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WO2007011285A1 - Agents thérapeutiques - Google Patents

Agents thérapeutiques Download PDF

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Publication number
WO2007011285A1
WO2007011285A1 PCT/SE2006/000879 SE2006000879W WO2007011285A1 WO 2007011285 A1 WO2007011285 A1 WO 2007011285A1 SE 2006000879 W SE2006000879 W SE 2006000879W WO 2007011285 A1 WO2007011285 A1 WO 2007011285A1
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WO
WIPO (PCT)
Prior art keywords
compound
disorders
formula
compounds
optionally substituted
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PCT/SE2006/000879
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English (en)
Inventor
Fabrizio Giordanetto
Tord Inghardt
Original Assignee
Astrazeneca Ab
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Publication of WO2007011285A1 publication Critical patent/WO2007011285A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to certain compounds of formula I, to processes for preparing such compounds, to their use in the treatment of obesity, psychiatric and neurological disorders, and to pharmaceutical compositions containing them.
  • MCH Melanin concentrating hormone
  • MCH promotes eating and weight gain
  • US 5,849,708 recent work has indicated that MCH promotes eating and weight gain.
  • MCH and its agonists have been proposed as treatments for anorexia nervosa and weight loss due to AIDS, renal disease, or chemotherapy.
  • antagonists of MCH can be used as a treatment for obesity and other disorders characterised by compulsive eating and excessive body weight.
  • MCH projections are found throughout the brain, including the spinal cord, an area important in processing nociception, indicates that agents acting through MCHIr, such as compounds of formula I, will be useful in treating pain.
  • MCH receptor 1 MCHIr
  • MCH2r MCH receptor 2
  • MCHIr is present in rodent species (Tan et al. Genomics 2002 Jun;79(6):785-92). In mice lacking MCHrI, there is no increased feeding response to MCH, and a lean phenotype is seen, suggesting that this receptor is responsible for mediating the feeding effect of MCH (Marsh et al. Proc. Natl. Acad. ScL USA, 2002 Mar 5;99(5):3240-5). In addition, MCHrI antagonists have been demonstrated to block the feeding effects of MCH (Takekawa et al. Eur. J. Pharmacol. 2002 Mar 8;438(3): 129-35), and to reduce body weight & adiposity in diet-induced obese rats (Borowsky et al. Nature Med.
  • MCHrI antagonists have been proposed as a treatment for obesity and other disorders characterised by excessive eating and body weight.
  • WO 2004/092181 discloses heterocyclic compounds, which are antagonists to the MCHrI.
  • MCHrI antagonists that are more potent, more selective, more bioavailable and produce less side effects than known compounds in this field.
  • a pharmaceutical formulation comprising a compound of formula I, and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a compound of formula I is provided, in the preparation of a medicament for the treatment or prophylaxis of conditions associated with obesity.
  • a method is provided of treating obesity, psychiatric disorders, anxiety, anxio-depressive disorders, depression, bipolar disorder,
  • ADHD cognitive disorders, memory disorders, schizophrenia, epilepsy, and related conditions, and neurological disorders and pain related disorders
  • administering a pharmacologically effective amount of a compound of Formula I to a patient in need thereof.
  • a method is provided of treating obesity, type II diabetes, Metabolic syndrome and prevention of type II diabetes comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof.
  • the invention relates to compounds of the general formula (I)
  • a and B independently represent C or N
  • R 1 and R 2 independently represent H, C 1-3 alkyl (optionally substituted with one or more
  • R 3 represents H, C 1-3 alkyl (optionally substituted with a hydroxy, methoxy, amino, methylamino, dimethylamino, pyrrolidinyl or morpholinyl group), R 4 and R 5 independently represent H, C 1-3 alkyl (optionally substituted with a hydroxy, methoxy, amino, methylamino, dimethylamino, pyrrolidinyl or morpholinyl), or;
  • R 4 and R 5 are joined to form, together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, piperazine or morpholine ring (optionally substituted with hydroxy, oxo, C 1-3 alkyl (optionally substituted with hydroxy, methoxy or dimethylamino) or with a Ci- 3 alkoxy group (optionally substituted with hydroxy, methoxy or dimethylamino)), and tautomers, optical isomers and racemates thereof as well as pharmaceutically acceptable salts thereof.
  • a and B both represent C
  • R 1 represents Cl, F, CF 3 , CHF 2 , CH 2 F, methyl, OCF 3 or OCHF 2 ,
  • R 2 represents H, Cl, F or CH 3
  • R 3 represents methyl, ethyl, iso-propyl, hydroxyethyl or dimethylaminoethyl
  • R 4 and R 5 independently represent H, methyl, hydroxyethyl or dimethylaminoethyl, or; R R 44 aanndd RR 55 aarree jjooiinneedd ttoo ffoorrmm,, ttooggeetthheerr wwiitthh tthhee nniittrrooggeen atom to which they are attached, a pyrrolidine, piperidine, piperazine or morpholine ring.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable acid addition salts.
  • a suitable pharmaceutically acceptable salt of a compound of Formula I is, for example, an acid-addition salt of a compound of Formula I which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as:
  • (lS)-(+)-10-camphorsulfonic acid cyclohexylsulfamic acid; phosphoric acid; dimethylphosphoric acid; p-toluenesulfonic acid; L-lysine; L-lysine hydrochloride; saccharinic acid; methanesulfonic acid; hydrobromic acid; hydrochloric acid; sulphuric acid; 1,2-ethanedisulfonic acid; (+/-)-camphorsulfonic acid; ethanesulfonic acid; nitric acid; p-xylenesulfonic acid; 2-mesitylenesulfonic acid; 1,5-naphthalenedisulfonic acid; 1- naphthalenesulfonic acid; 2-naphthalenesulfonic acid; benzenesulfonic acid; maleic acid;
