WO2007064273A1 - Phenyl urea derivatives - Google Patents

Abstract

The present invention relates to compounds of formula (I) and processes for preparing such compounds, their use in the treatment of obesity, psychiatric and neurological disorders, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Description

PHENYL UREA DERIVATIVES

Field of inveNtion The present invention relates to certain CBi antagonists or inverse agonists, 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

It is known that certain CBi antagonists or inverse agonists (known as antagonists or inverse agonists) are useful in the treatment of obesity, psychiatric and neurological disorders (WO01/70700 and EP 656354).

However, there is a need for CBi antagonists or inverse agonists with other therapeutic effects, improved physicochemical properties and/or DMPK properties and/or pharmacodynamic properties.

Description of the invention

Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures.

The term "C_m-_n" or "C_m._a group" used alone or as a prefix, refers to any group having m to n carbon atoms.

The term hydrocarbon" used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.

The term "hydrocarbon radical" or "hydrocarbyl" used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon.

The term "alkyl" used alone or as a suffix or prefix, refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising 1 to about 12 carbon atoms. Illustrative examples of alkyls include, but are not limited to, Ci^alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2- methyl-1-butyl, 3-methyl-l -butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l- pentyl, 3-methyl-l-pentyl, 4-methyl-l-ρentyl, 2-methyl-2-pen1yl, 3-methyI-2-pentyl, A- methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3₃3-dimethyI-l-buryl, 2-ethyl-l -butyl, buiyl, isobutyl, t-butyl, penryl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as heptyl, and octyl. An alkyl can be unsubstituted or substituted with one or two suitable substituents.

The term "cycloalkyl," used alone or as suffix or prefix, refers to a saturated monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms. Examples of cycloalkyls include, but are not limited to, C3-7cycϊoaIkyI groups, such as cyclopropyl, cyclobutyl, cyclqpentyl, cyclohexyl, and cycloheptyl, and saturated cyclic andbicyclic terpenes. A cycloalkyl can be unsubstituted or substituted by one or two suitable substituents. Preferably, the cycloalkyl is a monocyclic ring or bicyclic ring.

The term "aryl" used alone or as suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e.g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms. As used herein, the term "heterocyclyl" or "heterocyclic" or "heterocycle" refers to a ting-containing monovalent and divalent structures having one or more heteroatoms, independently selected from N, O and S, as part of the ring structure and comprising from 3 to 20 atoms in the rings, more preferably 3- to 7- membered rings. "Member" of the ring refers to the number of ring atoms including both carbon atoms and heteratoms. For example, a 5-membered heterocyclyl refers to a ring strcture comprising from 5 ring-forming atoms wherein at least one of the ring-forming atoms is N, O or S. In addition, for example, C1.5 heterocyclyl refers to a heterocyclyl having 1 to 5 carbon atoms excluding the heteroatoms of the ring. Heterocyclic groups may be saturated, or partially saturated or unsaturated, containing one or more double bonds, and heterocyclic groups may contain more than one ring as in the case of polycyclic systems. The heterocyclic rings described herein may be substituted on carbon or on a heteroatom atom if the resulting compound is stable. If specifically noted, nitrogen in the heterocyclyl may optionally be quatemized. It is understood that when the total number of S and O atoms in the heterocyclyl exceeds 1, then these heteroatoms are not adjacent to one another. When a heterocycle contains more than one ring, the rings may be fused or unfused. Fused rings generally refer to at least two rings share two atoms therebetween. Heterocycle may have aromatic character or may not have aromatic character.

The term "heteroaromatic" used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N₃ O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring(s), wherein the ring-containing structure or molecule has an aromatic character (e.g., 4n + 2 delocalized electrons).

The term "heterocyclic group," "heterocyclic moiety," "heterocyclic," or "heterocyclo" used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.

The term "heterocyclyl" used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.

The term, "heteroaryl" used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character. Exemplary heteroaryl includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isomiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl.

The term "heterocylcoalkyl" used alone or as a suffix or prefix, refers to a monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and having no unsaturation. Examples of heterocycloalkyl groups include pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, andpyranyl. A heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents. Preferably, the heterocycloalkyl group is a monocyclic or bicycKc ring, more preferably, a monocyclic ring, wherein the ring comprises from 3 to 6 carbon atoms and form 1 to 3 heteroatoms, referred to herein as Cs-ήheterocycloalkyl. The term "alkoxy" used alone or as a suffix or prefix, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical. Exemplary alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, andpropargyloxy. Halogen includes fluorine, chlorine, bromine and iodine.

"Halogenated," used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens.

"RT" or "rt" means room temperature.

In one aspect, the invention provides a compound of formula I, and pharmaceutically acceptable salts thereof

I wherein R¹ and R² are independently selected from hydrogen, -OH, -CN, -NEb, halogen, Cj.

