MXPA06006288A - Azabicyclic heterocycles as cannabinoid receptor modulators - Google Patents

Abstract

The present application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents and methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents. The compounds have the general Formula I. including all prodrugs, pharmaceutically acceptable salts and stereoisomers, R1, R2, R3, R4, R5, m and n are described herein.

Description

AZABICICLIC HETEROCICLES AS CANABINOID RECEIVER MODULATORS Field of the Invention Delta-9-tetrahydrocannabinol or Delta-9 THC, the main active component of cannabis sativa (marijuana), is a member of a large family of lipophilic compounds (ie, cannabinoids) that mediate the physiological and psychotropic drugs that include the regulation of appetite, immunosuppression, analgesia, inflammation, emesis, antinociception, sedation, and infraocular pressure. Other members of the cannabinoid family include the endogenous ligands (arachidonic acid derivatives), anandamide, 2-arachidonyl glycerol and 2-arachidonyl glycerol ether. Cannabinoids work through the selective binding to, and the activation of, the cannabinoid receptors coupled to the G protein. Two types of cannabinoid receptors have been cloned and include CB-1 (LA Matsduda, et al, Nature, 346, 561- 564 (1990)), and CB-2 (S. Munro et al., Nature, 365, 61-65 1993)). The CB1 receptor is highly expressed in the central and peripheral nervous systems (M. Glass, et al., Neuroscience, 77, 299-318 (1997)), whereas the CB-2 receptor is highly expressed in immune tissue, particularly in the spleen and tonsils. The CB2 receptor is also expressed in other cells of immune systems, such REF .: 173338 as lymphoid cells (S. Galiegue, et al., Eur J Biochem, 232, 54-61 (1995)). The agonist activation of cannabinoid receptors results in the inhibition of cAMP accumulation, stimulation of MAP kinase activity, and closed calcium channels. BACKGROUND OF THE INVENTION There is substantial evidence that cannabinoids regulate appetite behavior. Stimulation of CB-1 activity by anandamide or Delta-9 THC results in increased dietary intake and weight gain in multiple species including humans (Williams and Kirkham, Psychopharm., 143 315-317 (1999)). The genetic age of CB-1 results in mice that are hypophagic and skinny relative to wild-type baits (DiMarzo, et al., Nature, 410, 822-825 (2001)). Studies published with the antagonists in the small molecule CB-1 have shown a reduction in dietary intake and body weight in rats (Trillou, et al., Am. J.

Physi ol. Regul. In tegr. Comp. Physiol. , R345-R353, (2003)). Chronic administration of the antagonist AM-251 of CB-1 for two weeks results in a substantial reduction in body weight and a reduction in adipose tissue mass (Hildebrandt, et al., Eur. J. Pharm, 462, 125-132 (2003)). There are multiple studies evaluating the anorexic effect of the antagonist Sanofi CB-1, SR-14176 (Rowland et al., Pyschophar., 159, 111-116 (2001); Colombo et al., Life Sci., 63, 113-117. (1998)). There are at least two CB-1 antagonists in clinical trials for appetite regulation, SR-141716 from Sanofi and SLV-319 from Solvay. The published phase IIb data reveal that body weight is reduced dependently on the dose of SR-141716 in human subjects during a 16-week trial period. CB-1 antagonists have also been shown to promote cessation of smoking behavior. Phase II clinical data on cessation of smoking were presented in September 2002 at the information meeting of Sanofi-Synthelabo. These data show that 30.2% of patients treated with the higher dose of SR-141716 show an abstinence from cigarette smoking compared to 14.8% for placebo. Detailed Description of the Invention The present application describes compounds according to formula I, pharmaceutical compositions comprising at least one compound according to formula I and optionally one or more additional therapeutic agents and methods of treatment using the compounds according to the invention. Formula I, either alone or in combination with one or more additional therapeutic agents. The compounds have the general formula I including all prodrugs, pharmaceutically acceptable salts and steroisomers, R1, R2, R3, R4, R5, and m are described herein: Definitions The following definitions apply to the terms as used throughout this specification, unless otherwise limited in terms of specific. As used herein, the term "alkyl" means branched or unbranched hydrocarbon chains containing 1 to 20 carbons, preferably 1 to 12 carbons, and more preferably 1 to 8 carbons, in the normal chain, such as, methyl , ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl and the like. In addition, alkyl groups, as defined herein, may optionally be substituted on any of the available carbon atoms with one or more functional groups commonly linked to such chains, such as, but not limited to hydroxy, halo, haloalkyl, mercapto , or thio, cyanoalkylthio cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, carbalkoyl, carboxamido, carbonyl, alkenyl, alkynyl, nitro, amino, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, amido, -OC (0) NR8R9, -OC (0) R8, -OP03H, -OS03H, and the like to form alkyl groups such as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl and the like. Unless indicated otherwise, the term "alkenyl" as used herein by itself or as part of another group refers to straight or branched chains of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 up to 8 carbons with one or more double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4, 8, 12-tetradecatrienyl, and the like Further, the alkenyl groups, as defined in present, can optionally be substituted at any available carbon atom with one or more functional groups commonly attached to such chains, such as, but not limited to halo, haloalkyl, alkyl, alkoxy, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxyl , heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, n itro, cyano thiol, alkylthio and / or any of the alkyl substituents set forth herein. Unless indicated otherwise, the term "alkynyl" as used herein by itself or as part of another group, refers to straight or branched chains of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons with one or more triple bonds in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptinyl, 4-heptinyl, 3-octinyl, 3-noninyl, 4-decinyl, 3-undecinyl, 4-dodecinyl and the like. In addition, the alkynyl groups as defined herein may optionally be substituted at any available carbon atom with one or more functional groups commonly attached to such chains, such as, but not limited to halo, haloalkyl, alkyl, alkoxy, alkenyl , aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and / or any of the alkyl substituents set forth herein. Unless otherwise indicated, the term "cycloalkyl" as used herein alone or as part of a group including cyclic hydrocarbon groups (containing one or more double bonds) saturated or partially unsaturated containing 1 to 3 rings, attached or fused, including monocyclylalkyl, bicyclylalkyl, and tricycloalkyl, containing a total of 3 to 20 carbons that form the rings, preferably 3 to 10 carbons forming the ring and which can be fused to 1 or 2 aromatic rings as described by aryl, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl, cyclohexenyl, In addition, any cycloalkyl can optionally be substituted through any of the available carbon atoms with one or more groups selected from hydrogen, halo, haloalkyl, alkyl, alkoxy, haloalkyloxy, hydroxyl, alkenyl, alkynyl, aryl, aryloxy, heteroaryl, heteroaryloxy , arylalkyl, heteroarylalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, amino, nitro, cyano, thiol and / or alkylthio and / or any of the alkyl substituents. The term "cycloalkylalkyl" as used herein alone or as part of another group, refers to alkyl groups as defined above having a cycloalkyl substituent wherein "cycloalkyl" and / or "alkyl" groups may be optionally substituted as defined above.