  • a given chemical formula or name shall encompass all tautomers, all stereo and optical isomers and racemates thereof as well as mixtures in different proportions of the separate enantiomers, where such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof.
  • Isomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or HPLC.
  • the diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography.
  • stereoisomers may be made by chiral synthesis from chiral starting materials under conditions, which will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. All stereoisomers are included within the scope of the invention.
  • alkyl denotes either a straight chain or branched alkyl group.
  • alkyl include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl.
  • Preferred alkyl groups are methyl, ethyl, propyl, isopropyl and tertiary butyl.
  • alkoxy denotes a group O-alkyl, wherein alkyl is as defined above.
  • the compounds of the invention may be prepared as outlined below according to any of the following methods. However, the invention is not limited to these methods, the compounds may also be prepared as described for structurally related compounds in the prior art.
  • R 1 , R 2 , R 3 , R 4 , R 5 A and B are a ss pprreeviously defined, with an diazotizing agent such as sodium or potassium nitrite or t-butyl nitrite in a solvent or solvent mixture containing acetic acid (75-100%) and water (0-25%), followed by alkaline aqueous work up, a method described e.g. in Daidone, G. et al. Heterocycles 43(11), 2385-96 (1996).
  • compounds of formula I may be prepared via a Suzuki or a Stille coupling reaction of a compound of formula VII with a compound of formula VIE
  • T represents B(OH) 2 or Sn(alkyl) 3 and Z represents a suitable leaving group such as I, Br or triflate.
  • Compounds of formula ⁇ may be prepared by coupling of compounds of formula IX with compounds of formula X at a temperature in the range of O 0 C to 150 0 C, preferably in the range of 2O 0 C to 80°C in the presence of a solvent, for example THF, DCM, NMP, DCM/water (i.e. a two phase system) or DMF, optionally in the presence of a suitable inorganic or organic base, e.g. DIPEA or TEA, and a standard amide coupling reagent, e.g. HATU, TBTU, TFFH, PyBroP, EDC, or DCC, the latter two of which may optionally be polymer supported. Suitable additives such as HOBt and HOAt may optionally be used.
  • a solvent for example THF, DCM, NMP, DCM/water (i.e. a two phase system) or DMF
  • a suitable inorganic or organic base e.g. DIPEA or TEA
  • the compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
  • Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • Enantiomers may be isolated by separation of racemate for example by fractional crystallisation, resolution or HPLC.
  • the diastereomers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography.
  • the stereoisomers may be made by chiral synthesis from chiral starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent.
  • compositions will normally be administered via the oral, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient either as a free base, or a pharmaceutically acceptable inorganic or organic addition salt, in a pharmaceutically acceptable dosage form.
  • the compositions may be administered at varying doses.
  • Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are about 0.001-10 mg/kg body weight, preferably 0.01-3 mg/kg body weight.
  • Oral formulations are preferred particularly tablets or capsules which may be formulated by methods known to those skilled in the art to provide doses of the active compound in the range of 0.5 mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg and 250 mg.
  • a pharmaceutical formulation including any of the compounds of the invention, or pharmaceutically acceptable derivatives thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers.
  • the compounds of the invention may also be combined with other therapeutic agents, which are useful in the treatment of disorders associated with obesity, psychiatric disorders, neurological disorders and pain.
  • the compounds of formula (I) are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related conditions, and neurological disorders such as dementia, multiple sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease.
  • the compounds are also potentially useful for the treatment of immune, cardiovascular, reproductive and endocrine disorders, and diseases related to the respiratory and gastrointestinal systems.
  • the compounds are also potentially useful as agents for ceasing consumption of tobacco, treating nicotine dependence and/or treating nicotine withdrawal symptoms, reducing the craving for nicotine and as anti-smoking agents.
  • the compounds may also eliminate the increase in weight that normally accompanies the cessation of smoking.
  • the compounds are also potentially useful as agents for treating or preventing diarrhea.
  • the compounds are also potentially useful as agents for reducing the craving/relapse for addictive substances that include, but are not limited to psychomotor-active agents such as nicotine, alcohol, cocaine, amphetamines, opiates, benzodiazepines and barbiturates.
  • addictive substances include, but are not limited to psychomotor-active agents such as nicotine, alcohol, cocaine, amphetamines, opiates, benzodiazepines and barbiturates.
  • the compounds are also potentially useful as agents for treating drug addiction and/or drug abuse.
  • the compounds are also potentially useful as agents for treating pain disorders, including but not limited to acute and chronic nociceptive, inflammatory and neuropathic pain and migraine.