₆alkyl, halogenated C^alkyl, C _walkoxy, halogenated C^alkoxy, -NR⁵C(O)-R⁵, - NR⁵C(=0)-0-R^s, -SC=O)₂-NR⁵R⁵ and -O-S(=O)₂-R⁵; wherein each R⁵ is independently selected from hydrogen, Ci^alkyl, halogenated Q-galkyl, Cs-ecycloalltyl, and halogenated Cs-βcycloalkyl; R³ is selected from hydrogen and Ci-salkyl;

R⁴ is selected from Cs-gcycloalkyl, C₃.₅heterocycloa.lcyl, Ci-sheteroaryl and phenyl, wherein said C₃^cycloalkyl, Cs-sheterocycloalkyl, Ci_sheteroaryl and phenyl are optionally and independently substituted with one or more groups selected from -OH, -CN, -NH2, halogen, Chalky., hydroxy-Ci.₆alkyl, amino-Ci^alkyl, halogenated C^alkyl, Ci.galkoxy, and halogenated C^alkoxy;

Ar¹ is selected from Ci-sheteroaryl and phenyl, wherein said Ci-sheteroaryl and phenyl are optionally and independently substituted with one or more groups selected from -OH, -CN, -NH2, halogen, C_1-6alkyl, hydroxy-C_{1 -6}alkyl, amino-C_{1 -6}alkyl, halogenated C_{1- 6}alkyl, C_{1 -6}alkoxy, and halogenated C_1-6alkoxy; and m and n are independently selected from 1, 2, 3, and 4.

In one embodiment, the compounds of the present invention are represented by formula I, wherein

R¹ and R² are independently selected from hydrogen, -OH, -CN, -NH₂, halogen, C_{1 - 6}alkyl, halogenated C_1-6alkyl, C_{1 -6}alkoxy, halogenated C_1-6alkoxy, -NR⁵C(=O)-R⁵, -NR⁵C(=O)-O-R⁵, -S(=O)₂-NR⁵R⁵ and -0-S(=O)₂-R⁵; wherein each R⁵ is independently selected from hydrogen, C_{1 -6}alkyl, halogenatedC_{1 -6}alkyl, C_3-6cycloalkyl, and halogenated C_3-6cycloalkyl;

R³ is selected from hydrogen and C_{1 -3}alkyl;

R⁴ is selected from C₃.₆cycloa.kyl and C_{1 -5}heteroaryl, wherein said C_3-6cycloalkyl, and Ci-sheteroaryl are optionally and independently substituted with one or more groups selected from -OH, -CN, -ISIH₂, halogen, Chalky!, hydroxy-Ci-βalkyl, amino-C.-βalkyl, halogenated Ci^alkyl, Ci-βalkoxy, and halogenated Ci^alkoxy;

Ar¹ is a Ci-sheteroaryl, wherein said d-sheteroaryl is optionally substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, Ci-βalkyl, hydroxy-Cwalkyl, ammo-Ci-βalkyl, halogenated Ci-galkyl, Ci-βalkoxy, and halogenated Ci-galkoxy; and m and n are independently selected from 1 and 2. Ih another embodiment, the compound of the invention may be represented by formula I, wherein

R¹ and R² are hydrogen;

R³ is Ci.₃alkyl;

R⁴ is C3^cycloalkyl, wherein said C₃^cycloalkyl are optionally and independently substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, C^aUcyl, hydroxy-Ci-galkyl, amino-Ci.6alkyl, halogenated Ci-βalkyl, Cwalkoxy, and halogenated Ci- galkoxy; and

Ar¹ is a five-membered Ci^heteroaryl containing one or more nitrogens as heteroatoms, wherein said Ci jjheteroaryl is optionally substituted with one or more groups selected from -OH, -CN, -NH2, halogen, C^alkyl, hydroxy-Ci.6alkyl, amino-Ci-ealkyl, halogenated Ci_-6alkyl, C^alkoxy, and halogenated Ci.6alkoxy. In a further embodiment, R¹ and R² are independently selected from hydrogen, - OH, -CN, -NH₂, halogen, C_1-6alkyl, halogenated C_1-6alkyl, C_1-6alkoxy, halogenated C_{1- 6}alkoxy, -NR⁵C(=O)-R⁵, -NR⁵C(=O)-O-R⁵, -S(=O)₂-NR⁵R⁵ and -O-S(=O)₂-R⁵; wherein each R⁵ is independently selected from hydrogen, C_1-6alkyl, halogenated C_1-6alkyl, C_{3- 6}cycloalkyl, and halogenated C_3-6cycloalkyl.

Particularly, R¹ and R² are independently selected from hydrogen, -OH, -CN, -NH₂, halogen1 C_1-6alkyl, halogenated C_1-6alkyl, C_1-6alkoxy, and halogenated C_1-6alkoxy.

More particularly, R¹ and R² are independently selected from hydrogen, -OH, -CN, -NH₂, halogen, C_1-3alkyl, halogenated C_1-3alkyl, C_1-3alkoxy, and halogenated C_1-3alkoxy. Even more particularly, R¹ and R² are hydrogen.

In an even further embodiment, m and n are independently selected from 1, 2 and 3.

Particularly, m and n are independently selected from 1 and 2.

More particularly, m and n are 1.

In a yet even further embodiment, R³ is selected from hydrogen and Ci-galkyl. Particularly, R³ is C₁.3aH.yl. More particularly, R³ is methyl.