Unless otherwise indicated, the term "aryl" as used herein alone or as part of another group refers to monocyclic and aromatic bicyclic groups containing 6 to 10 carbons in the ring portion (such as phenyl) or naphthyl- including 1-naphthyl and 2-naphthyl) and may optionally include 1 to 3 additional rings fused to the carbocyclic ring or a heterocyclic ring, for example, X > . -CO: -c? EC-. 00-, CO- CO. XX) - x - In addition, "aryl" as defined herein, may optionally be substituted with one or more functional groups, such as halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl , arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, alkoxycarbonyl, arylcarbonyl, arylalkenyl, aminocarbonylaryl, arylthio, arylsulfinyl, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroaryl-heteroaryl, heteroaryloxy, hydroxyl, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl, or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, ammonicarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulf inylalkyl, arylsulfonylamino, or arylsulfoaminocarbonyl and / or any of the alkyl substituents set forth herein. Unless indicated otherwise, the term "heteroaryl" as used herein alone or as part of another group, refers to a 5- or 6-membered aromatic ring that includes 1, "2, 3, or 4 heteroatoms. such as nitrogen, oxygen, or sulfur Such rings may be fused to an aryl, cycloalkyl, heteroaryl, or heterocyclyl and include possible N-oxides as described in Katritzky, AR and Rees, CW, eds Comprehensive Heterocyclic Chemistry: I e Structure, Reactions Synthesis and Uses of Heterocyclic Carzpounds 1984, Pergaon Press, New York, NY, and Katritzky, AR, Ress CW, Scriven, EF, eds Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 1996, Elsevier Science, Inc. , Tárrytown, NY, and references herein.In addition "heteroaryl" as defined herein, may optionally be substituted with one or more substituents such as the substituents included above in the definition of "substituted alkyl" and "aryl". I replaced it. " Examples of the heteroaryl groups include the following: O- Ó- .Ó -. & . OR . OR-. and the like The term "heteroarylalkyl" as used herein alone or as part of another group, refers to alkyl groups as defined above having a heteroaryl substituent, wherein the heteroaryl and / or alkyl groups may optionally be replaced as defined above. The term "heterocycle", "heterocycle", "heterocyclyl" or "heterocyclic ring" as used herein represents a substituted or unsubstituted stable 4 to 7 membered monocyclic ring system which may be saturated or unsaturated, and consists of carbon atoms, with 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring can be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl and other heterocycles described in Katritzky, AR and Rees, CW, eds Comprehensive Heterocyclic Chemistry: The Structure, Reactions Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, MY; and Katritzky, A.R., Ress C., Scriven, E.F., Eds Comprehensive Heterocyclic Chemistry II: A Review of the Terature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, NY; and references in the present. The term "heterocycloalkyl" as used herein alone or as part of another group, refers to alkyl groups as defined above having heterocyclyl substituents, wherein the heterocyclyl and / or alkyl groups may optionally be substituted as defined above.

The term "arylalkyl" "arylkenyl" and "arylalkynyl" as used alone or as part of another group, refers to alkyl, alkenyl and alkynyl groups as described above has an aryl substituent. Representative examples of arylalkyl include, but are not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, phenethyl, benzhydryl and naphthylmethyl and the like. The terms "alkoxy", "aryloxy", "heteroaryloxy", "arylalkyloxy", or "heteroarylalkyloxy" as used herein alone or as part of another group include an alkyl or aryl group as defined above linked through an oxygen . The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine and iodine, with bromine, chlorine or fluorine being preferred. The term, "cyano," as used herein, refers to a -CN group. The term "ethylene", as used herein, refers to a group -CH2-. The term "nitro", as used herein, refers to a group -N0. The compounds of the formula I can be present as salts, which are also within the scope of this invention. Preferred are pharmaceutically acceptable salts (ie, non-toxic, physiologically acceptable). If the compounds of the formula I have, for example, at least one basic center, they can form acids by addition of salts, These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with organic carboxylic acids, such as alkanocarboxylic acids of 1 to 4 carbon atoms, for example, acetic acid, which are substituted or unsubstituted, for example, by halogen as chloroacetic acid, such as acids saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, italic or terephthalic acid, as well as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, as well as amino acids, (for example aspartic or glutamic or lysine or arginine), or benzoic acid, or with organic sulfonic acids, as well as alkyl acids (C_-C) or arylsulfonic which are unsubstituted or substituted, for example by halogen, for example methyl or p-toluenesulphonic acid. The corresponding acid addition salts can also be formed having, if desired, a basic center present additionally. The compounds of the formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts, or salts with ammonia or an organic amine, as well as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example, ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine. The corresponding internal salts can also be formed. Salts which are unsuitable for pharmaceutical uses but which can be used, for example, for isolation or purification of free compounds of the formula I or their pharmaceutically acceptable salts, are also included. Preferred salts of the compounds of the formula I containing a basic group include monohydrochloride, acid sulfate, methanesulfonate, phosphate, nitrate or acetate. Preferred salts of the compounds of the formula I containing an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines. The term "modulator" refers to a chemical compound capable of either improving (e.g., "agonist" activity) or partially improving (e.g., "partial agonist" activity) or inhibiting (e.g., "antagonistic" activity or "inverse agonist" activity) a functional property of biological activity or process (e.g., enzyme activity or receptor binding); such improvement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction path, and / or may only be manifest in particular cell types. The term "bioactive metabolite" as used herein refers to any functional group contained in a compound of formula I with an open valency for further substitution wherein such substitution may, in biotransformation, generate a compound of formula I. such functional groups of bioactive metabolites include, but are not limited to, -OH, -NH or functional groups wherein the hydrogen can be replaced with a functional group such as -P03H2 for example, which, in biotransformation generates a functional group of -OH or -NH of a compound of the formula I. The term "prodrug esters" as used herein includes esters and carbonates formed by the reaction of one or more hydroxyls of the compounds of the formula I with alkyl, alkoxy, or aryl substituted for acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates and the like . Prodrug esters may also include, but are not limited to, groups such as phosphate esters, phosphonate esters, phosphonamidate esters, sulfate esters, sulfonate esters and sulfonamidate esters wherein the ester may be further substituted with groups which confer a pharmaceutical advantage such as, but not limited to, favorable aqueous solubility or in vivo exposure to the bioactive component of formula I. The term "prodrug" as used herein includes functionality of bioactive amine or hydroxyl-containing compounds of the formula I to form substituted alkyl, acyl, sulfonyl, phosphoryl, or carbohydrate derivatives.

Such derivatives are formed by reacting compounds of formula I with alkylating, acylating, sulfonating, or phosphorylating reagents employing procedures known to those skilled in the art. The alkylation of amines of the formula I can result in, but is not limited to, derivatives that include spacer units for other prodrug portions such as alkoxymethyl, acyloxymethyl, phosphoryloxymethyl, or substituted sulfonyloxymethyl groups. The alkylation of amines of formula I can result in the generation of quaternary amine salts that act in vivo to provide the bioactive agent (ie, the compounds of formula I). The term "prodrug" as used herein includes the precursor for the compound of formula I which, during bioactivation, can form a bioactive metabolite of formula I. Examples of such prodrugs can be found in Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) Chapter 1"Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities" pp. 1-92 including subsection 6"Ring-Opened derivatives as prodrugs for cyclic drugs" pp. 51-55. Preferred prodrugs consist of a compound of formula I wherein a pendant hydroxyl is phosphorylated to generate a phosphate derivative. Such a prodrug may also include a spacer group between the compound of the formula I and the phosphate group, such as a methyleneoxy group. The methods for generating such prodrug of a compound of formula I are known to those skilled in the art, and are listed in the following references. Preferred prodrugs also consist of a compound of formula I wherein a pendant amine, such as a pyridine group, is alkylated with a group, such as methyl or acyloxymethylene, to form a quaternary ammonium ion salt. Methods for generating such prodrug of a compound of formula I are known to those skilled in the art and are listed in the following references. Any compound that can be converted in vivo to provide the bioactive agent (ie, the compound of formula I) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. A comprehensive description of prodrugs and prodrug derivatives are described in: The Practice of Medicinal Chemistry, Camilla G. Wermu.th et al., Ch. 31, (Academic Press, 1996); Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pp. 113-191 (Harwood Academic Publishers, 1991). Hydrolysis in Drug and Prodrug Metabolism, B. Testa and J. M. Mayer, (Verlag Hevetica Chimica Acta AG, Zurich, Switzerland; Wiley-VCH, Weinheim, Federal Republic of Ger any, 2003) Ettmayer, P .; Amidon, G. L.; Clement, B. "Lessons Learned from Marketed and Investigational Prodrugs" J. Med. Chem. 2004, 47 (10), 2393-2404. Davidsen, S. K. et al., "N- (Acyloxyalkyl) pyridinium Salts as Soluble Prodrugs of a Potent Platelet Activating Antagonist Factor" J. Med. Chem. 1994, 37 (26), 4423-4429. The references are incorporated herein by reference. An administration of a therapeutic agent of the invention includes administration of a therapeutically effective amount of the agent of the invention. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent to treat or procure a treatable condition by administration of a composition of the invention. That amount is sufficient to exhibit a detectable or preventive or relieving therapeutic effect. The effect may include, for example, treatment or prevention of the conditions listed here. The precise amount effective for a subject will depend on the size of the subject and their health, the nature and extent of the condition to be treated, recommendations of the treating physician, and therapeutics or combination of therapeutics selected for administration. All stereoisomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers on any of the carbon atoms that include any of one of the substituents R. Consequently, the compounds of the formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for preparation can use racemates, enantiomers or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic techniques, chiral HPLC or fractional crystallization. The compounds of formula I of the invention can be prepared as shown in the following schemes and description thereof, in addition to relevant published literature procedures that can be used by any person skilled in the art. The reagents and exemplary procedures for these reactions appear hereinafter and in the working examples.