  • the present invention provides a compound of formula I as claimed in any previous claim for use as a medicament.
  • the present invention provides the use of a compound of formula I in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, anxiety, anxio-depressive disorders, depression, bipolar disorder, ADHD, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related conditions, neurological disorders such as dementia, multiple sclerosis,
  • Parkinson's disease Huntington's chorea and Alzheimer's disease and pain related disorders, including but not limited to acute and chronic nociceptive, inflammatory and neuropathic pain and migraine, comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof.
  • the present invention provides a method of treating obesity, psychiatric disorders such as psychotic disorders, anxiety, anxio-depressive disorders, depression, bipolar disorder, ADHD, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related conditions, and neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Huntington's chorea and Alzheimer's disease and pain related disorders, including but not limited to acute and chronic nociceptive, inflammatory and neuropathic pain and migraine, comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof.
  • psychiatric disorders such as psychotic disorders, anxiety, anxio-depressive disorders, depression, bipolar disorder, ADHD, cognitive disorders, memory disorders, schizophrenia, epilepsy, and related conditions
  • neurological disorders such as dementia, multiple sclerosis, Parkinson's disease, Huntington's chorea and Alzheimer's disease and pain related disorders, including but not limited to acute and chronic nociceptive, inflammatory and neuropathic pain and migraine, comprising administering
  • the compounds of the present invention are particularly suitable for the treatment of obesity.
  • the present invention provides a method of treating obesity, type ⁇ diabetes, Metabolic syndrome and a method of preventing type II diabetes comprising administering a pharmacologically effective amount of a compound of formula I to a patient in need thereof.
  • the compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of disorders associated with the development and progress of atherosclerosis such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes and obesity.
  • a compound of the present invention may be used in combination with a compound that affects thermogenesis, lipolysis, fat absorption, satiety, or gut motility.
  • the compounds of the invention may be combined with another therapeutic agent that decreases the ratio of LDL/HDL or an agent that causes a decrease in circulating levels of LDL-cholesterol.
  • the compounds of the invention may also be combined with therapeutic agents used to treat complications related to micro- angiopathies.
  • the compounds of the invention may be used alongside other therapies for the treatment of metabolic syndrome or type 2 diabetes and its associated complications; these include biguanide drugs, insulin (synthetic insulin analogues), oral antihyperglycemics (these are divided into prandial glucose regulators and alpha-glucosidase inhibitors) and PPAR modulating agents.
  • the compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof may be administered in association with a PPAR modulating agent.
  • PPAR modulating agents include but are not limited to a PPAR alpha and/or gamma agonist, or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof.
  • Suitable PPAR alpha and/or gamma agonists, pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs thereof are well known in the art.
  • the combination of the invention may be used in conjunction with a sulfonylurea.
  • the present invention also includes a compound of the present invention in combination with a cholesterol-lowering agent.
  • the cholesterol-lowering agents referred to in this application include but are not limited to inhibitors of HMG-CoA reductase (3- hydroxy-3-methylglutaryl coenzyme A reductase).
  • HMG-CoA reductase inhibitor is a statin.
  • cholesterol-lowering agent also includes chemical modifications of the HMG-CoA reductase inhibitors, such as esters, prodrugs and metabolites, whether active or inactive.
  • the present invention also includes a compound of the present invention in combination with an inhibitor of the ileal bile acid transport system (IBAT inhibitor).
  • IBAT inhibitor an inhibitor of the ileal bile acid transport system
  • the present invention also includes a compound of the present invention in combination with a bile acid binding resin.
  • a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration one or more of the following agents selected from: a CETP (cholesteryl ester transfer protein) inhibitor; a cholesterol absorption antagonist; a MTP (microsomal transfer protein) inhibitor ; a nicotinic acid derivative, including slow release and combination products; a phytosterol compound ; probucol; an anti-obesity compound, for example orlistat (EP 129,748) and sibutramine (GB 2,184,122 and US 4,929,629); an antihypertensive compound, for example an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an andrenergic blocker, an alpha andrenergic block
  • ACE angiotensin converting enzyme
  • a method for the treatment of type 2 diabetes and its associated complications in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a method of treating hyperlipidemic conditions in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof in simultaneous, sequential or separate administration with an effective amount of a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • a pharmaceutical composition which comprises a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • kits comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof.