Li a further embodiment, R⁴ is selected from Ca-βcycloalkyi and Cj-sheteroaryl, wherein said Cs-ecycloalkyl, and Ci.sheteroaryl are optionally and independently substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, C^aHcyl, hydroxy-Ci-_fialkyl, amino-C^alkyl, halogenated Ci-galkyl, Ci-βalkoxy, and halogenated Ci. βalkoxy.

Particularly, R⁴ is a C₃^cycloalkyl, wherein said C₃^cycloall!yl is optionally substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, Ci-βalkyl, hydroxy-Ci-βalkyl, amino-Ci-ealkyl, halogenated C^alkyl, Ci^alkoxy, and halogenated Ci- βalkoxy. More particularly, R⁴ is cyclohexyl, wherein said cyclohexyl is optionally substituted with one or more groups selected from -OH, -CN₅ -NH₂, halogen, C_halky!, hydroxy-Ci.₃alkyl, amino-Ci.3alkyl, halogenated Ci.3alkyl, Ci.₃alkoxy, and halogenated Ci. ₃alkoxy.

Even more particularly, R⁴ is cyclohexyl. Ia another embodiment, Ar¹ is a Ci-sheteroaryl, wherein said Ci-sheteroaryl is optionally substituted with one or more groups selected from -OH, -CN, -NH2, halogen, Ci^alkyl, hydroxy-Ci-βalkyl, amino-C_Lsaliyl, halogenated Q^alkyl, Ci-βalkoxy, and halogenated Q^alkoxy.

Particularly, Ar¹ is a heteroaryl containing one or more nitrogens as ring heteroatoms and a radical of said heteroaryl being located on a nitrogen atom said one or more nitrogens, wherein said heteroaryl is optionally substituted with one or more groups selected from -OH, -CN, -NH₂₅ halogen, Ci-galkyl, hydroxy-Ci-galkyl, amino-Ci^alkyl, halogenated Ci.salkyl, Q-βalkoxy, and halogenated C walkoxy.

More particularly, Ar¹ is a five-membered Ci-₄heteroaryl containing one or more nitrogens as heteroatoms, wherein said Ci-4ieteroaryl is optionally substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, Q-ealkyl, hydroxy-Ci-ealkyl, amino-

Ci-βalkyl, halogenated Ci^alkyl, Ci-βalkoxy, and halogenated Ci-galkoxy.

Even more particularly, Ar¹ is selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl, wherein said pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl are optionally substituted with one or more groups selected from -OH, -CN, - NH2, halogen, C.-salkyl, hydroxy-Ci^alkyl, amino-Cijalkyl, halogenated Ci^alkyl, Ci.

₃alkoxy, and halogenated Ci^alkoxy.

"Pharmaceutically acceptable salt", where such salts are possible, includes both pharmaceutically acceptable acid and base 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 hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid; or, for example a salt of a compound of Formula I 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-hydroxye<hyl)amine.

Throughout the specification and the appended claims, a given chemical formula or name shall encompass 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 and solvates thereof such as for instance hydrates. 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 diastereoraers may be isolated by separation of isomer mixtures for instance by fractional crystallisation, HPLC or flash chromatography. Alternatively the stereoisomers may be made by chiral synthesis from cbiral 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. AU tautomers, where possible, are included within the scope of the invention. The present invention also encompasses compounds containing one or more isotopes for example ¹⁴C, * ¹C or ¹⁹F and their use as isotopically labelled compounds for pharmacological and metabolic studies.

The present invention also encompasses prodrugs of a compound of formula I that is compounds which are converted into a compound of formula I in vivo. Methods of preparation

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.

Compounds of formula I, wherein R¹, R², R³, R⁴, m and n are as defined above, may be prepared by reacting a compound of formula II

with Ar^l-H, wherein Ar¹ is a heteroaryl having at least one nitrogen ring atom, at a temperature in the range of -25 to 150⁰C, in the presence of an inert solvent, for example dimethylfoπnamide, and optionally in the presence of one or more bases, for example, NaH.

Compounds of formula II may be prepared by the following general synthetic scheme (Scheme I) and adaptations thereof or by analogous-methods known to those skilled in the art. It will be appreciated by those skilled in me art that during the reaction sequence certain functional groups will require protection followed by deprotection at an appropriate stage, see "Protective Groups in Organic Synthesis", 3rd Edition (1999) by Greene and Wuts.

Scheme i

The groups are defined as above.

Compounds with different stereochemistry may be prepared with starting materials having different stereochemistry. Pharmaceutical preparations

The compounds of the invention 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. Depending upon the disorder and patient to be treated and the route of administration, 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. According to a further aspect of the invention there is also provided 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. Pharmacological properties 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. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items), for the treatment of psychiatric disorders such as psychotic and/or mood disorders, schizophrenia, cognitive deficiency associated with schizophrenia, 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., Guillain-Barre^" syndrome). 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 drag-induced mood, anxiety and/or sleep disorder with onset during withdrawal, and alcohol and/or drug relapse.

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.

The compounds are also potentially useful for the 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. conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, 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, obesiry- 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. 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 gastroesophageal reflux, ulcers).

The compounds are also potentially useful as agents in 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. The compounds are also potentially useful as agents in treatment of (esophageal) achalasia.

