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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to certain salts of l,5-diaryl ⁇ yrazole-3-carboxamides, to processes for preparing such compounds, to their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
• Background of the invention relates to certain salts of l,5-diaryl ⁇ yrazole-3-carboxamides, to processes for preparing such compounds, to their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.
• CB 1 modulators are useful in the treatment of obesity, psychiatric and neurological disorders (WOO 1/70700 EP 658,546 and EP 656,354).
• CB 1 modulators with improved physicochemical properties and/or DMPK properties and/or pharmacodynamic properties.
• Pyrazoles having anti-inflammatory activity are disclosed in WO 95/15316, WO96/38418, WO97/11704, WO99/64415, EP 418 845 and WO2004050632.
• WO2004050632 discloses 1,1 -dimethylethyl [2- [4-[3 - [(ethylmethylamino)carbonyl] - 1 -(4-methoxyphenyl)- 1 H- pyrazol-5-yl]phenoxy]ethyl]carbamate, 5-[4-(2-aminoethoxy)phenyl]-N-ethyl- 1 -(4- methoxyphenyl)-N-methyl-lH-pyrazole-3-carboxamide, l-[[5-[4-(2-aminoethoxy)phenyl]- 1 -(4-methoxyphenyl)- lH-pyrazol-3-yl]carbonyl]piperidine and 1,1 -dimethylethyl [2-[4- [l-(4-methoxyphenyl)-3-(l-piperidinylcarbonyl)-lH-pyrazol-5-yl]phenoxy]
• R 1 represents a) a C 1-3 alkoxy group substituted by one or more of the following i) fiuoro ii) a group NR c R d in which R c and R d independently represent H, a group or Q- ⁇ alkoxycarbonyl group provided that one of R c and R d is other than H or iii) a 1,3- dioxolan-2-yl group b) R 1 represents a C 4-O aIkOXy group optionally substituted by one or more of the following i) fiuoro ii) a group NR c R d in which R c and R d independently represent H, a C ⁇ aUcyl group or Q-galkoxycarbonyl group provided that one of R c and R d is other than H or iii) a l,3-dioxolan-2-yl group c) a group of formula phenyl(CH 2 ) p O- in
• R 2 represents a Ci -3 alkyl group, a C 1-3 alkoxy group, hydroxy, nitro, cyano or halo n is 0, 1, 2 or 3;
• R 3 represents a) a group X-Y-NR 7 R 8 in which X is CO or SO 2 , Y is absent or represents NH optionally substituted by a C h alky!
• R 7 and R 8 independently represent : a Ci -6 alkyl group optionally substituted by 1, 2, or 3 groups represented by W; a C 3- i 5 cycloalkyl group optionally substituted by 1, 2, or 3 groups represented by W; a (C 3- i 5 cycloalkyl)Ci, 3 alkylene group optionally substituted by 1, 2, or 3 groups represented by W; a group -(CH 2 ) r (phenyl ) s in which r is 0,1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl groups are optionally independently substituted by one, two or three groups represented by Z; a saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally o one of the following : oxygen, sulphur or an additional nitrogen wherein the heterocyclic group is optionally substituted by one or more Ci -3 alkyl groups, hydroxy or benzyl ; a group - (CH 2 ) t
• R 4 represents H, halo, hydroxy, cyano, a C ⁇ aUcyl group, a C 1-6 alkoxy group or a C 1- ⁇ alkoxyC ⁇ alkylene group which contains a maximum of 6 carbon atoms, each of which groups is optionally substituted by one or more fluoro or cyano;
• Z represents a Q ⁇ alkyl group, a C ⁇ alkoxy group, hydroxy, halo, trifiuoromethyl, o trifluoromethylthio, difluoromethoxy, trifluoromethoxy, trifluoromethylsulphonyl, nitro, amino, mono or di C ⁇ salkylamino, Cioalkylsulphonyl, Ci -3 alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di Ci -3 alkyl carbamoyl and acetyl; and W represents hydroxy, fluoro, a Ci- 3 alkyl group, a C 1-3 alkoxy group, amino, mono or di Ci- 3 alkylamino, a Ci- ⁇ alkoxycarbonyl group or a heterocyclic amine selected from morpholinyl, pyrrolidinyl, piperdinyl or piperazinyl in which the heterocyclic amine is optionally substituted by a C ⁇ aUc
• a suitable pharmaceutically acceptable salt of a compound of Formula A is, for example, an acid-addition salt of a compound of Formula A which is sufficiently basic, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of Formula A which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a sodium, calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Only 2 specific salts of compounds of Formula A are disclosed in
• the drug substance In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations comprising the active compound. Further, in the manufacture of drag compositions, it is important that a reliable, reproducible and constant plasma concentration profile of drag is provided following administration to a patient.
• the drug substance, and compositions containing it should preferably be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the active component's physico-chemical characteristics
• the present invention provides a compound selected from: butane- 1 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin- 1 -ylcarbamoyl)-
• 4,4,4-trifluorobutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- y lcarbamoyl)-2H-pyrazol-3 -yl]phenyl ester; propane-l-sulfonic acid-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-ylcarbamoyl)- 2H-pyrazol-3-yl]-2,6-difluorophenyl ester; propane- 1 -sulfonic acid 4-[2-(2,4-dichloro ⁇ henyl)-5-(piperidin- 1 -ylcarbamoyl)-2H- pyrazol-3-yl]phenyl ester; propane-1 -sulfonic acid 4-[4-bromo-2-(2,4-dichlorophenyl)-5-(piperidin-l-ylcarbam
• 5-chlorothiophene-2-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- ylcarbamoyl)-2 ⁇ -pyrazol-3 -yljphenyl ester; in the form of a methanesulphonate salt (mesylates salt) , a hemi-1,5- naphthalenedisulphonate salt, a 1,2-ethanedisulfonic acid salt, a hydrochloride salt or a hydrogen sulphate salt but excluding 4- ⁇ l-(2,4-dichloro ⁇ henyl)-4-methyl-3-[(piperidin-l- ylamino)carbonyl]-lH-pyrazol-5-yl ⁇ phenyl pyridine-3-sulfonate hydrochloride.