  • kits comprising: a) a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof; in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • kits comprising: a) a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a compound from one of the other classes of compounds described in this combination section or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • a compound of the formula I or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of metabolic syndrome or type 2 diabetes and its associated complications in a warm-blooded animal, such as man.
  • a compound of the formula I or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, and one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, in the manufacture of a medicament for use in the treatment of hyperlipidaemic conditions in a warm-blooded animal, such as man.
  • a combination treatment comprising the administration of an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of an effective amount of one of the other compounds described in this combination section, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or a prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment.
  • Flash column chromatography employed MERCK normal phase silica gel 60 A (40-63 ⁇ m) or a Biotage Horizon Pioneer® HPFC system equipped with FLASH 12+M or FLASH 25+M or 40+M silica cartridges. Mass spectra were recorded on a Waters Micromass ZQ single quadrupole equipped with a pneumatically assisted electrospray interface (LC-MS). HPLC analyses were performed on a Gynkotek P580 HPG, gradient pump with a Gynkotek UVD 170S UV- Vis detector.
  • Methyl 3-armno-5-(4-chlorophenyl)thiophene-2-carboxylate (2.00 g, 7.47 mmol) was refluxed in a solution of potassium hydroxide (2.0 g, 36 mmol) in 50 mL of water and 50 mL of methanol for 2 h. Methanol was evaporated and the residue was diluted to the double volume with water and washed with ethyl acetate. The aqueous layer was acidified with NaHSO 4 (aq) and the precipitate was filtered, washed with water and dried to give 1.85 g (98%) of the desired compound.
  • 1 H NMR (DMSOd 6 ) ⁇ 7.62 (m, 2H), 7.48 (m, 2H), 6.96 (s, IH).
  • MCHrI radioligand binding 0 Assays were performed on membranes prepared from CHO-Kl cells expressing the human Melanin concentrating hormone receptor 1 (hMCHrl, 5.45 pmol/mg protein; Euroscreen). Assays were performed in a 96-well plate format in a final reaction volume of 200 ⁇ l per well. Each well contained 6 ⁇ g of membrane proteins diluted in binding buffer (50 mM Tris, 3 mM MgCl 2 , 0.05 % bovine serum albumin and the radioligand 125 I-MCH (IM344 5 Amersham) was added to give 10 000 cpm (counts per minute) per well.
  • binding buffer 50 mM Tris, 3 mM MgCl 2 , 0.05 % bovine serum albumin and the radioligand 125 I-MCH (IM344 5 Amersham
  • D is the slope factor
  • x is the original known x values
  • y is the original known y values.
  • the compounds exemplified herein had an IC 50 of less than 100 nM in the abovementioned human MCHrI binding assay.
  • Preferred compounds had an activity of less than 20 nM. For instance, an IC 50 value of 2 nM was obtained for the compound of Example 1.
  • Membranes expressing recombinant hMCHrl (5.45 pmol/mg protein; Euroscreen) were prepared in assay buffer (50 mM HEPES, 100 mM NaCl, 5 mM MgCl 2 , 1 mM EDTA, 200 ⁇ M DTT, 20 ⁇ M GDP (Sigma) containing 0.1 ⁇ g/ml BSA, pH7.4) before assay.
  • the assays were performed using membranes at 6 ⁇ g/well in an assay volume of 200 ⁇ L and the appropriate concentrations of compounds prepared in DMSO or in HOAc.
  • the reaction was started by addition of 0.056 nM [ 35 S]GTP ⁇ S (Specific activity >1000 Ci/mmol; Amersham) and an ED 8 O concentration of MCH (determined for each membrane and each MCH batch). Non-specific binding was determined using 20 ⁇ M non-radiolabelled GTP ⁇ S. Plates were incubated for 45 min at 3O 0 C.
  • Free and bound GTP ⁇ S were separated by filtration binding using GF/B filter mats presoaked in wash buffer (50 mM Tris, 5 mM MgCl 2 , 50 mM NaCl, pH 7.4) using a Micro96 cell harvester (Skatron Instruments) and the filters then dried at 50 0 C before counting using a 1450 Microbeta TRILUX (Wallac). Data are means ⁇ SD for experiments performed in triplicate. IC 5O values of antagonists were determined using non-linear regression analysis of concentration response curves using Activity Base.
  • hERG activity hERG testing was performed using a modified version of the method described by Kiss L, Bennett PB, Uebele VN, Koblan KS, Kane SA, Neagle B, Schroeder K. "High throughput ion-channel pharmacology: planar-array-based voltage clamp" Assay Drug Dev Technol. 1, 127-35. (2003).
  • the compound of Example 1 had an IC 50 exceeding 5 ⁇ M in the abovementioned assay.
  • mice Female C57B1/6J mice were given ad libitum access to calorie-dense 'cafeteria' diet (soft chocolate/cocoa-type pastry, chocolate, fatty cheese and nougat) and standard lab chow for 8-10 weeks until a body weight of 45-50 grams was achieved. Compounds to be tested were then administered systemically (iv, ip, sc or po) once daily for a minimum of 5 days, and the body weights of the mice monitored on a daily basis.
  • Compounds of the invention have the advantage that they may be more potent, more selective (e.g. vs. ion channels such as hERG and/or vs. GPCR' s related to MCHrI) more efficacious in vivo, be less toxic, be longer acting, produce fewer side effects, be more easily absorbed, be less metabolised and/or have a better pharmacokinetic profile than, or have other useful pharmacological or physicochemical properties over, compounds known in the prior art.
  • vs. ion channels such as hERG and/or vs. GPCR' s related to MCHrI