Ia another aspect the present invention provides a compound of formula I as previously defined for use as a medicament

In a further aspect 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 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. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non-essential food items), for the treatment of psychiatric disorders such as psychotic and/or mood disorders, schizophrenia, cognitive deficiency associated with schizophrenia, cognitive deficiency associated with schizophrenia, 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-reiated disorders, neuroinflammatory disorders (e.g., Guillain-Barre syndrome).

In a further aspect the present invention provides the use of a compound of formula I 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.

Li a further aspect the present invention provides the use of a compound of formula I 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. In a further aspect the present invention provides the use of a compound of formula

I 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. conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, diabetes mellitus, dyslipidemia, fatty liver, gout, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hyperuricacidemia, impaired glucose tolerance, unpaired 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. 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 gastroesophageal reflux, ulcers).

In a further aspect the present invention provides the use of a compound of formula I 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 disorders (e.g. arthritis deformans, inflammation, inflammatory sequelae of viral encephalitis, osteoarthritis) and orthopedic disorders. hi a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I 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. binge eating, anorexia, bulimia and compulsive), cravings (for drugs, tobacco, alcohol, any appetizing macronutrients or non- essential food items), for the treatment of psychiatric disorders such as psychotic and/or mood disorders, schizophrenia, cognitive deficiency associated with schizophrenia, schizoaffective 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., Guiliam-Barre syndrome). In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I 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.

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I 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.

In a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I 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. conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, 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. 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 gastroesophageal reflux, ulcers). in a still further aspect the present invention provides a method comprising administering a pharmacologically effective amount of a compound of formula I 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..

The compounds of the present invention are particularly 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).

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.

In another aspect the present invention provides a compound of formula I as previously defined for use as a medicament.

In a further aspect 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, 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. In a still further aspect 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. 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 formula I to a patient in need thereof. The compounds of the present invention are particularly 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) treatments). 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. Combination Therapy 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 drags, mat 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. For example, 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. Inpatients with diabetes mellitus 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).

In another aspect of the invention, the compound of formula I, 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. In addition 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). Suitably the HMG-CoA reductase inhibitor is a statin.

In the present application, 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). 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.

According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, 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 pbytosterol 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 angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, an adrenergic blocker, an alpha adrenergic blocker, a beta adrenergic blocker, a mixed alpha/beta adrenergic blocker, an adrenergic stimulant, calcium channel blocker, an AT-I blocker, a saluretic, a diuretic or a vasodilator; a melanin concentrating hormone (MCH) modulator; an NPY receptor modulator; an orexin receptor modulator; a phosphoinositide-dependent protein kinase (PDK) modulator; or modulators of nuclear receptors for example LXR, FXR, RXR, GR, ERRα, β₅ PPARα, β, γ andRORalpha; a monoamine transmission-modulating agent, for example a selective serotonin reuptake inhibitor (SSRI), a noradrenaline reuptake inhibitor (NARI)_> a noradrenaline- serotonin reuptake inhibitor (SNRI), a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressive agent (TCA), a noradrenergic and specific serotonergic antidepressant (NaSSA); an antipsychotic agent for example olanzapine and clozapine; a serotonin receptor modulator; a leptin/Ieptin 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 warm-blooded animal, such as man in need of such therapeutic treatment. According to an additional further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, 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).

Therefore in an additional feature of the invention, there is provided 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 formula I, 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. Therefore in an additional feature of the invention, there is provided 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 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.

According to a further aspect of the invention mere is provided a pharmaceutical composition which comprises a compound of formula I, 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.

According to a further aspect of the present invention there is provided a kit comprising a compound of formula I, 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. According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, 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.

According to a further aspect of the present invention there is provided a kit comprising: a) a compound of formula I, 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.

According to another feature of the invention mere is provided the use of a compound of the formula I, 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.

According to another feature of the invention there is provided the use of a compound of the formula I, 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.

According to a further aspect of the present invention there is provided a combination treatment comprising the administration of an effective amount of a compound of the formula I, 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 maα in need of such therapeutic treatment. Furthermore, 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. It will be understood that there are medically accepted definitions of obesity and being overweight. 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. Pharmacological Activity Compounds of the present invention are active against the receptor product of the

CBl gene. 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 WOO 1/70700 or EP 656354. Alternatively the assay may be performed as follows. IOμg of membranes prepared firom cells stably transfected with the CBl gene were suspended in 200μl of 10OmM NaCl, 5mM MgCl₂, ImM EDTA, 5OmM HEPES (pH 7.4), ImM DTT, 0.1% BSA and lOOμM GDP. To this was added an EC80 concentration of agonist (CP55940), the required concentration of test compound and O.lμCi [^3SS]-GTPγS. The reaction was allowed to proceed at 30⁰C for 45 miα. Samples were then transferred on to GF/B filters using a cell harvester and washed with wash buffer (5OmM Tris (pH 7.4), 5mM MgCl₂, 5OmM NaCl). Filters were then covered with scintilant and counted for the amount of [³⁵S]-GTPγS retained by the filter.

Activity is measured in the absence of all ligands (minimum activity) or in the presence of an EC80 concentration of CP55940 (maximum activity). These activities are set as 0% and 100% activity respectively. At various concentrations of novel ligand, activity is calculated as a percentage of the maximum activity and plotted. The data are fitted using the equation y=A+((B-A)/l+((C/x) UD)) and Ihe IC50 value determined as the concentration required to give half maximal inhibition of GTPγS binding under the conditions used.