• the present invention provides one or more of the following: butane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-ylcarbamoyl)-
• 4,4,4-trifluorobutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hydrogen sulphate; propane- 1 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-ylcarbamoyl)-
• 3,3,3-trifluoropropane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- ylcarbamoyl)-2H-pyrazol-3-yl] ⁇ henyl ester mesylate; 3,3 ,3 -trifluoropropane-1 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester hemi-l,5-naphthalenedisulphonate;
• 3,3-dimethylbutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- ylcarbamoyl)-2H-pyrazol-3-yl] ⁇ henyl ester hydrochloride; 3,3-dimethylbutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester mesylate;
• a compound of the invention in substantially crystalline form.
• substantially crystalline we include greater than 20%, preferably greater than 30%, and more preferably greater than 40% (e.g. greater than any of 50, 60, 70, 80 or 90%) crystalline.
• a compound of the invention in partially crystalline form we include 5% or between 5% and 20% crystalline.
• the degree (%) of crystallinity may be determined by the skilled person using X- ray powder diffraction (XRPD). Other techniques, such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry, may also be used.
• Compounds of the invention may have improved stability when compared to compounds disclosed in
• chemical stability we include that it may be possible to store compounds of the invention in an isolated form, or in the form of a formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g. in an oral dosage form, such as a tablet, capsule etc.), under normal storage conditions, with an insignificant degree of chemical degradation or decomposition.
• solid state stability we include that it may be possible to store compounds of the invention in an isolated solid form, or in the form of a solid formulation in which it is provided in admixture with pharmaceutically acceptable carriers, diluents or adjuvants (e.g. in an oral dosage form, such as a tablet, capsule etc.), under normal storage conditions, with an insignificant degree of solid state transformation (e.g. crystallisation, recrystallisation, solid state phase transition, hydration, dehydration, solvatisation or desolvatisation).
• pharmaceutically acceptable carriers, diluents or adjuvants e.g. in an oral dosage form, such as a tablet, capsule etc.
• normal storage conditions include temperatures of between minus 80 and plus 5O 0 C (preferably between 0 and 40 0 C and more preferably room temperatures, such as 15 to 30 0 C), pressures of between 0.1 and 2 bars (preferably at atmospheric pressure), relative humidities of between 5 and 95% (preferably 10 to 60%), and/or exposure to 460 lux of UV/visible light, for prolonged periods (i.e. greater than or equal to six months).
• compounds of the invention may be found to be less than 15%, more preferably less than 10%, and especially less than 5%, chemically degraded/decomposed, or solid state transformed, as appropriate.
• crystallise salts of compounds of the present invention may be from a melt, under supercritical conditions, or achieved by sublimation. However, it is preferable that crystallisation occurs from an appropriate solvent system.
• a process for the preparation of a crystalline compound of the invention which comprises crystallising a compound of the invention from an appropriate solvent system.
• Crystallisation temperatures and crystallisation times depend upon the salt that is to be crystallised, the concentration of that salt in solution, and the solvent system that is used.
• Crystallisation may also be initiated and/or effected by way of standard techniques, for example with or without seeding with crystals of the appropriate crystalline compound of the invention.
• crystalline forms of the compounds of the invention may be readily characterised using X-ray powder diffraction (XRPD) methods, for example as described hereinafter.
• XRPD X-ray powder diffraction
• crystallisations are preferably carried out by seeding with nuclei and/or seed crystals of the desired crystalline form in substantially complete absence of nuclei and/or seed crystals of other crystalline forms.
• Seed crystals of appropriate compound may be prepared, for example, by way of slow evaporation of solvent from a portion of solution of appropriate salt.
• Compounds of the invention may be isolated using techniques which are well known to those skilled in the art, for example decanting, filtering or centrifuging. Compounds may be dried using standard techniques. Further purification of compounds of the invention may be effected using techniques, which are well known to those skilled in the art. For example impurities may be removed by way of recrystallisation from an appropriate solvent system. Suitable temperatures and times for the recrystallisation depend upon the concentration of the salt in solution, and upon the solvent system that is used.
• the resultant salt may be in a form which has improved chemical and/or solid state stability, as mentioned hereinbefore.
• Compounds of the invention have the advantage that they may be more efficacious, be less toxic, be longer acting, have a broader range of activity, be more potent, produce fewer side effects, be more easily absorbed, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance), than, and/or have other useful pharmacological, physical, or chemical, properties over, compounds known in the prior art.
• Compounds of the invention may have the further advantage that they may be administered less frequently than compounds known in the prior art.
• Compounds of the invention may also have the advantage that they are in a form which provides for improved ease of handling. Further, compounds of the invention have the advantage that they may be produced in forms which may have improved chemical and/or solid state stability (including e.g. due to lower hygroscopicity). Thus, such compounds of the invention may be stable when stored over prolonged periods.
• Compounds of the invention may also have the advantage that they may be crystallised in good yields, in a high purity, rapidly, conveniently, and at a low cost.
• the compounds of the invention may be prepared as outlined below. However, the invention is not limited to these methods.