Abbreviations The following abbreviations are used in the Schemes, Examples and elsewhere here: Ac = Acetyl AcOH = acetic acid Boc = Tert-butoxycarbonyl DCM = dichloromethane DIPEA = N, N-diisopropylethylamine DMF = N, N-dimethylformamide EtOAc = acetate ethyl Et3N = triethylamine Et20 = diethyl ether HOBt = 1-hydroxybenzotriazole hydrate CLAR = high performance liquid chromatography. LAH = lithium aluminum hydride LC / EM = high performance liquid chromatography and mass spectrometry MeOH = methanol EM or mass spec = mass spectrometry NMR = nuclear magnetic resonance GP = protection group TA = room temperature TFA = trifluoroacetic acid THF = tetrahydrofuran Min = minute (s) h = hour (s) L = liter mL = milliliter μL = microliter g = gram (s) mg = milligram (s) mol = moles mmol = millimole (s) M = nanomolar Compounds of The present invention can be prepared by methods illustrated in the accompanying drawings.

Preparation Methods. The compounds of the present invention can be prepared by methods such as those found in the exemplary processes described in the following schemes and working examples, as well as relevant published literature processes that are used by one skilled in the art. The solvents, temperatures, pressures, and other reaction conditions can easily be selected by one skilled in the art. The materials are commercially available or can be easily prepared by one of ordinary skill in the art using known methods. The reagents and exemplary procedures for these reactions appear hereinafter and in the working examples. The protection and deprotection in the processes below can be carried out by methods generally known in the art (see, for example, T. W. Greene &P. G. M. Wuts, "Protecting Groups in Organic Synthesis", 3rd Edition, Wiley, 1999). General methods of organic synthesis and functional group transformations are found in Trost, B. M. and Fleming, I., eds. Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry. 1991, Pergamon Press, New York, NY.; March, J., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed. 1992, New York, NY: John Wiley & Sons; Katritzky, A.R., Meth-Cohn, 0. and Rees, C.W., eds. Comprehensive Organic Functional group Trans format ions l? T ed. 1995, Elsevier science Inc., Tarrytown, NY.; Larock, R.C., Comprehensive Organic Trans format ions. 1989, New York, NY: VCH Publishers, Inc .; and references in the present. The compounds of the formula I-XVII can be interconverted to other compounds of the formula I-XVII by those skilled in the art or described in the references and examples herein. For all the reaction schemes and compounds described below, R1, R2, R3, R4, R6, R7, R8, R9 are as described for the compound of the formula I.

Reaction scheme I III 11A The compounds of formula I of the present invention can be synthesized from compounds of formula II or III wherein L is hydrogen, halide, or a metalloid such as tin, boron and the like by reaction with a metalloid compound such as n-butyllithium. , isopropylmagnesium chloride, lithium naphthalide, LiTMP and the like as described, for example, in Mongin, F. And Queguiner, G. Tetrahedron, 2001, 57 (19), 4059-4090; Turck, A. et al. Tetrahedron, 2001, 57 (21), 4489-4505; to give the compound of formula II where L is a metalloid such as lithium or magnesium and the like, or such metal is exchanged for another metal such as zinc, tin, palladium and the like. The reaction with another group L, R1-L or R2-L gives the compounds of the formula II which can furthermore be reacted under similar conditions to give the compounds of the formula I.

Reaction scheme II IV The compounds of the formula I of the invention where R5 is -OR6, -NR8R9, or -NR8S (0) pR9 can be prepared as described in Scheme II by coupling compound of formula IV wherein L represents a starting group, such as chloro, fluoro, trifluorosulfonyloxy- and the like, with R5-M or an appropriate precursor for R5-M known to those of skill in the art, where M is hydrogen or metalloid, such as boron, tin, zinc, copper, potassium, sodium and the like. This coupling can optionally be facilitated by catalysts such as Pd (0), Cu (I) and the like. Examples of these transformations can be found in the present and in: Wagaw, S. and Buchwald, S.L., J. Org. Chem., 1996, 61 (21), 7240-7241; Konno, S. et al., Chem. Pharm. Bull. , 1982, 30 (1), 152-157; Abdel-Rahman, R.M. and Ghareib, M., Indian J. Chem., 1987, 26B, 496-500; Saad, H.A. et al., Indian J. Chem., 1998, 37B, 1142-1148; Wolfe, J.P. et al., Acc. Chem. Res. , 1998, 31 (12), 805-818; Wolfe, J.P. et at., J. Org. Chem., 2000, 65 (4), 1158-1174; Hartwig, J.F., Acc.

Chem. Res., 1998, 31 (12), 852-860; Alonso, D.A. et al., J. Org. Chem., 2002, 67 (46), 5588-5594; Miyaura, N. and Suzuki, A, Chem. Rev., 1995, 95 (7), 2457-2483; Littke, AF. et at. , _J. Am. Chem. Soc, 2000, 122 (17), 4020-4028; Nishimura, M. et al., Tetrahedron, 2002, 58, 5779-5787; Miller, J.A. and Farrell, R.P., Tetrahedron Lett. , 1998, 39 (40), 7275-7278; Mitchell, T.N. , Synthesis, 1992 (9), 803-815; Sato, N. and Narita, N., Synthesis, 2001 (10), 1551-1555; Nannini, G. et al., Eur. J. Med. Chem. -Chmica Therapeutica, 1979, 14 (1), 53-60; Matsuda, T. et al., Bioorg. Med. Chem. Lett., 2001 (11), 2369-2372; Konno, S. et al., Chem. Pharm. Bull., 1982, 30 (1), 152-157; Sato, N.and Narita, N., Synthesis, 2001 (10), 1551-1555; and references in the present. Alternatively, compounds of formula IV where L is oxygen or nitrogen, can be alkylated, sulfonated, or admixed using, for example, a base such as KC03 and an alkylating agent such as methylodide or an aldehyde and a reducing agent such as acetaldehyde and sodium cyanoborohydride and the like as described, for example, in Abdel-Magid, AF et al., J. Org. Chem. 1996, 61 (11), 3849-3862. Or compounds of the formula IV wherein L is oxygen or nitrogen can be reacted with a sulfonating reagent such as f-sulphonylchloride, C1-S (0) PR9 and the like, or an acylating reagent such as acetyl chloride, methylchloroformate, and the like, to form compounds of the formula I wherein n means a double bond and m means a single bond.