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. In this regard, 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 CB 1 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 increasing the free fraction of drug) or solubility compared to representative reference CB 1 antagonists/inverse agonist agents.

The utility of the compounds of the present invention in the treatment of obesity and related conditions is demonstrated by a decrease in body weight in cafeteria diet- induced obese 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 8-1 Oweeks. 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.

Examples

Abbreviations

DMF dimethylformamide

DMSO Dimethyl Sulfoxide

DEA Diethylamine

EtOAc ethyl acetate

THF tetrahydrofuran.

Example 1: iV-fcvclohexvlmethvft-/ vlmethvlϊcvclohexvllmethvtturea.

Methyl frg«s-4-{f(cvctohexylcarbonvRamino1niethvBcvcIohexanecarboxyIate. To a solution of frα»s-4-(ammomethyl)cyclohexanecarboxylic acid (9.4 g, 60.0 mmol) in. MeOH (100 mL) was slowly added thionyl chloride (7.2 g, 60 mmol) at r.t. The reaction mixture was stirred for 2 hours, then concentrated. The crude methyl trans-4- (aminomethyl)cyclohexanecarboxylate hydrochloride was dissolved in CH₂CI₂ (150 mL) and treated with triethylamine (18 g, 180 mmol) at 0 °C, followed by addition of cyclohexanecarbonyl chloride (9.7 g, 66 mmol). After being stirred overnight at r.t, the reaction mixture was condensed to give a residue, which was extracted repeatedly with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to provide the title product as a solid (15.6 g, 92 %). ¹H NMR (400 MHz, CDCl₃) δ 0.92 (m, 2H), 1.20 (m, 3H), 1.38 (m, 5H), 1.63 (m, 1H), 1.74 (m, 6H), 1.97 (m, 3H), 2.18 (m, IH), 3.06 (t, J=6.4 Hz, 2H), 3.61 (s, 3H), 5.42 (s, IH).

(fraH5-4-(r(Cvclohex\'lmethyl)amino1methyl}cvcIohexyπmethanol.

To a solution of methyl trans-4-

{[(cyclohexylcarbonyl)amino]methyl}cyclohexanecarboxylate (14.0 g, 50.0 mmol) in THF (200 mL) was added LiAlH₄ (1.9 g, 50 mmol) at r.t. The mixture was refluxed for 12 hours, followed by addition OfBH₃ (1 M in THF, 150 mL, 150 mmol) at r.t. After refluxing 12 hours, the mixture was adjusted to approx. pH 5 with hydrochloric acid. The reaction mixture was extracted, repeatedly with, ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to provide the crude product, which was purified by silica gel column chromatography to provide the title product (8.9 g, 80 %). ¹H NMR (400 MHz, CDCl₃) δ 0.92 (m, 6H), 1.18 (m, 3H), 1.15- 1.82 (m, 12H), 2.46 (m, 4H), 2.98 (m, IH), 3.38 (m, 2H).

e₂I-Bu

ftfrαHy^-fllteff-ButvKdimethvDsilvnoxylinethylicvcIohexyllmethvB

(cvclohexyImfcthvDamine.

To a solution of (fr<ms-4-{[(c ydohexylmemyl)ammo]memyl}cydohexyl)methanol (7.2 g, 30.0 mmol) and imidazole (3.1 g, 45 mmol) in CH₂Cl₂ (100 mL) was added tert- butyldimeihylsilyl chloride (4.5 g, 30 mmol) at r.t. After stirring 4 hours at r.t, the reaction mixture was condensed, extracted with ethyl acetate, washed with brine, dried over Na₂SO₄, filtered and concentrated to provide file title product (10.6 g, 100 %). ¹H NMR (400 MHz, CDCl₃) δ 0.01 (s, 6H), 0.85 (m, 13H), 1.15 (m, 2H), 1.40 (m, 4H), 1.72 (m, 11H), 2.40 (m, 4H), 3.35 (d, J=6.0 Hz, 2H).

THF;

JV-{ffrfl?ιs^ffffe^butvIfdimethvLMylloxy>--iethyl)cvcIohexyl]methvB-JV- (cvciohexylmethylVJV-methvI-iy-phenvIurea. To a solution of {[trans-4-({[tert- butyl(dimethyl)silyl]oxy}methyl)cyclohexyl]methyl} (cydohexylmethyl)amine (10.6 g, 30.0 rmnol) and triethylarnine (3.6 g, 36 mmol) in THF (100 mL) was added isocyanatόbenzene (4.3 g, 36 mmol) at r.t After 4 hours at r.t, the reaction mixture was treated with NaH (60%, 4.8 g, 120 mmol) atO ⁰C for 1 hour, followed by addition of methyl iodide (17.0 g, 120 mmol). After stirring for 12 hours at r.t, the mixture was quenched at 0 °C by slow addition of aqueous NH4CI solution, extracted with ethyl acetate, washed with brine, dried over NaaSO^ filtered and concentrated to provide the title product in quantitative yield. ¹H NMR (400 MHz, CDCl₃) δ 0.01 (s, 6H), 0.84 (m, 13H), 1.08 (m, 6H), 1.60 (m, 9H), 1.74 (m, 2H), 2.82 (m, 4H), 3.12 (s, 3H), 3.33 (d, J=6.0Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 7.05 (m, IH), 7.27 (m, 2H).

