impliquant une lésion neurologique tels que l'accident cérébral vasculaire, le traumatisme cérébral, l'ischémie intracérébrale, les traumatismes crâniens et les hémorragies.
PCT/GB2001/004317 2000-09-27 2001-09-27 Derives de dihydroimidazo[2,1-b]thiazole et de dihydro-5h-thiazolo[3,2-a]pyrimidine possedant une affinite pour les recepteurs 5-ht Ceased WO2002026747A1 (fr)

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WO2011097336A3 (fr) * 2010-02-04 2011-12-01 The Board Of Trustees Of The University Of Illinois Agonistes hautement sélectifs du récepteur 5-ht(2c) ayant une activité antagoniste au niveau du récepteur 5-ht(2b)
US8317808B2 (en) 2008-02-18 2012-11-27 Covidien Lp Device and method for rolling and inserting a prosthetic patch into a body cavity
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US8906045B2 (en) 2009-08-17 2014-12-09 Covidien Lp Articulating patch deployment device and method of use
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US9034002B2 (en) 2008-02-18 2015-05-19 Covidien Lp Lock bar spring and clip for implant deployment device
US9044235B2 (en) 2008-02-18 2015-06-02 Covidien Lp Magnetic clip for implant deployment device
US9301826B2 (en) 2008-02-18 2016-04-05 Covidien Lp Lock bar spring and clip for implant deployment device
US9393093B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US9393002B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US9398944B2 (en) 2008-02-18 2016-07-26 Covidien Lp Lock bar spring and clip for implant deployment device
US9833240B2 (en) 2008-02-18 2017-12-05 Covidien Lp Lock bar spring and clip for implant deployment device
US9999424B2 (en) 2009-08-17 2018-06-19 Covidien Lp Means and method for reversibly connecting an implant to a deployment device

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US9833240B2 (en) 2008-02-18 2017-12-05 Covidien Lp Lock bar spring and clip for implant deployment device
US10695155B2 (en) 2008-02-18 2020-06-30 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US8753359B2 (en) 2008-02-18 2014-06-17 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US10182898B2 (en) 2008-02-18 2019-01-22 Covidien Lp Clip for implant deployment device
US8808314B2 (en) 2008-02-18 2014-08-19 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US10159554B2 (en) 2008-02-18 2018-12-25 Covidien Lp Clip for implant deployment device
US9301826B2 (en) 2008-02-18 2016-04-05 Covidien Lp Lock bar spring and clip for implant deployment device
US9005241B2 (en) 2008-02-18 2015-04-14 Covidien Lp Means and method for reversibly connecting a patch to a patch deployment device
US9034002B2 (en) 2008-02-18 2015-05-19 Covidien Lp Lock bar spring and clip for implant deployment device
US8317808B2 (en) 2008-02-18 2012-11-27 Covidien Lp Device and method for rolling and inserting a prosthetic patch into a body cavity
US9107726B2 (en) 2008-02-18 2015-08-18 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US9398944B2 (en) 2008-02-18 2016-07-26 Covidien Lp Lock bar spring and clip for implant deployment device
US9393093B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US9393002B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US8888811B2 (en) 2008-10-20 2014-11-18 Covidien Lp Device and method for attaching an implant to biological tissue
US8906045B2 (en) 2009-08-17 2014-12-09 Covidien Lp Articulating patch deployment device and method of use
US9999424B2 (en) 2009-08-17 2018-06-19 Covidien Lp Means and method for reversibly connecting an implant to a deployment device
WO2011097336A3 (fr) * 2010-02-04 2011-12-01 The Board Of Trustees Of The University Of Illinois Agonistes hautement sélectifs du récepteur 5-ht(2c) ayant une activité antagoniste au niveau du récepteur 5-ht(2b)
US8754132B2 (en) 2010-02-04 2014-06-17 The Board Of Trustees Of The University Of Illinois Highly selective 5-HT(2C) receptor agonists that show anti-psychotic effects with antagonist activity at the 5-HT(2B) receptor
US8492591B2 (en) 2010-02-04 2013-07-23 The Board Of Trustees Of The University Of Illinois Highly selective 5-HT(2C) receptor agonists that show anti-psychotic effects with antagonist activity at the 5-HT(2B) receptor

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