• the salts may be prepared by reacting a compound prepared as described in
• the appropriate acid for example methanesulphonic acid, naphthalene- 1, 5 -disulphonic acid, 1,2- ethanedisulfonic acid, sulphuric acid or hydrochloric acid in an inert solvent, for example butanone at a temperature in the range of 0-100°C and isolating the solid salt.
• the salt may be isolated by cooling the reaction solution and optionally seeding the solution with the desired product and/or concentrating the solution.
• the product may be isolated by adding an antisolvent to a solution of the product in an inert solvent.
• the solid may be collected by methods known to those skilled in the art for example filtration or centrifugation.
• inert solvent refers to a liquid that dissolves or partially dissolves the free base and/or the acid and/or the product salt but does not react with the starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product.
• the present invention provides the compound obtainable by reacting one of the following: butane- 1 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin- 1 -ylcarbamoyl)-
• 4,4,4-trifluorobutane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester; propane-l-sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l-ylcarbamoyl)-
• 2H-pyrazol-3-yl]phenyl ester with either a) a molar equivalent hydrochloric acid or b) a molar equivalent methanesulphonic acid or c) a half a molar equivalent of sulphuric acid or d) a half a molar equivalent of 1,5-naphthalenedisulphonic acid or e) a half a molar equivalent of 1,2-ethanedisulfonic acid in butanone.
• R 1 represents a) a C 1-3 alkoxy group substituted by one or more of the following i) fluoro ii) a group NR c R d in which R c and R d independently represent H, a group or Ci- 6 alkoxycarbonyl group provided that one of R c and R d is other than H or iii) a 1,3- dioxolan-2-yl group b) R 1 represents a C 4- 6alkoxy group optionally substituted by one or more of the following i) fluoro ii) a group NR c R d in which R c and R d independently represent H, a Ci- 6 alkyl group or Ci- ⁇ alkoxycarbonyl group provided that one of R c and R d is other than H or iii) a l,3-dioxolan-2-yl group c) a group of formula phenyl(CH 2 ) p O- in which p is I 3 2
• R 2 represents a C 1-3 alkyl group, a C 1-3 alkoxy group, hydroxy, nitro, cyano or halo n is O, 1, 2 or 3;
• R 3 represents a) a group X-Y-NR 7 R 8 in which X is CO or SO 2 ,
• Y is absent or represents NH optionally substituted by a C 1-3 alkyl group; and R 7 and R 8 independently represent : a Ci- 6 alkyl group optionally substituted by 1, 2, or 3 groups represented by W; a C 3- i5cycloalkyl group optionally substituted by 1, 2, or 3 groups represented by W; a (C3.]5cycloalkyl)C 1-3 alkylene group optionally substituted by 1, 2, or 3 groups represented by W; a group -(CH 2 )r(phenyl ) s in which r is 0,1, 2, 3 or 4, s is 1 when r is 0 otherwise s is 1 or 2 and the phenyl groups are optionally independently substituted by one, two or three groups represented by Z; a saturated 5 to 8 membered heterocyclic group containing one nitrogen and optionally one of the following : oxygen, sulphur or an additional nitrogen wherein the heterocyclic group is optionally substituted by one or more C 1-3 alkyl groups, hydroxy or benzy
• R 4 represents H, halo, hydroxy, cyano, a C ⁇ alkyl group, a Ci- 6 alkoxy group or a C 1- ⁇ alkoxyC ⁇ ealkylene group which contains a maximum of 6 carbon atoms, each of which groups is optionally substituted by one or more fluoro or cyano;
• Z represents a C 1-3 allcyl group, a C 1-3 alkoxy group, hydroxy, halo, trifluoromethyl, trifluoromethylthio, difluoromethoxy, trifiuoromethoxy, trifluoromethylsulphonyl, nitro, amino, mono or di C 1-3 alkylamino, C 1-3 alkylsulphonyl, Ci ⁇ alkoxycarbonyl, carboxy, cyano, carbamoyl, mono or di C 1-3 alkyl carbamoyl and acetyl; and
• W represents hydroxy, fluoro, a C 1-3 alkyl group, a Ci. 3 alkoxy group, amino, mono or di C 1 . 3 alkylamino, a C ⁇ ⁇ alkoxycarbonyl group or a heterocyclic amine selected from morpholinyl, pyrrolidinyl, piperdinyl or piperazinyl in which the heterocyclic amine is optionally substituted by a C ⁇ alkyl group or hydroxyl; but excluding 1,1-dimethylethyl [2-[4-[3-[(ethylmethylamino)carbonyl]-l-(4- methoxyphenyl)-lH-pyrazol-5-yl]phenoxy]ethyl]carbamate and 1,1-dimethylethyl [2-[4- [l-(4-methoxy ⁇ henyl)-3-(l-piperidinylcarbonyl)-lH-pyrazol-5- yl]phenoxy]eth
• 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 or a pharmaceutically acceptable 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 0.01-1 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 0.5mg to 500mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25mg, 50mg, lOOmg and 250mg.
• 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 formula (I) are useful for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g.
• psychiatric disorders such as psychotic and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (e.g., Gilles de Ia Tourette's syndrome), attention disorders like ADD/ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, dementia of ageing, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild dementia of ageing), neurological and/or neurodegenerative disorders (e.g.
• the compounds are also potentially useful for the prevention or treatment of dependence and addictive disorders and behaviours (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.
• dependence and addictive disorders and behaviours e.g., alcohol and/or drug abuse, pathological gambling, kleptomania
• drug withdrawal disorders e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal
• the compounds are also potentially useful for the prevention or treatment of neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma.
• neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity
• treatment of spinal cord injury such as dystonias, dyskinesias, akathisia, tremor and spasticity
• spinal cord injury such as spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma.
• sleep disorders e
• Atherosclerosis arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischaemic attack, peripheral vascular disease, systemic inflammation o of the vasculature, septic chock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia, metabolic disorders (e.g.
• diabetes mellitus diabetes mellitus
• dyslipidemia fatty liver
• gout hypercholesterolemia
• hyperlipidemia hypertriglyceridemia
• 5 hyperuricacidemia impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity- hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g.
• the compounds are also potentially useful as agents in treatment of (esophageal) achalasia.
• the present invention provides a compound of the invention as previously defined for use as a medicament.
• the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g.
• psychiatric disorders such as psychotic and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (e.g., Gilles de Ia Tourette's syndrome), attention disorders like ADD/ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, dementia of ageing, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild dementia of ageing), neurological and/or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory disorders, and neuroinflammatory disorders, and neuroinflammatory disorders, and/or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer'
• the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of dependence and addictive disorders and behaviours (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.
• addictive disorders and behaviours e.g., alcohol and/or drug abuse, pathological gambling, kleptomania
• drug withdrawal disorders e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal
• the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma.
• the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of immune, cardiovascular disorders (e.g.
• Atherosclerosis arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischaemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic chock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia, metabolic disorders (e.g.
• diabetes mellitus diabetes mellitus
• dyslipidemia fatty liver
• gout hypercholesterolemia
• hyperlipidemia hypertriglyceridemia
• hyperuricacidemia impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity- hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g.
• hypogonadism in males treatment of hypogonadism in males, treatment of infertility or as contraceptive, menstrual abnormalities/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-deficient subjects, hirsutism in females, normal variant short stature) and diseases related to the respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-esophageal reflux, ulcers).
• respiratory e.g. asthma and chronic obstructive pulmonary disease
• gastrointestinal systems e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastro-esophageal reflux, ulcers).
• the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of dermatological disorders, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disoerders (e.g. arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders.
• cancers e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct
• craniopharyngioma e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct
• the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof for the prophylaxis or treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention of weight gain (e.g., medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g.
• psychiatric disorders such as psychotic and/or mood disorders, schizophrenia and schizo-affective disorder, bipolar disorders, anxiety, anxio-depressive disorders, depression, mania, obsessive-compulsive disorders, impulse control disorders (e.g., Gilles de Ia Tourette's syndrome), attention disorders like ADD/ ADHD, stress, and neurological disorders such as dementia and cognitive and/or memory dysfunction (e.g., amnesia, Alzheimer's disease, Pick's dementia, dementia of ageing, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild dementia of ageing), neurological and/or neurodegenerative disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory disorders (e.g. Multiple Sclerosis, Raynaud's syndrome, Parkinson's disease, Huntington's chorea and Alzheimer's disease), demyelinisation-related disorders, neuroinflammatory disorders (e.
• the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof for the prophylaxis or treatment of dependence and addictive disorders and behaviours (e.g., alcohol and/or drug abuse, pathological gambling, kleptomania), drug withdrawal disorders (e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal delirium; amphetamine withdrawal; cocaine withdrawal; nicotine withdrawal; opioid withdrawal; sedative, hypnotic or anxiolytic withdrawal with or without perceptual disturbances; sedative, hypnotic or anxiolytic withdrawal delirium; and withdrawal symptoms due to other substances), alcohol and/or drug-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.
• dependence and addictive disorders and behaviours e.g., alcohol and/or drug abuse, pathological gambling, kleptomania
• drug withdrawal disorders e.g., alcohol withdrawal with or without perceptual disturbances; alcohol withdrawal deli
• the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof for the prophylaxis or treatment of neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity, treatment of spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma.
• neurological dysfunctions such as dystonias, dyskinesias, akathisia, tremor and spasticity
• spinal cord injury such as spinal cord injury, neuropathy, migraine, vigilance disorders, sleep disorders (e.g., disturbed sleep architecture, sleep apnea, obstructive sleep apnea, sleep apnea syndrome), pain disorders, cranial trauma.
• the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof for the prophylaxis or treatment of immune, cardiovascular disorders (e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left ventricular hypertrophy, myocardial infarction, transient ischaemic attack, peripheral vascular disease, systemic inflammation of the vasculature, septic chock, stroke, cerebral apoplexy, cerebral infarction, cerebral ischaemia, cerebral thrombosis, cerebral embolism, cerebral hemorrhagia, metabolic disorders (e.g.
• cardiovascular disorders e.g. atherosclerosis, arteriosclerosis, angina pectoris, abnormal heart rhythms, and arrhythmias, congestive heart failure, coronary artery disease, heart disease, hypertension, prevention and treatment of left
• diabetes mellitus diabetes mellitus
• dyslipidemia fatty liver
• gout hypercholesterolemia
• hyperlipidemia hypertriglyceridemia
• hyperuricacidemia impaired glucose tolerance, impaired fasting glucose, insulin resistance, insulin resistance syndrome, metabolic syndrome, syndrome X, obesity- hypoventilation syndrome (Pickwickian syndrome), type I diabetes, type II diabetes, low HDL- and/or high LDL-cholesterol levels, low adiponectin levels), reproductive and endocrine disorders (e.g.