JV-fcyclohexYlmethvBrΛr-πfraiis^flivdroxymethvftcvcIohexyllmethyll-JV¹- methyl-iV-phenylurea.

To a solution of N-{[trans-4-({[tert- butyl(dimethyl)silyl]oxy}me&yl)(^d^ phenylurea (14.6 g, 30.0 mmol) in THF (50 mL) was added TBAF (1.0 M in THF, 50 mL, 50 mmol) at 0 °C. After stirring for 12 hours at r.t., the reaction mixture was condensed, quenched with aqueous NH₄CI solution, extracted with ethyl acetate, washed with brine, dried over Na₂SO_4, filtered and concentrated to provide a crude product, which was purified by silica gel column chromatography to provide the title product (8.5 g, 76 %). ¹H NMR (400 MHz, CDCl₃) 50.78 (m, 4H), 0.94 (m, 2H), 1.13 (m, 2H), 1.37 (m, 2H), 1.60 (m, 9H), 1.78 (m, 2H), 2.80 (d, J=6.8 Hz₅2H), 2.82 (d, J=7.2 Hz, 2H), 3.10 (s, 3H), 3.39 (m, 2H), 7.01 (d, J=8.0 Hz, 2H), 7.05 (m, IH), 7.26 (m, 2H).

JV-fffrgjw-^fltromomethyllcvclohexyllmethvK-iV-fcvclohexylmethylWV'- methyl-JV-phenvIurea.

To a solution of JV-(cyclohexylmethyl)-iV-{[ftτflns-4- (hydroxymethyl)cyclohejiyl]methyl}-iV^l-methyl-N^'-phenylurea (7.5 g, 20.0 mmol) and triethylamine (4.0 g, 40 mmol) in CH₂CI₂ (100 mL) was added methanesulfonyl chloride (4.5 g, 30 mmol) at 0 °C . After 2 hours at r.t, the reaction mixture was quenched at 0 °C by slowly addition of aqueous NaHCO₃ solution, extracted with ethyl ether, washed with brine, dried over Na₂SO₄, filtered and concentrated to provide a crude product, which was refluxed with LiBr (3.5 g, 40 mmol) in acetone (100 mL) for 12 hours. After concentrating in vacuo, the residue was quenched with aqueous NH₄CI solution, extracted with ethyl ether, washed with brine, dried over Na₂SO₄, filtered and concentrated to provide a crude product. Purification by silica gel column chromatography provided the title product (7.0 g, 80 %). ¹H NMR (400 MHz, CDCl₃) δ 0.75 (m, 4H), 0.90 (m, 2H), 1.13 (m, 4H), 1.50 (m, 5H), 1.61 (m, IH), 1.80 (m, 2H), 2.75 (d, J=6.4 Hz, 2H), 2.80 (d, J=7.2 Hz, 2H), 3.07 (s, 3H), 3.17 (d, J=6.0 Hz, 2H), 6.97 (d, J=8.0 Hz, 2H), 7.01 (m, IH), 7.22 (m, 2H).

JV-(cyclohexγlmethvI)-Λ^-methyl--V-ρhenvI-iV-U^-g/i-f-4-flg-ρyrazol-l- ylmethyltevclohexyUmethvUurea.

To a solution of 1H-pyrazole (204 mg, 3.0 mmol) in DMF (8 mL) was added NaH (60%, 160 mg, 4.0 mmol) at 0 °C. After 30 min, N-{[trans-4- (bromomethyl)cyclohexyl]methyl}-N-(cyclohexylmethy ) -N'methyl -N'- phenylurea (100 mg, 0.23 mmol) was added into the reaction mixture. The reaction was stirred for 24 hours atr.t, then quenched with aqueous NH₄Cl solution, extracted with ethyl acetate, washed with brine, dried over Na₂SO₄, filtered and concentrated to provide a crude product. Purification by silica gel column chromatography provided the title product (88 mg, 91 %). ¹H NMR (400 MHz, CDCl₃) 50.81 (m, 4H), 0.93 (m, 2H), 1.19 (m, 4H), 1.64 (m, 10H), 1.82 (m, IH), 2.83 (d, J=6.8 Hz, 2H), 2.87 (d, J=7.2 Hz, 2H), 3.15 (s, 3H), 3.94 (d, J=7.2 Hz, 2H), 6.22 (s, IH), 7.06 (m, 3H), 7.30 (m.3H), 7.49 (d, J=1.6 Hz, IH). MS (ESI) (M+H)⁺ 422.3.

Example 2: JV-fcvclohexylmethylViV-fffra/«f^(f4^hvdroxymethyl>-ljg-iinidazoI-l- yllmβthvBcvclohKtvDmeth'vH-JV-ii-iCt-i'yl-iV'-pheiiyliirea.