Reaction scheme III Compounds of the formula V wherein L is a leaving group such as chloro, fluoro, trifluorosulf onyloxy and the like, can be reacted with an oxygen nucleophile such as the potassium salt of trimethylsilanol, or sodium hydroxide and the like for forming compounds of the formula I wherein R5 is O and R4 is H or, under basic conditions in the presence of an alkylating agent, such intermediates can furthermore be transformed into compounds of the formula I wherein R5 is O and R4 is defined in claim 1. Examples of these transformations can be found in the present and in: Nannini, G. et al. Eur. J. Med. Chem-Chi. Ther. 1979, 14 (1), 53-60; Yu et al. J. Med. Chem. 2003, 46 (4), 457-460 and references found herein. Reaction scheme IV The compounds of the formula VI can be alkylated with an electrophile such as a benzyl substitution halide, an alkyl halide, an aryl halide, a heteroaryl halide and the like in the presence of a base such as KC03 and solvents such as DMF, THF , and the like, optionally catalyst by palladium, copper and the like to give compounds of the formula I. Examples of such transformations can be found herein, and in, Edmondson, SD, Mastracchio, A., Parmee, ER Org. Lett. 2000, 2 (8), 1109-1112 and references herein. Reaction scheme V VIII VII VI Compounds of the formula VIII wherein L is a starting group such as chlorine, fluorine, trifluoromethylsulphonate, and the like, can be reacted with hydrazine in a solvent such as DMF, pyridine, THF and the like to give the compounds of formula VII as exemplified herein and in Nannini, G. Et al. Eur. J. Ed. Chem. -Chim. Ther. 1979, 14 (1), 53-60 and references herein. The compounds of the formula VII can be reacted with a bis-activated carbonyl such as carbonyl-1,1-diimidazole, phosgene, and the like to give the compounds of the formula VI.

Reaction scheme VI X IX VIII Compounds of formula X are described wherein P is defined as a protective group known to those of experience in the art; many of the examples of P can be found in, T.W. Greene & P.G.M. Wuts, "Protecting Goups in Organic Synthesis", 3rd edition, Wiley, 1999, and methods for installing and removing such protective groups are included in the reference and citations herein. When P resides in oxygen, then k is a single bond and 1 is a double bond; alternatively, when P resides in nitrogen, then k is a double bond and 1 is a single bond. The protecting group, P, in the compounds of formula X can be removed to give compounds of formula IX which are further converted to compounds of formula VIII wherein L is a leaving group such as fluorine, chlorine, trifluoromethylsulfonate and the like. For example, the conversion of the compound of the formula X wherein P is an optionally substituted benzyl group occurs with AlCl3 in toluene to give the compound of the formula IX. In the course of these transformations, R4, R5, n and m can interconvert to other groups selected from the definitions of R4, R5, n and m. Examples of similar methods can be found in the present and in Nannini, G. et al. Eur. J. Med. Chem. -Chim. Ther. 1979, 14 (1), 53-60 and references herein. The compounds of the formula IX can be reacted with P0C13 to give the compounds of the formula VIII wherein L is chloro. Examples of similar transformations can be found in the present and in Yu et al. J. Med. Chem. 2003, 46 (4), 457-460 and references herein. Reaction scheme VII XII XI.A XI.B Compounds of formula XII wherein L is a starting group such as chlorine, bromine and the like, and P is defined in the description of reaction scheme VI, can be converted to the compounds of formula XI by the reaction of R1-M or R2-M optionally catalyzed by a transition metal such as palladium, copper and the like. M is defined as a metalloid such as tin, boron, sodium, lithium and the like or M can be an activated hydrogen that is lost during coupling to compounds of formula XII or XI.

Compounds of formula XI can be reacted with R1-M or R2-M optionally catalyzed by a transition metal such as palladium, copper and the like to give compounds of formula X. Examples of such transformations can be found in the present and in: Matyus, P. et al. Synlett 2004, (7), 1123-1139; Miyaura, N., Suzuki, A. Chem. Rev. 1995, 95, 2457-2483; Karmas, G and Spoerri, P.E., _J. Am. Chem. Soc. , 1956, 78 (10), 2141-2144; Matsuda, T. et al. Bioorg. Med. Chem,. Lett., 2001 (11), 2369-2372; Konno, S. et al, Chem. Pharm. Bull. , 1982, 30 (1), 152-157; Akita, Y., Shimazaki, M. and Ohta, A., Synthesis, 1981 (12), 974-975; and references in the present. Reaction scheme VIII xvi xv xiv xm XII Compounds of formula XVI wherein L is an activated group such as chlorine, bromine, and the like and Z is O, or N are commercially available, or can be synthesized by those skilled in the art. The reaction of the compounds of the formula XVI with the compound of the formula XV, hydrazine for example (where R4 is hydrogen), in a solvent such as DMF, water or THF, or in the absence of a cosolvent, gives the compounds of the formula XIV. Examples of such transformations can be found in the present and in: Chambers, R.D .; Musgrave, W.K.R.; Sargent, C.R. J. Chem. Soc. Perkin I, 1981, 1071-1077. The compound of the formula XIV wherein R 4 is hydrogen can be converted to a compound of the formula XIII with a base, such as K 2 CO 3 in solvents such as DMF, THF and the like. The compound of formula XIII can further be transformed with a base, such as K2CO3 in solvents such as DMF, THF and the like to give compounds of formula XII wherein P is defined in the discussion of reaction scheme VI. Scheme of reaction IX I xvp Compounds of formula I containing a bioactive metabolite, as defined above, can be converted to a prodrug of formula XVII by methods known to those skilled in the art, including methods described or referenced in the above citations. Examples of such transformations include, but are not limited to, transformation of a -OH group to a phosphate by methods known to those skilled in the art, and described in Haftendorn, R., Ulbrich-Hoffmann, R. Tetrahedron 1995, 51 (4), 1177-1186, Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985) and references herein. The compounds of the formula I containing an -NH group can be sulphated as described in Tschamber, T., Streith, J. Heterocycles 1990, 30 (1), 551-559. The compounds of the formula I containing a nitrogen can be reacted with an alkylating agent such as chloromethylacetate and the like to give a prodrug which, during biotransformation, can release the compounds of the formula I. The standard protecting groups can be used at any stage of the synthesis, for example, in the manipulation of the functional group to convert the compound of the formula I to another compound of the formula I. The parallel synthesis can be used in the preparation of compounds, for example, where the intermediates have an activated reaction center: such as, but not limited to, the triazolone nitrogen, the pyridazinone nitrogen, a heteroaryl chloride reactive for the chemical coupling Suzuki or a carboxylic acid for the amide coupling chemistry. EXAMPLES The following examples serve to better illustrate, but not to limit, some of the preferred embodiments of the invention.

Analytical HPLC methods used in the characterization of examples The analytical HPLC / MS was performed on Shimadzu LCIOAS liquid chromatographs and Waters ZMD mass spectrometers using the following methods: Unless indicated otherwise, method A is used in the characterization of intermediates or final compounds of the examples listed in the experiments or in the tables. Method A. Linear gradient from 0 to 100% solvent B over 4 minutes with 1 minute wait at 100% B; UV display at 220 nm Column: Phenomenex Luna C18 4.6 x 50 mm Flow rate: 4 ml / min Solvent A: 0.2% phosphoric acid, 90% water, 10% methanol Solvent B: 0.2% phosphoric acid, 90 % methanol, 10% water. EXAMPLE 1 Preparation of 7,8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazole [4,3-b] pyridazine-3,6 (2H, 5H) -dione EXAMPLE 1 Preparation of 4,5-dichloro-1,2-dihydropyridazine-3,6-dione.