• hypogonadism in males treatment of hypogonadism in males, treatment of infertility or as contraceptive, menstrual abnormalities/emmeniopathy, polycystic ovarian disease, sexual and reproductive dysfunction in women and men (erectile dysfunction), GH-def ⁇ cient subjects, hirsutism in females, normal variant short stature) and diseases related to the respiratory (e.g. asthma and chronic obstructive pulmonary disease) and gastrointestinal systems (e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastroesophageal reflux, ulcers).
• respiratory e.g. asthma and chronic obstructive pulmonary disease
• gastrointestinal systems e.g. dysfunction of gastrointestinal motility or intestinal propulsion, diarrhea, emesis, nausea, gallbladder disease, cholelithiasis, obesity-related gastroesophageal reflux, ulcers).
• the present invention provides a method comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof for the prophylaxis or treatment of dermatological disorders, cancers (e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct), craniopharyngioma, Prader-Willi syndrome, Turner syndrome, Frohlich's syndrome, glaucoma, infectious diseases, urinary tract disorders and inflammatory disorders (e.g. arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders.
• dermatological disorders e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallbladder, bile duct
• craniopharyngioma e.g. colon, rectum, prostate, breast, ovary, endometrium, cervix, gallblad
• the compounds of the present invention are particulary suitable for the treatment of obesity or being overweight, (e.g., promotion of weight loss and maintenance of weight loss), prevention or reversal of weight gain (e.g., rebound, medication-induced or subsequent to cessation of smoking), for modulation of appetite and/or satiety, eating disorders (e.g. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items).
• obesity disorders e.g. binge eating, anorexia, bulimia and compulsive
• cravings for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items.
• the compounds of formula (I) are useful for the treatment of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders(e.g. 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, septic shock and diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea).
• the compounds are also potentially useful as agents in treatment of extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.
• the compounds may also eliminate the increase in weight that normally accompanies the cessation of smoking.
• the present invention provides a compound of the invention as previously defined for use as a medicament.
• the present invention provides the use of a compound of the invention in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia, bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive- compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g.
• diarrhea and extended abuse, addiction and/or relapse indications, e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.
• treating drug e.g. treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms.
• the present invention provides a method of treating obesity, psychiatric disorders such as psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions, neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis), Parkinson's Disease, Huntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems (e.g. diarrhea), and extended abuse, addiction and/or relapse indications, e.g.
• psychotic disorders such as schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders like ADHD, epilepsy, and related conditions
• neurological disorders such as dementia, neurological disorders (e.g. Multiple Sclerosis
• treating drug (nicotine, ethanol, cocaine, opiates, etc) dependence and/or treating drug (nicotine, ethanol, cocaine, opiates, etc) withdrawal symptoms comprising administering a pharmacologically effective amount of a compound of the invention to a patient in need thereof.
• the compounds of the present invention are particulary suitable for the treatment of obesity, e.g. by reduction of appetite and body weight, maintenance of weight reduction and prevention of rebound.
• the compounds of the present invention may also be used to prevent or reverse medication-induced weight gain, e.g. weight gain caused by antipsychotic (neuroleptic) treatment(s).
• the compounds of the present invention may also be used to prevent or reverse weight gain associated with smoking cessation.
• the compounds of the present invention are suitable for use in treating the above indications in juvenile or adolescent patient populations.
• the compounds of the present invention may also be suitable for use in the regulation of bone mass and bone loss and therefore useful in the treatment of osteoporosis and other bone diseases.
• the compounds of the invention may be combined with another therapeutic agent that is useful in the treatment of obesity such as other anti-obesity drugs, that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fat absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or G-I motility.
• another therapeutic agent that is useful in the treatment of obesity
• anti-obesity drugs that affect energy expenditure, glycolysis, gluconeogenesis, glucogenolysis, lipolysis, lipogenesis, fat absorption, fat storage, fat excretion, hunger and/or satiety and/or craving mechanisms, appetite/motivation, food intake, or G-I motility.
• the compounds of the invention may further be combined with another therapeutic agent that is useful in the treatment of disorders associated with obesity such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes, sleep apnea, asthma, heart disorders, atherosclerosis, macro and micro vascular diseases, liver steatosis, cancer, joint disorders, and gallbladder disorders.
• a compound of the present invention may be used in combination with a another therapeutic agent that lowers blood pressure or 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 microangiopathies.
• the compounds of the invention may be used alongside other therapies for the treatment of obesity and its associated complications the metabolic syndrome and type 2 diabetes, these include biguanide drugs, insulin (synthetic insulin analogues) and oral antihyperglycemics (these are divided into prandial glucose regulators and alpha- glucosidase inhibitors).
• the compound of the invention, or a pharmaceutically acceptable salt 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 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.
• the term "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.
• the present invention also includes a compound of the present invention in combination with a bile acid sequestering agent, for example colestipol or cholestyramine or cholestagel.
• a combination treatment comprising the administration of an effective amount of a compound of the invention, or a pharmaceutically acceptable salt 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-coagulant; an omega-3 fatty acid ; another anti-obesity compound for example sibutramine, phentermine, orlistat, bupropion, ephedrine, thyroxine; an antihypertensive compound for example an bile acid sequestering agent,
• NaSSA an antipsychotic agent for example olanzapine and clozapine; a serotonin receptor modulator; a leptin/leptin receptor modulator; a ghrelin/ghrelin receptor modulator; a DPP-IV inhibitor; 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 warmblooded animal, such as man in need of such therapeutic treatment.
• 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 warmblooded animal, such as man in need of such therapeutic treatment.
• a combination treatment comprising the administration of an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with the simultaneous, sequential or separate administration of very low calorie diets (VLCD) or low-calorie diets (LCD).