The title compound was prepared by the method described for Example 1 from N- {[trans-4-(bromomethyl)cyclohexyl]methyl}-N-(cyclohexylmethyl)-N'-methyl-N'- phenylurea. To a solution of lH-imidazol-4-ylmethanol (196 mg, 2.0 mmol) in DMF (5 s mL) was added NaH (60 %, 160 mg, 4.0 mmol) at 0 ⁰C. After 30 min, N~{[irans-4- (bromomethyl)cyclohexyl]methyl}τN-(cyclo^ (100 mg, 0.23 mmol) was added to the reaction mixture. After stirring 24 hours at r.t, and the reaction was quenched with aqueous NH₄CI solution, extracted with ethyl acetate, washed with brine, dried over Na₂SO₄ filtered and concentrated to provide the crude product 0 Purification by silica gel column chromatography provided the title product ¹H NMR (400 MHz, CDCl₃) δ 0.80 (m, 4H), 0.93 (m, 2H), 1.16 (m, 4H), 1.56 (m, 4H), 1.66 (m, 7H), 2.82 (d, J=6.8 Hz, 2H), 2.88 (d, J=7.6 Hz, 2H), 3.15 (s, 3H), 3.72 (d, J=6.4 Hz, 2H), 4.60 (s, 2H), 6.82 (s, IH), 7.05 (d, J=7.2 Hz, 2H), 7.11 (m, IH), 7.27 (m, 2H), 7.38 (s, IH). MS (ESI) (M+H)⁺ 452.3. 5

Claims

We Claim:

1. A compound of formula I or pharmaceutically acceptable salts thereof

I wherein

R¹ and R² are independently selected from hydrogen, -OH, -CN, -NH₂, halogen, C1- ₆alkyl, halogenated C_1-6alkyl, C_1-6alkoxy, halogenated C_1-6alkoxy, -NR⁵C(=O)-R⁵, - NR⁵C(=O)-O-R⁵, -S(=O)₂-NR⁵R⁵ and -O-S(=O)₂-R⁵; wherein each R⁵ is independently selected from hydrogen, C_1-6alkyl, halogenated C_1-6alkyl, C₃.6cycloalkyl, and halogenated C3-₆cycloalkyl;

R³ is selected from hydrogen and Ci^alkyl;

R⁴ is selected from C_3-6cycloalkyl, C_3-5heterocycloalkyl, C_1-5heteroaryl and phenyl, wherein said C_3-6cycloalkyl, C_3-5heterocycloalkyl, C_1-5heteroaryl and phenyl are optionally and independently substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, Ci-galkyl, hydroxy-C^alkyl, amino-Ci-ealkyl, halogenated Cj^alkyl, Ci-βalkoxy, and halogenated Ci_-6alkoxy;

Ar¹ is selected from C^heteroaryl and phenyl, wherein said Cj-sheteroaryl and phenyl are optionally and independently substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, Ci^alkyl, hydroxy-Ci-βalkyl, amino-Ci-βalkyl, halogenated Ci- βalkyl, Ci-galkoxy, and halogenated Ci_-6alkoxy; and m and n are independently selected from 1, 2, 3, and 4.

2. A compound as claimed in claim 1, wherein

R¹ and R² are independently selected from hydrogen, -OH, -CN, -NH₂, halogen, Q- βalkyl, halogenated Ci-βalkyl, Ci^alkoxy, halogenated Ci-galkoxy, -NR⁵C(=O)-R⁵, -NR⁵C(=O)-O-R⁵, -S(=O)₂-NR⁵R⁵ and -O-S(=O)₂-R⁵; wherein each R⁵ is independently selected from hydrogen, Ci^alkyl, halogenated Ci-βalkyl, Ca-βcycloalkyl, and halogenated C₃.₆cycloalkyl;

R³ is selected from hydrogen and Q^alkyl;

R⁴ is selected from C_3-6cycloalkyl and C^sheteroaryl, wherein said C₃.₆cycloalkyl, and Cμsheteroaryl are optionally and independently substituted with one or more groups selected from -OH, -CN, -NHfe, halogen, Ci^alkyl, hydroxy-Ci^alkyl, amino-Ci-βalkyl, halogenated Ci-βalkyl, Ci^alkoxy, and halogenated Q-βalkoxy;

Ar¹ is a Q-sheteroaryl, wherein said Ci-sheteroaryl is optionally substituted with one or more groups selected from -OH, -CN, -NH2, halogen, Ci-galkyl, hydroxy-Ci.₆alkyl, amino-Ci-6alkyl, halogenated Ci-βalkyl, Ci^alkoxy, and halogenated Ci-βalkoxy; and m and n are independently selected from 1 and 2.

3. A compound as claimed in claim 1 , wherein

R¹ and R² are hydrogen; R³ is Ci_-3alkyl;

R⁴ is Cs-δcycloalkyl, wherein said C_3-(;cycloalkyl are optionally and independently substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, C^aUcyl, hydroxy-Ci-βalkyl, amino-Ci.₆alkyl, halogenated Ci-βalkyl, Ci.βalkoxy, and halogenated Ci- galkoxy; and Ar¹ is a five-membered C_1-4heteroaryl containing one or more nitrogens as heteroatoms, wherein said C_1-4heteroaryl is optionally substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, C_1-6alkyl, hydroxy-C_1-6alkyl, amino-C_1-6alkyl, halogenated C_1-6alkyl, C_1-6alkoxy, and halogenated C_1-6alkoxy.