To a round bottom flask was added water (170 ml) and hydrazine dichlorohydrate salt (41.9 gm, 398.8 mmol). The solution was brought to reflux and dichloromandelic anhydride (66.6 gm, 398.9 mmol) was added in portions. The reaction was stirred at reflux for 30 minutes. After this time, the solution was cooled to room temperature and the solid was collected by filtration to give the title compound, 4,5-dichloro-1,2-dihydropyridazine-3,6-dione (65 gm, 90% yield) as a white solid. MS (M + l) = 181.0.

EXAMPLE IB Preparation of 2-bensyl-6- (benzyloxy) -4,5-dichloropyridazin-3 (2H) -one.

To a round bottom flask was added 4,5-dichloro-1,2-dihydropyridazine-3,6-dione (20 gm, 73.8 mmol), DMF (200 ml), potassium carbonate (20.36 gm, 147.6 mmol) and benzylbromide (15.14 gm, 88.56 mmol). The reaction was stirred at 50 ° C for 6 hours and then stirred at room temperature overnight. After this time, the reaction was poured into a 1: 1 mixture of water: hexane (2000 mL). The resulting mixture was stirred at room temperature for 1 hour. A precipitated solid formed and the precipitate was collected by filtration to give the title compound, 2-benzyl-6- (benzyloxy) -4,5-dichloropyridazon-3 (2H) -one (23.9 gm, 90% yield) as a light yellow solid. ^ (DMSO-Dd) 7.45 (m, 2H), 7.35 (m, 4H), 7.30 (m, 4H), 5.26 (s, 2H), 5.17 (s, 2H).

EXAMPLE 1C Preparation of 2-benzyl-6- (benzyloxy) -4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one.

To a round bottom flask was added 2-benzyl-6- (benzyloxy) -4,5-dichloropyridazin-3- (2H) -one (20 gm, 55.4 mmol), 4-chlorophenylboronic acid (19.07 gm, 121.88 mmol ), 2N sodium carbonate (124.7 ml, 249.3 mmol), toluene (200 ml) and Pd (PPh3) (3.2 gm, 2.77 mmol). The reaction was stirred at 100 ° C for 36 hours. After this time, the solution was cooled to room temperature and the organic layer was separated. The organic layer was washed with water (100 ml), saturated aqueous NaCl (100 ml). The organic layer was dried (MgSO), filtered and concentrated. The crude material was recrystallized from methanol (150 ml) at -25 ° C. The solid was collected by filtration to give the title compound, 2-benzyl-6- (benzyloxy) -4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one, (19.5 gm, 70% yield ) as a light yellow solid.

MS (M + H) = 513.1.

EXAMPLE ID Preparation of 4,5-bis (4-chlorophenyl) -1,2-di-idropyridazin-3,6-dione.

To a round bottom flask was added 2-benzyl-6- (benzyloxy) -4,5-bis (4-chlorophenyl) pyridazin-3 (2H) -one (15.5 gm, 30.21 mmol), toluene (70 ml) and alumina chloride (10.08 gm, 75.54 mmol). The reaction was stirred at 90 ° C for 2 hours. After this time, the reaction was cooled to 0 ° C and water (200 ml) was slowly added to the reaction. The solution was extracted with ethyl acetate (3 L). The organic layer was washed with water (200 ml) and saturated aqueous NaCl (200 ml). The organic layer was dried (MgSO), filtered and concentrated. The title compound, 4,5-bis (4-chlorophenyl) -1,2-dihydropyridazine-3,6-dione, is obtained as a solid and used without further purification. MS (M + H) = 330.9, 333.0. EXAMPLE ID Preparation of 3,6-dichloro-4,5-bis (4-chlorophenyl) pyridazine.

To 4, 5-bis (4-chlorophenyl) -1,2-dihydropyridazine-3,6-dione was added POCl 3 (50 ml), dropwise. The resulting reaction mixture was heated to reflux for 2 hours. The reaction turned black. After this time, POCl3 was removed under reduced pressure. Ice (250 gm) was slowly added to the residue followed by the slow addition of water (250 ml). A solid precipitate formed which was then collected by filtration to give the product as a dark solid. The crude product was dissolved in CHC1 (250 ml) and the solution was filtered through Celite (30 ml). The filtrate was collected and concentrated to a brown solid. The crude solid was recrystallized from CHC12 (30 ml) and hexanes (500 ml) to give the title compound, 3,5-dichloro-4,5-bis (4-chlorophenyl) pyridazine as a beige solid (5.0 gm). , 45% for the 2 stages). EM; (M + H) = 368.5, 370.5. EXAMPLE 1E Preparation of 1- (6-chloro-4,5-bis (4-chlorophenyl) pyridazin-3-yl) idrazine.

To a round bottom flask was added 3,5-dichloro-4,5-bis (4-chlorophenyl) pyridazine (4.5 gm, 12.2 mmol), pyridine. (20 ml) and hydrazine monohydrate (1494 gm, 30.49 mmol). The reaction mixture was stirred at 120 ° C for 1 hour. After this time, the reaction mixture was cooled to room temperature. Water (400 ml) was then added and the solid precipitated. The solution was filtered and the solid was collected and air dried overnight to give the title compound, 1- (6-chloro-4,5-bis (4-chlorophenyl) pyridazin-3-yl) hydrazine (3.7 gm, 83% yield) as a solid. MS (M + H) = 364.9 EXAMPLE 1F Preparation of 6-chloro-7,8-bis (4-chlorophenyl) [1,2,4] triazole [4,3-b] pxridazin-3 (2H) -one.

To a round bottom flask was added THF (50 ml) and carbonyldiimidazole (CDI) (8.11 gm, 50 mmol). After the CDI was completely dissolved, 1- (6-chloro-4,5-bis (4-chlorophenyl) pyridazin-3-yl) hydrazine (3.65 gm, 10 mmol) was added in 4 portions over 10 minutes. The reaction was stirred at room temperature for 2 hours. After this time, the reaction was poured into water (300 ml). The solution was filtered to give the product 6-chloro-7,8-bis (4-chlorophenyl) - [1,2,4] triozolo [4,3-b] pyridazin-3 (2H) -one to give the compound of the title chloro-7, 8-bis (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (3.6 gm, 92% yield) as a solid . MS (M + H) = 390.9, 392.9; ^ NMR (DMSO-D6) 7.39-7.44 (m, 4H), 7.28 (m, 4H).

EXAMPLE 1G Preparation of 6-chloro-7,8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one.

To a round bottom flask was added 6-chloro-7,8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) - ona (1200 mg, 3077 mmol), DMF (10 mL), potassium carbonate (0.64 gm, 4.62 mmol), and iodomethane (0.89 gm, 6.15 mmol). The reaction was stirred at room temperature for 4 hours. After this time, water (200 ml) was added to the reaction and a solid precipitated. The solid was collected by filtration to give the title compound, 6-chloro-7,8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazolo [4, 3-b] pyridazin-3 (2 H) -one (1.1 gm, 89% yield). MS (M + H) = 404.9, 406.9; X H NMR (DMSO-D6) 7.42 (m, 4 H), 7.28 (, 4 H), 3.56 (s, 3 H). 13CRMN (DMSO-D6) 147.95, 147.08, 136.18, 135.51, 133.95, 133.37, 131.85, 131.65, 131.20, 128.86, 128.09, 128.01, 32.95.

EXAMPLE 1H Preparation of 7,8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazolo [4, 3-b] pyridazine-3,6 (2H, 5H) -dione.