• VLCD very low calorie diets
• LCD low-calorie diets
• a method for the treatment of obesity 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 the invention, or a pharmaceutically acceptable salt 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 the invention, or a pharmaceutically acceptable salt 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 the invention, or a pharmaceutically acceptable salt 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 the invention, or a pharmaceutically acceptable salt 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 the invention, or a pharmaceutically acceptable salt 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 the invention, or a pharmaceutically acceptable salt 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 invention or a pharmaceutically acceptable salt 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 obesity and its associated complications in a warm-blooded animal, such as man.
• a compound of the invention or a pharmaceutically acceptable salt 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 invention, or a pharmaceutically acceptable salt 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.
• a compound of the invention may also be combined with therapeutic agents that are useful in the treatment of disorders or conditions associated with obesity (such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis, osteoarthritis and some cancers) and psychiatric and neurological conditions.
• obesity such as type II diabetes, metabolic syndrome, dyslipidemia, impaired glucose tolerance, hypertension, coronary heart disease, non-alcoholic steatohepatitis, osteoarthritis and some cancers
• psychiatric and neurological conditions psychiatric and neurological conditions.
• a patient may be identified by, for example, measuring body mass index (BMI), which is calculated by dividing weight in kilograms by height in metres squared, and comparing the result with the definitions.
• BMI body mass index
• the affinity of the compounds of the invention for central cannabinoid receptors is demonstrable in methods described in Devane et al , Molecular Pharmacology, 1988, 34,605 or those described in WO01/70700 or EP 656354.
• the assay may be performed as follows. lO ⁇ g of membranes prepared from cells stably transfected with the CBl gene were suspended in 200 ⁇ l of 10OmM NaCl, 5mM MgCl 2 , ImM EDTA, 5OmM HEPES (pH 7.4), ImM DTT, 0.1% BSA and lOO ⁇ M GDP.
• the compounds of the present invention are active at the CBl receptor (IC50 ⁇ 1 micromolar). Most preferred compounds have IC50 ⁇ 200 nanomolar.
• the compounds of the invention are believed to be selective CBl antagonists or inverse agonists.
• the potency, selectivity profile and side effect propensity may limit the clinical usefulness of hitherto known compounds with alleged CBl antagonistic/inverse agonistic properties.
• preclinical evaluation of compounds of the present invention in models of gastrointestinal and/or cardiovascular function indicates that they offer significant advantages compared to representative reference CBl antagonist/inverse agonist agents.
• the compounds of the present invention may provide additional benefits in terms of potency, selectivity profile, bioavailability, half-life in plasma, blood brain permeability, plasma protein binding (for example higher free fraction of drug) or solubility compared to representative reference CBl antagonists/inverse agonist agents.
• 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 8-10weeks. 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. Simultaneous assessment of adiposity was carried by means of DEXA imaging at baseline and termination of the study. Blood sampling was also carried out to assay changes in obesity-related plasma markers.
• LiHMDSA Lithium bis(trimethylsilyl)amide bis(trimethylsilyl)amide
• Mass spectra were recorded on either a Micromass ZQ single quadrupole or a Micromass
• LCZ single quadrupole mass spectrometer both equipped with a pneumatically assisted electrospray interface (LC-MS).
• 1 H NMR measurements were performed on either a Varian Mercury 300 or a Varian Inova 500, operating at 1 H frequencies of 300 and 500 MHz respectively. Chemical shifts are given in ppm with CDCl 3 as internal standard. CDCl 3 is used as the solvent for NMR unless otherwise stated.
• Purification was performed on a semipreparative HPLC ( High Performance Liquid Chromatography ) with a mass triggered fraction collector, Shimadzu QP 8000 single quadrupole mass spectrometer equipped with 19 x 100 mm C8 column.
• the mobile phase used was, if nothing else is stated, acetonitrile and buffer (0.1 M ammonium acetatetacetonitrile 95:5).
• acetonitrile and buffer 0.1 M ammonium acetatetacetonitrile 95:5
• a Rromasil CN E9344 250 x 20 mm i.d.
• Heptane:ethyl acetate:DEA 95:5:0.1 was used as mobile phase (1 ml/min).
• Fraction collection was guided using a UV-detector (330 nm).
• HPLC-parameters for purity analysis HPLC-system: Agilent 1100 Column: Zorbax Eclipse XDB-C8 150x4.6 mm Time of analysis: 15 min Flow: 1.5 ml/min Mobilphase: A: water, 5% MeOH
• the free base (usually 15-30 mg) was dissolved in butanone (for example 0.08 to 0.2 ml usually 0.8-2 ml) and if necessary together with methanol (usually less than 1 ml).
• the solution was optionally put in an ultrasonic bath (Decon FS200b).
• drying temperature should not be too high, for example greater than 45 0 C, otherwise decomposition of the salt may occur. Vacuum drying is preferred.
• the following salts were formed as described in the general procedure by using appropriate acid.
• Hemi-l,5-naphthalenedisulphonate melting point 270-274 0 C.
• Mesylate melting point 218-223 0 C.
• Hydrochloride melting point: 104-108 0 C.
• Mesylate melting point 141-145 0 C.
• Hemi-l,5-naphthalenedisulphonate melting point 271-274 0 C.
• Hemi-l,5-naphthalenedisulphonate melting point: 159-164 0 C.
• Hemi-l,5-naphthalenedisulphonate melting point 161-164 0 C.
• Hemi-l,5-naphthalenedisulphonate melting point 276-279 0 C.
• Example 8 Propane- 1 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester Hydrochloride: melting point: 185- 189 0 C.
• Hemi-l,5-naphthalenedisulphonate melting point 156-161 0 C.