4. A compound as claimed in claim 1, wherein

Ar¹ is a heteroaryl containing one or more nitrogens as ring heteroatoms and a radical of said heteroaryl being located on a nitrogen atom said one or more nitrogens, wherein said heteroaryl is optionally substituted with one or more groups selected from - OH, -CN, -NH₂, halogen, C_1-6alkyl, hydroxy-C_1-6alkyl, amino-C_1-6alkyl, halogenated C_1- 6alkyl, C_1-6alkoxy, and halogenated C_1-6alkoxy.

5. A compound as claimed in claim 1 , wherein Ar¹ is selected from pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl, wherein said pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl are optionally substituted with one or more groups selected from -OH, -CN₅ -NH₂, halogen, Ci^alkyl, hydroxy-Ci^alkyl, amino-Ci.₃alkyl, halogenated Ci-3alkyl, Ci-3alkoxy, and halogenated Ci^alkoxy.

6. A compound selected from one or more of the following: N-(cyclohexyhnethyl)-iV-methyl-N-phenyl-N- { \trans-A-{ lH-pyrazol- 1 - ylmethyl)cyclohexyl]methyl}urea; N-(cyclohexybnethyl)-N-[(frα«J-4-{[4-(hydroxymethyl)-lH-imidazol-l - yl]methyl} cyclohexyl)methyl] -N'-methyl-N'-phenylurea; and pharmaceutically acceptable salts thereof.

7. A compound as claimed in any of claims 1 to 6 for use as a medicament.

8. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable adjuvant, diluent or carrier.

9. Use of a compound according to any one of claims 1 to 6 in the preparation of a medicament for the treatment or prophylaxis of obesity, psychiatric disorders such as psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, and related conditions, and neurological disorders such as dementia, neurological disorders, Parkinson's Disease, Ηuntington's Chorea and Alzheimer's Disease, immune, cardiovascular, reproductive and endocrine disorders, septic shock, diseases related to the respiratory and gastrointestinal systems, and extended abuse, addiction and/or relapse indications.

10. A method of treating obesity, psychiatric disorders, psychotic disorders, schizophrenia and bipolar disorders, anxiety, anxio-depressive disorders, depression, cognitive disorders, memory disorders, obsessive-compulsive disorders, anorexia, bulimia, attention disorders, epilepsy, and related conditions, neurological disorders, neurological disorders, 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 system, and extended abuse, addiction and/or relapse indications, comprising administering a pharmacologically effective amount of a compound according to any one of claims 1 to 6 to a patient in need thereof.

11. A method of treating schizophrenia comprising administering a pharmacologically effective amount of a compound as claimed in any one of claims 1-6 to a patient in need thereof.

12. A method of treating cognitive deficiency associated with schizophrenia comprising administering a pharmacologically effective amount of a compound as claimed in any one of claims 1-6 to a patient in need thereof.

13. A compound as defined in any one of claims 1-6 for use in the treatment of obesity.

14. A compound as claimed in any one of claims 1-6 for use in the treatment of schizophrenia.

15. A compound as claimed in any one of claims 1 -6 for use in the treatment of cognitive deficiency associated with schizophrenia.

16. A process for the preparation of a compound of formula I, prepared by reacting a compound of formula II

II

with Ai^-H, at a temperature in the range of -25 to 150⁰C, in the presence of an inert solvent, wherein

R¹ and R² are independently selected from hydrogen, -OH, -CN, -NEb, halogen, C₁- ₆alkyl, halogenated Ci_-6alkyl, Ci_-6alkoxy, halogenated Ci_₆alkoxy, -NR⁵C(=O)-R⁵, - NR⁵C(=O)-O-R⁵, -S(=O)₂-NR⁵R⁵ and -O-S(=O)₂-R⁵; wherein each R⁵ is independently selected from hydrogen, C^alkyl, halogenated Ci-_δalkyl, Ca-βcycloalkyl, and halogenated Cs-gcycloalkyl;

R³ is selected from hydrogen and Ci^alkyl;

R⁴ is selected from C₃.6cycloalkyl, Ca-sheterocycloalkyl, Q.sheteroaryl and phenyl, wherein said C_3-6cycloalkyl, C_3-5heterocycloalkyl, C_1-5heteroaryl and phenyl are optionally and independently substituted with one or more groups selected from -OH, -CN, -NH₂, halogen, C_{1 -6}alkyl, halogenated C_{1 -6}alkyl, C_1-6alkoxy, hydroxy-C_1-6 alkyl, amino-C_1-6alkyl, and halogenated C_1-6alkoxy;

Ar¹ is a heteroaryl containing one or more nitrogens as ring heteroatoms, wherein said heteroaryl is optionally substituted with one or more groups selected from -OH, -CN, - NH₂, halogen, C_1-6alkyl, hydroxy-C_1-6alkyl, amino-C_1-6alkyl, halogenated C_1-6alkyl, C₁. ₆alkoxy, and halogenated C_1-6alkoxy, and m and n are independently selected from 1, 2, 3, and 4.