To a round bottom flask was added 7,8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazolo [4, 3-b] pyridazine-3,6 (2H, 5H) - dione (1.2 gm, 3.29 mmol), THF (15 ml), and potassium trimethylsilanoalt (1.7 gm, 13.2 mmol). The reaction was refluxed for 2 hours. The reaction was then cooled to room temperature, and the solution was concentrated under reduced pressure. The residue was treated with water (20 ml) and the pH adjusted to 5 using IN HCl. To the resulting solution was added ethyl acetate (15 ml) and hexanes (15 ml) and the solution was stirred for 5 minutes. A precipitate was collected by filtration to give the title compound, 7,8-bis (4-chlorophevyl) -2-methyl- [1,2,4] triazolo [4, 3-b] pyridazine-3, 6 (2H , 5H) -dione (1.2 gm, 95% yield) as a yellow solid. MS (M + H) = 386.9 1 HNMR (DMSO-D6) 12.60 (s, 1H), 7.34 (d, 2H), 7.29 (d, 2H), 7.23 (d, 2H), 7.15 (d, 2H), 3.46 (s, 3H).

EXAMPLE 2 Preparation of 7,8-Bis (4-chlorophenyl) - [1,2,4] triazole [4,3-b] pyridazine-3,6 (2H, 5H) -dione.

To a round bottom flask was added 6-chloro-7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (100 mg , 0.256 mmol), prepared as described in Example 1F, THF (5 ml) and potassium trimethylsilanolate (132 mg, 1026 mmol). The reaction mixture was stirred at 852C for 1.5 hours. After this time, the solution was cooled to room temperature and the reaction was diluted with water (25 ml). The pH of the solution was adjusted to 4 with IN HCl. The resulting solution was extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with water (20 ml), saturated NaCl (20 ml). The organic layers were dried (MgSO4), filtered and concentrated to give the title compound, 7, 8-bis (4-chlorophenyl) - [1, 2, 4] triazolo [4, 3-b] pyridazine-3, 6 (2H-5H) -dione (900 mg, 95% yield) as a yellow solid. MS (M + H) = 372.9 EXAMPLE 3 Preparation of 2- (4- (Trifl romethyl) benzyl) -6-sloro-7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4, 3-b] pyridazin-3 (2H) -one.

To a solution of 6-chloro-7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one (750 mg, 1.92 mmol) , prepared as described in Example 1F, in DMF (10 mL) was added K2C03 (270 mg, 1.95 mmol) and 4- (trifluoromethyl) benzyl bromide (460 mg, 1.92 mmol). The reaction mixture was stirred at 75 ° C for 1 hour under Argon. It was cooled to room temperature, diluted with water (50 L) and the solid collected by filtration. The solid was washed with water (25 mL x 2) and dried in a vacuum oven at 50 ° C overnight to give the title compound, 2- (4- (trifluoromethyl) encyl) -6-chloro-7,8. bis (4-chlorophenyl) - [1,2,4] triazole [4, 3-b] pyridazin-3 (2H) -one, (990 mg, 94%) as a yellow powder. CLAR: 4.23 min; MS: M + H = 549.

EXAMPLE 4 Preparation of 2- (4- (Trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -6- (methylamino) - [1,2,4] triazole [4,3-b] pyridazin-3 (2H) -one.

A mixture of 2- (4- (trifluoromethyl) benzyl) -β-chloro-7,8-bis (4-chlorophenyl) - [1,2,4] triazole [4, 3-b] pyridazin-3 (2H) -one (50 mg, 0.091 mmol), prepared as described in Example 3, and 2.0 M methyl amine in THF (0.4 ml) was stirred at reflux for 12 hours. After this time, the reaction mixture was cooled to room temperature and diluted with water (5 ml). The resulting solution was extracted with EtOAc (5 ml x 3). The combined organic layers were washed with water (5 ml x 2) followed by saturated aqueous NaCl (5 ml x 2). The organic layer was dried over MgSO4, filtered and concentrated to obtain the crude product. The crude product was purified by reverse phase preparative HPLC to give the title compound, 2- (4-trifluoromethyl) benzyl-7,8-bis (4-chlorophenyl) -6- (methylamino) - [1,2,4 ] triazolo [4, 3-b] pyridazin-3 (2H) -one (31.5 mg, 64%) as a pale yellow solid. CLAR: 4.17 min; MS: M + H = 544; XH NMR (CDC13), ppm: 7.55 (2H, d, J = 10.0 Hz), 7.47 (2H, d, J = 10.0 Hz), 7.34 (2H, d, J = 10.0 Hz), 7.21 (2H, d, J = 10.0 Hz), 7.09 (2H, d, J = 10.0 Hz), 7.05 (2H, d, J = 10.0 Hz), 5.18 (2H, s), 4.19-4.21 (1H, br), 2.95 (3H, d, J = 5.0 Hz). EXAMPLE 5 Preparation of 7,8-Bis (4-chlorophenyl) -2-methyl-5- ((5- (trifluoromethyl) pyridin-2-yl) methyl) - [1,2,4] triazole [4,3- b] pyridazine-3,6 (2H, 5H) -dione.

EXAMPLE 5A Preparation of 2- (Chloromethyl) -5- (trifluoromethyl) pyridine.

The mixture of (5- (trifluoromethyl) pyridine) -2-yl) methanol HCL salt (293 mg, 1.4 mmol) and SOCl 2 (1.5 mL) was stirred for 10 min. After this time, the solution was concentrated under reduced pressure to give the title compound, HCl salt of 2- (Chloromethyl) -5- (trifluoromethyl) pyridine.

EXAMPLE 5B Preparation of 7,8-Bis (4-chlorophenyl) -2-methyl-5- ((5- (trifluoromethyl) pyridin-2-yl) methyl) - [1,2,4] triazole [4,3- b] pyridazine-3,6 (2H, 5H) -dione.

The solution of 8-bis (4-chlorophenyl) -2-methyl- [1,2,4] triazole [4, 3-b] pyridazine-3,6 (2H, 5H) -dione (430 mg, 1.11 mmol), prepared as described in Example 1, 2- (chloromethyl) -5- (trifluoromethyl) pyridine (1.4 mmol), K2CO3 (620 mg, 4.5 mmol) in DMF (10 mL), was heated to 802C. for 1 hour. After this time, the solution was cooled to room temperature and diluted with ethyl acetate. The resulting solution was then washed with water. The organic layer was dried over NaSO 4, filtered and concentrated under reduced pressure. The crude product was purified using column chromatography on silica gel using an automated system eluting with a gradient of (20-50% ethyl acetate-Hexane) to give the title compound, 7, 8-bis (4-chlorophenyl) -2-methyl-5- ((5- (trifluoromethyl) pyridin-2-yl) methyl) - [1,2, 4] triazole [4, 3-b] pyridazine-3, 6 (2H, 5H) -dione (110 mg, 18%) as a light yellow solid. In addition, the 0-allylated product, 7, 8-bis (4-chlorophenyl) -2-methyl-6- ((5- (trifluoromethyl) pyridin-2-y1) methoxy) -5,6-dihydro- [1, 2,4] triazole [4, 3-b] pyridazin-3 (2H) -one is obtained from the HPLC separation of the crude product. 7, 8-Bis (4-chlorophenyl) -2-methyl-5- ((5 (trifluoromethyl) pyridin-2-yl) methyl) - [1,2,4] triazole [4, 3-b] pyridazine-3 , 6 (2H, 5H) -dione: MS, M + H = 546; X H NMR (CDCl 3) δ 8.75 (HH), 7.90 (1H), 7.49 (ÍH), 7.29 (2H), 7.22-7.18 (4H), 7.10 (2H), 615 (2H), 353 (3H). EXAMPLE 6 Preparation of 7, 8-bxs (4-chlorophenyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) - [1,2,4] triazolo [4,3-b] pyridazine-3,6 ( 2H, 5H) -dione.