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Abstract

La présente invention concerne des composés de formule (I), des procédés de préparation desdits composés, leur utilisation dans le traitement de l’obésité, de troubles psychiatriques, de troubles cognitifs, de troubles de la mémoire, de la schizophrénie, de l’épilepsie, et des maladies associées, de troubles neurologiques tels que la démence, la sclérose en plaques, la maladie de Parkinson, la chorée de Huntington et la maladie d'Alzheimer, et de troubles liés à la douleur, ainsi que des compositions pharmaceutiques les contenant.
PCT/SE2006/000879 2005-07-15 2006-07-13 Agents thérapeutiques WO2007011285A1 (fr)

Applications Claiming Priority (4)

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SE0501689 2005-07-15
SE0501689-4 2005-07-15
SE0501878-3 2005-08-24
SE0501878 2005-08-24

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012036233A1 (fr) * 2010-09-17 2012-03-22 塩野義製薬株式会社 Dérivé hétérocyclique condensé ayant une activité antagoniste du récepteur de l'hormone de concentration de la mélanine
US20150087672A1 (en) * 2012-05-10 2015-03-26 Takeda Pharmaceutical Company Limited Aromatic ring compound

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004092181A1 (fr) * 2003-04-11 2004-10-28 Smithkline Beecham Corporation Antagonistes heterocycliques de mchr1

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004092181A1 (fr) * 2003-04-11 2004-10-28 Smithkline Beecham Corporation Antagonistes heterocycliques de mchr1

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012036233A1 (fr) * 2010-09-17 2012-03-22 塩野義製薬株式会社 Dérivé hétérocyclique condensé ayant une activité antagoniste du récepteur de l'hormone de concentration de la mélanine
US20150087672A1 (en) * 2012-05-10 2015-03-26 Takeda Pharmaceutical Company Limited Aromatic ring compound
US9440987B2 (en) * 2012-05-10 2016-09-13 Takeda Pharmaceutical Company Limited Aromatic ring compound

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