• Hemi-l,5-naphthalenedisul ⁇ honate melting point 175-18O 0 C.
• Example 10 Pyridine-3 -sulfonic acid 4-[2-(2,4-dichlorophenyl)-4-methyl-5-(piperidin-l- ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester Mesylate: melting point 225-227 0 C. Hemi-l,5-naphthalenedisulphonate: melting point 168-172 0 C
• Step A 1 -(4-Benzyloxyphenyr) ⁇ ropan- 1 -one
• Step B 1 -(4-BenzyloxyphenylV2-bromopropan- 1 -one l-(4-Benzyloxyphenyl)propan-l-one (4.80 g, 20.0 mmol) was suspended in acetic acid (25 ml) and cooled to 0 0 C. Bromine (3.20 g, 20.0 mmol) was added dropwise and the reaction mixture stirred two hours at room temperature at which point the reaction mixture was a clear, yellow solution. After cooling, water (100 ml) was added and the product extracted with ether (2 x 100 ml).
• a solution of sodium ethoxide was generated from sodium metal (0.53 g, 23.0 mmol) in 30 ml abs. ethanol. To this solution was added ethyl acetoacetate (3.00 g, 23.0 mmol) at 0 0 C. After 30 min. this solution was added to a solution of l-(4-benzyloxyphenyl)-2-bromo- propan-1-one (6.17 g, 19.0 mmol) in ethanol : toluene (30 : 15 ml) and the reaction mixture stirred overnight.
• Step E 5-(4-Benzyloxyphenyl)-l-f2 1 4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylic acid piperidin-1-ylamide
• 5-(4-Benzyloxyphenyl)-l -(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (1.84 g, 4.07 mmol) was suspended in dichloromethane and a few drops of DMF added followed by the addition of oxalyl chloride (1.03 g, 8.14 mmol). The reaction mixture was refluxed for two hours.
• Triethylamine (0.73 ml, 5.2 mmol) was added followed by 1-aminopiperidine (0.28 ml, 2.9 mmol) and the mixture was stirred at room temperature for 3 hours.
• Water 100 ml was added and the mixture was extracted with CH 2 Cl 2 (3x50 ml), dried (Na 2 SO 4 ), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2, EtOAc) afforded 215 mg (15%) of the title o compound as a white solid.
• Step B l-(2,4-Dichlorophenyl)-5-(4-hvdroxyphenyl)-4-methyl-lH-pyrazole-3-carboxylic acid morpholin-4-ylamide
• Step B 3 3 ,3 -Trifluoropropane- 1 -sulfonic acid 4-r2-C2.4-dichlorophenyl)-4-methyl-5- (piperidin-l-ylcarbamoyl)-2H- ⁇ yrazol-3-yllphenyl ester
• Triethylamine 42 ⁇ l, 0.30 mmol was added followed by 3,3,3-trifluoropropane-l- sulfonyl chloride (59 mg, 0.30 mmol), purchased from Manchester Organics (but may also be prepared in an analogous manner to the method described in WO200010968 for 4,4,4- trifluorobutane-1-sulfonyl chloride), and the reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with CH 2 Cl 2 (3x20 ml), dried (Na 2 SO 4 ), filtered and concentrated.
• Step B 1 -f 4-Benzyloxy-3 ,5-difluorophenyl)-2-bromopropan- 1 -one l-(4-Benzyloxy-3,5-difluorophenyl) ⁇ ropane-l-one (7.43 g, 26.9 mmol) was suspended in acetic acid (35 ml).
• a solution of sodium ethoxide was generated from sodium metal (0.74 g, 32.0 mmol) in 40 ml absolute ethanol. To this solution was added ethyl acetoacetate (4.16 g, 32.0 mmol) at 0 0 C. After 30 min. this solution was added to a solution of l-(4-benzyloxy-3,5- difluorophenyl)-2-bromopropan-l-one (9.30 g, 26.2 mmol) in ethanol : toluene (40 : 20 ml) and the reaction mixture stirred overnight.
• Step E 4-Benzyloxy-3 ,5-difluorophenyD- 1 -(2,4-dichlorophenyl)-4-methyl- IH- pyrazole-3-carboxylic acid piperidin-1-ylamide
• 5-(4-Benzyloxy-3,5-difluorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylic acid (5.46 g, 11.2 mmol) was suspended in dichloromethane (60 ml) and a few drops of DMF added followed by the addition of oxalyl chloride (4.70 ml, 55.8 mmol). The reaction mixture was boiled under reflux for 1.5 hours.
• Step B 5-(4-Benzyloxyphenyl)-l-f2,4-dichlorophenyl)-lH-pyrazole-3-carboxylic acid ethyl ester
• 4-(4-Benzyloxyphenyl)-2,4-dioxobutyric acid ethyl ester (27.2 g, as Li salt from previous 5 step) was suspended in ethanol (350 ml) and 2,4-dichlorophenylhydrazine (17.8 g, 83.3 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure and the residue was dissolved in acetic acid and the resulting mixture was refluxed for 24 h.
• the reaction mixture was diluted with ethyl acetate (IL) and then washed with saturated NaHCO 3 (6x250 ml) and brine (100 ml). o The organic layer was dried (MgSO 4 ), filtered and concentrated under reduced pressure to give an oil. The oil was purified by flash chromatography (SiO 2 , 20% EtOAc in heptane). The product fraction was concentrated under reduced pressure and the remaining material was then further purified by recrystallisation (ethyl acetate/heptane) to give a white solid (19.6, 57% over 2 steps).