EXAMPLE 6A Preparation of 6-chloro-7, 8-bis (4-chlorophenyl) -2- ((2- (trimethylsilyl) ethoxy) methyl] - [1,2,4] triazole [4, 3-b] pyridazin- 3 (2H) -one To a solution of 6-chloro-7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one (0.43 g, 1.1 mmol), prepared as described in Example 1F, in NaOH (8 mL) at 0 ° C was added NaH (57 mg, 1.4 mmol). After 15 min., 2-trimethylsilylethoxymethyl chloride (0.25 ml, 1.4 mmol) was added. The reaction was stirred for 0.5 h at room temperature. After this time, water was added. The resulting solution was extracted with ethyl acetate. The organic layer was dried over Na 2 SO and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using an automated system eluting with a gradient of (ethyl acetate-hexanes) to give the title compound, 6-chloro-7,8-bis (4-chlorophenyl) -2- ((2- (2- (trimethylsilyl) ethoxy) ethoxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one as a yellow foam (0.48 g , 84%). EXAMPLE 6B Preparation of 7,8-bis (4-slorophenyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazine-3,6 ( 2H, 5H) -dione To the solution of 6-chloro-7,8-bis (4-chlorophenyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) - [1,2,4] triazolo [4, 3-b] pyridazin- 3 (2H) -one, (0.48 g, 0.92 mmol) in THF (20 ml) was added potassium trimethylsilyloxide (TMSOK) (0.25 g, 1.95 mmol). The solution was heated to reflux. After 0.5 h, the solution was cooled to room temperature and a solution of IN HCl was added until the reaction became acidic. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using an automated system to give the title compound, 7, 8-bis (4-chlorophenyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) - [ 1,2,4] triazolo [4, 3-b] pyridazine-3,6 (2H, 5H) -dione, (260 mg, 56%) as a yellow solid. EXAMPLE 7 Preparation of 5- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) - [1, 2, 4] triazolo [4, 3-b] pyridazine-3, 6 (2H, 5H ) -dione EXAMPLE 7A Preparation of 5- (4- (trifluoromethyl) benzyl) -7,8-bxs (4-chlorophenyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) - [1, 2, 4] triazolo [4 , 3-b] pyridazine-3, 6 (2H, 5H) -dione The solution of 7,8-bis (4-chlorophenyl) -2- ((2- (trimethylsilyl) ethoxy) ethyl) - [1,2,4] triazolo [4, 3-b] pyridazine-3,6 (2H , 5H) -dione, (112 mg, 0.22 mmol), was prepared as described in example 6B, 4- (trifluoromethyl) benzyl bromide (58 mg, 0.24 mmol), K2C03 (91 mg, 0.66 mmol) were heated in DMF (2 ml), at 80 ° C for 0.75 hours. After this time, the solution was cooled to room temperature and diluted with ethyl acetate. The resulting solution was washed with water. . The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give the title compound, 5- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -2- ((2 - (trimethylsilyl) ethoxy) methyl) - [1, 2, 4] triazolo [4, 3-b] pyridazine-3,6 (2H, 5H) -dione, (160 mg).

EXAMPLE 7B Preparation of 5- (4- (Trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) - [1,2,4] triazolo [4, 3-b] pyridazine-3, 6 (2H, 5H ) -dione The solution of 5- (4- (trifluoromethyl) benzyl) -7,8-bis (4-chlorophenyl) -2- ((2- (trimethylsilyl) ethoxy) methyl) - [1, 2, 4] triazolo [4, 3-b] pyridazine-3,6 (2H, 5H) -dione (118 mg, 0.18 mmol) in 4M HCl in dioxane (4 ml) in a sealed tube was heated at 90 ° C for 6 hours. After this time, the reaction mixture was cooled to room temperature, and subsequently concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give the title compound, the final product, 5- (4- (trifluoromethyl) encyl) -7,8-bis (4-chlorophenyl) - [1,2,4] ] triazolo [4, 3-b] pyridazine-3, 6 (2H, 5H) -dione, as a colorless foam 860 mg, 66%). MS M + H = 531; XH (CDC13) d 11.46 (ÍH), 7.70 (2H), 7.55 (2H), 7.27 (4H), 7.14 (2H), 7.06 (2H), 5.96 (2H).

EXAMPLE 8 Preparation of 6-chloro-7- (chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one and 6- chloro-8- (chlorophenyl) -7- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one EXAMPLE 8A Preparation of 2-benzyl-6- (bensyloxy) -5-sloro-4- (4-chlorophenyl) pyridazin-3 (2H) -one and 2-benzyl-6- (bensxloxy) -4-chloro-5- (4 -chlorophenyl) pyridazin-3 (2H) -one To a solution of 2-benzyl-6- (benzyloxy) -4,5-dichloropyridazin-3 (2H) -one (11.8 g, 32.7 mmol), prepared as described in Example IB, in toluene (200 ml) was added Pd (PPh3) 4 (2.26 g, 1.96 mmol). After 5 min., A 2N aqueous sodium carbonate solution (65 ml, 130 mmol) was added, followed by 4-chlorophenylboronic acid (7.16 g, 45.8 mmol). The reaction was stirred at 100 ° C for 6 h. After this time, the solution was cooled to room temperature and the reaction mixture was diluted with ethyl acetate. The resulting solution was washed with water, saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified using silgel column chromatography eluting with a gradient of 10-20% ethyl acetate / hexane to give the title compounds, 2-benzyl-6- (benzyloxy) -5-chloro-4 - (4-chlorophenyl) pyridazin-3 (2H) -one and 2-benzyl-6- (benzyloxy) -4-chloro-5- (4-chlorophenyl) pyridazin-3 (2H) -one which were obtained as a mixture. EXAMPLE 8B Preparation of 2-benzyl-6- (benzyloxy) -4- (4-chlorophenyl) -5- (pyridin-4-yl) pyridazin-3 (2H) -one and 2-bensyl-6- (benzyloxy) - 5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one To a solution of 2-benzyl-6- (benzyloxy) -5-chloro-4- (4-chlorophenyl) iridazin-3 (2H) -one and 2-benzyl-6- (benzyloxy) -4-chloro-5- (4-chlorophenyl) pyridazin-3 (2H) -one (9.9 g, 22.7 mmol), prepared as described in example 8A, in toluene (136 ml) was added Pd (PPh3) (2.35 g, 1.17 mmol). After 2 min. , a solution of 2N sodium carbonate (45.4 ml, 90.8 mmol) was added, followed by 4- (4, 4, 5, 5-tetramethyl-1,2,3-dioxoborolan-2-yl) pyridine (8.5 g, 41.4 mmol). The reaction was stirred at 100 ° C for 42 hours. After this time, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting solution was washed with water and saturated aqueous NaCl. The organic layer was dried over NaSO 4, filtered and concentrated. The crude product was purified by silgel column chromatography using an automated system and eluted with a gradient of 20-50% ethyl acetate-hexane to give the title compounds 2-benzyl-6- (benzyloxy) -4- (4-chlorophenyl) -5- (pyridin-4-yl) pyridazin-3 (2H) -one and 2-benzyl-6- (benzyloxy) -5- (4-chlorophenyl) -4- (pyridine- 4-yl) pyridazin-3 (2H) -one (4.5 g, 29% in 2 steps).