• Step C 1 -(2,4-DichlorophenylV5-(4-hydroxyphenyD- lH-pyrazole-3-carboxylic acid ethyl ester
• 5-(4-benzyloxyphenyl)-l-(2,4-dichlorophenyl)-lH-pyrazole-3-carboxylic acid ethyl ester 735 mg, 1.57 mmol
• (C ⁇ 3 ) 2 S (0.58 ml, 7.86 mmol)
• dichloromethane (30 ml) under nitrogen was added BF 3 -diethyl etherate (1.0 ml, 7.86 mmol) dropwise.
• the resulting mixture was stirred overnight at room temperature.
• Step D l-r2,4-Dichlorophenyl)-5-[4-(propane-l-sulfonyloxy)-phenyl1-lH-pyrazole-3- carboxylic acid ethyl ester l-(2,4-Dichlorophenyl)-5-(4-hydroxyphenyl)-lH-pyrazole-3-carboxylic acid ethyl ester (510 mg, 1.35 mmol) was suspended in dichloromethane (20 ml) under nitrogen and triethylamine (0.75 ml, 5.4 mmol) was added.
• Step A 4-Bromo- 1 -( " 2,4-dichlorophenyl)-5-[4-(propane- 1 -sulfonyloxy)phenyl "
• Step B Propane-l-sulfonic acid 4-[4-bromo-2-( ' 2,4-dichlorophenyl)-5-rpiperidin-l- ylcarbamoyl)-2H-pyrazol-3-yl]phenyl ester
• This compound was prepared in a similar manner to that described in 8 Step E. by reacting Q 4-bromo- 1 -(2,4-dichlorophenyl)-5-[4-(propane- 1 -sulfonyloxy)phenyl]-lH-pyrazole-3- carboxylic acid ethyl ester with 1-aminopiperidine hydrochloride to give 26mg of the title compound as a white solid. Yield: 25%
• Step B Methyl l-( " ir5-r4-(benzyloxy ' )phenyll-l-r2.4-dichlorophenylV4-methyl-lH- 5 pyrazol-3-yl1carbonyl ⁇ amino)cyclopentanecarboxylate
• Step D Methyl 1 - ⁇ IY 1 -(2,4-dichlorophenyl)-4-methyl-5- i4r(pro ⁇ ylsulfonyr)oxy1phenvU - lH-pyrazol-3-yl)carbonyl1amino
• the phases were separated and the orgainc phase washed with water and dried over MgSO 4 .
• the product was purified by preparatory ⁇ PLC (kromasil C8 column, ammonium acetate (aq, 0.1 M):acetonitrile, product came at about 88% acetonitrile) to give the product as an almost white powder (17 mg, 35%).
• Step A 4- ⁇ 1 -r2,4-dichlorophenyl * )-4-methyl-3-
• DCM dimethyl methyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-piperidin- l-yl-lH-pyrazole-3-carboxamide, prepared as Ex 1, Step F (200 mg, 0.45 mmol) and TEA (0.5 ml, 3.59 mmol) in DCM (2.5 ml) at -78 0 C, under ⁇ 2 (g).
• Step B tert-butyl [2-C4- 11 -(2,4-dichlorophenylV 4-methyl-3-[Ypiperidin- 1 - ylamino)carbonyl1-lH-pyrazol-5-yl)phenoxy)ethyl]ethylcarbamate l-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-N-piperidin-l-yl-lH- ⁇ yrazole-3- carboxamide, prepared as 1, Step F (151.6 mg, 0.34 mmol) and tert-butyl ethyl(2- hydroxyethyl)carbamate (408.6 mg, 1.73 mmol) were mixed in toluene (ImI) and reacted repeatedly in a single node microwave oven at 18O 0 C.
• Step A l-(2,4-Dichloro-3-fluorophenyl)-5-(4-methoxyphenyl)-4-methyl-lH-pyrazole-3- carboxylic acid
• Step B l-r2,4-Dichloro-3-fluoro-phenylV5-(4-methoxy-phenyl)-4-methyl-lH-pyrazole-3- carboxylic acid piperidin-1-ylamide l-(2,4-Dichloro-3-fluoro-phenyl)-5-(4-methoxy-phenyl)-4-methyl-lH- ⁇ yrazole-3- carboxylic acid (1.37 g, 3.43 mmol) was suspended in dichloromethane (20 ml) and a few drops of DMF added followed by the addition of oxalylchloride (0.87 g, 6.86 mmol). The reaction mixture was refiuxed for two hours.
• Step C l-(2,4-Dichloro-3-fluoro-phenylV5-(4-hvdroxy-phenyl ' )-4-methyl-lH-pyrazole-3- carboxylic acid piperidin-1-ylamide 1 -(2,4-Dichloro-3 -fluoro-phenyl)-5-(4-methoxy-phenyl)-4-methyl- lH-pyrazole-3 - carboxylic acid piperidin-1-ylamide (0.79 g, 1.66 mmol) was dissolved in 40 ml of dichloromethane at 0 0 C.
• Step D Propane- 1 -sulfonic acid 4-[2-(2.4-dichloro-3-fluoro-phenyl)-4-methyl-5- rpiperidin- 1 -ylcarbamoyl)-2H-pyrazol-3-yll-phenyl ester
• l-(2,4-dichloro-3-fluoro-phenyl)-5-(4-hydroxy-phenyl)-4-methyl-lH- pyrazole-3 -carboxylic acid piperidin-l-ylamide (0.36 g, 0.78 mmol) in dichloromethane (10 ml) was added triethylamine (0.22 ml, 1.56 mmol) and the reaction mixture cooled to 0 0 C.

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