EXAMPLE 8C Preparation of 4- (4-Chlorophenyl) -5- (pyridin-4-yl) -1,2-dihydropyridazine-3,6-dione To a solution of 2-benzyl-6- (benzyloxy) -4- (4-chlorofenyl) -5- (pyridin-4-yl) pyridazin-3 (2H) -one and 2-benzyl-6- (benzyl oxy) ) -5- (4-chlorophenyl) -4- (pyridin-4-yl) pyridazin-3 (2H) -one (2.8 g, 5.8 mmol) in toluene (35 ml) was added AlCl3 (3.1 g, 23.2 mmol). After stirring at 80 ° C for 30 min. After this time, the reaction mixture was cooled to room temperature and 40 ml of water was added. A precipitate was formed which was subsequently collected by filtration. The title compound, 4- (4-Chlorofenyl) -5- (pyridin-4-yl) -1,2-dihydropyridazine-3,6-dione was obtained as a yellow powder 81.1 g, 63%). EXAMPLE 8D Preparation of 3,6-dichloro-4- (4-chlorophenyl) -5- (pyridin-4-yl) pyridazine A sealed tube with 4- (4-chlorophenyl) -5- (pyridin-4-yl) -1,2-dihydropyridazine-3,6-dione (0.1 g, 0.33 mol) and POCl3 (0.3 ml, 3.2 mmol) was stirred at 135 ° C in an oil bath for lh. After this time, the solution was cooled to room temperature and emptied into 1.5 N NaOH-water with ice (9.3 ml, 14 mmol). Ethyl acetate was added to the resulting solution. The organic layer was washed with saturated aqueous NaCl. The organic layer was dried over NaS0, filtered and concentrated under reduced pressure to give the title compound 3,6-dichloro-4- (4-chlorophenyl) -5- (pyridin-4-yl) pyridazine, a brown foam (90 mg) which was used without further purification. EXAMPLE 8? Preparation of 6-sloro-7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one and 6- Chloro-8- (4-chlorophenyl) -7- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b] pyridazin-3 (2H) -one To a solution of 3,6-dichloro-4- (4-chlorophenyl) -5- (pyridin-4-yl) -pyridazine (0.69 g, 2.1 mmol) in ethanol (10 mL) was added hydrazine monohydrate (1.2 mL). , 24.7 mmol). The reaction was stirred at 80 ° C for 1 h. After this time, the reaction mixture was concentrated under reduced pressure. The crude product was then suspended in THF and CDI (1.36 mg, 8.4 mmol) was added. The mixture became a clear brown-colored solution, then became a suspension. After being stirred for 20 min., Ethyl acetate was added. The resulting solution was washed with water and saturated NaCl. The organic layer was dried over NaSO 4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a 5% -10% methanol-dichloroethane gradient to give 6-chloro-7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one as a brown solid (0.52 g) and 6-chloro-8- (4-chlorophenyl) -7- (pyridin-4-yl) - [1, 2, 4] triazolo [4, 3-b] pyridazin-3 (2H) -one as a light brown solid (0.27 g). EXAMPLE 9 Preparation of 7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4,3-b] pyridazine-3,6 (2H, 5H) -dione To the solution of 6-chloro-7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4, 3-b] pyridazin-3 (2H) -one ( 28 mg, 0.078 mmol), prepared as described in example 8B, in THF (3 ml) was added potassium trimethylsiloxide, TMSOK (36 mg, 0.28 mmol). The reaction mixture was refluxed for 1 h. After this time, the solution was cooled to room temperature. The solution was concentrated under reduced pressure. The resulting crude product was purified by reverse phase HPLC to give the title compound, 7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4, 3-b ] pyridazine-3, 6 (2H, 5H) -dione, (8 mg, 22%) as a yellow solid.

EXAMPLE 10 Preparation of 8- (4-chlorophenyl) -7- (pyridin-4-yl) - [1,2,4] triazolo [4, 3-b] pyridazine-3, 6- (2H, 5H) -dione To the solution of 6-chloro-8- (4-chlorophenyl) -7- (pyridin-4-yl) - [1,2,4} triazolo [4,3-b] pyridazin-3 (2H) -one (29 mg, 0.081 mmol), prepared as described in Example 9, in THF (3 ml) was added potassium trimethylsiloxide, TMSOK, (36 mg, 0. 28 mmol). The solution was heated to reflux for 15 min. after this time, the solution was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse phase HPLC to give the title compound, 8- (4-chlorophenyl) -7- (pyridin-4-yl) - [1,2,4] triazolo [4, 3-b] pyridazine-3, 6- (2H, 5H) -dione, (12 mg, 32%) as a solid, yellow. EXAMPLE 11 Preparation of 4- ((7- (-chlorophenyl) -2-methyl-3,6-dioxo-8- (pyridin-4-yl) -2,3-dihydro- [1,2,4] triazolo [ 4, 3-b] pyridazin-5 (6H) -yl) methyl) benzonitrile The solution of 7- (4-chlorophenyl) -2-methyl-8- (pyridin-4-yl) - [1,2, 4] triazolo [4, 3-b] pyridazine-3, 6 (2H, 5H) -dione (10 mg, 0.028 mmol), 4- (bromomethyl) benzonitrile (7 mg, 0.036 mmol), K2C03 (12 mg, 0.084 mmol), in DMF (0.5 mL), was heated at 80 ° C for 20 min. After this time, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 4- ((7- (4-chlorophenyl) -2-methyl-3,6-dioxo-8- (pyridin-4-yl) -2 , 3-dihydro- [1,2,4] triazolo [4, 3-b] pyridazin-5 (6H) -yl) ethyl) benzonitrile (6.5 mg, 40%) as the mono trifluoroacetate salt as a yellow solid . TA = 2.87, M + H = 469; XH NMR (CD30D) d 8.81 (2H), 7.71-7.60 (6H), 7.32 (2H), 7.07 (2H), 5.96 (2H), 3.57 (3H). EXAMPLE 12 Preparation of 4- ((7- (4-chlorophenyl) -3,6-dioxo-8- (pyridin-4-yl) -2,3-dihydro- [1,2,4] triazolo [4.3 -b] pyridazin-5 (6H) -yl) methyl) benzonitrile To the solution of 7- (4-chlorophenyl) -8- (pyridin-4-yl) - [1,2,4] triazolo [4, 3-b] pyridazine-3, 6- (2H, 5H) -dione (8 mg, 0. 023 mmol), prepared as described in example 9 in DMF (0.3 ml) was added K2C03 (5 mg, 0.036 ml) followed by 4- (bromomethyl) benzonitrile (5 mg, 0.025 mmol). After 15 min., The reaction mixture was diluted with ethyl acetate. The resulting solution was then washed with water. The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 4- ((7- (4-chlorophenyl) -3,6-dioxo-8- (pyridin-4-yl) -2,3-dihydro - [1,2,4] triazolo [4, 3-b] pyridazin-5 (6H) -yl) ethyl) benzonitrile, (4.2 mg, 32%) as a mono trifluoroacetate salt as a yellow foam. MS M + H = 454; XH (CD30D) d 8.68 (2H), 7.71-7.65 (6H), 7.28 (2H), 7.20 (2H), 5.94 (2H). EXAMPLE 13 Preparation of 4- ((8- (4-chlorophenyl) -3,6-dioxo-7- (piiridin-4-yl) -2,3-dxhydro- [1,2,4] triazolo [4.3 -b] pyridazxn-5 (6H) -yl) methyl) benzonitrile To the solution of 7- (4-chlorophenyl) -2-methyl-8- (pyridin-4-yl) - [1,2,4] triazolo [4, 3-b] pyridazine-3, 6- (2H, 5H) -dione (12 mg, 0.034 mmol), prepared as described in the example in DMF (0.5 ml) was added K2C03 (7 mg, 0.05 mmol) followed by 4- (bromomethyl) benzonitrile (8 mg, 0.041 mmol). After 15 min., The reaction mixture was diluted with ethyl acetate.

The resulting solution was washed with water. The organic layer was dried over Na 2 SO, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give the title compound, 4- ((8- (4-chlorophenyl) -3,6-dioxo-7- (pyridin-4-yl) -2,3-dihydro - [1,2,4] triazolo [4, 3-b] pyridazin-5 (6H) -i1) methyl) benzonitrile, (3.5 mg, 18%) as a mono trifluoroacetate salt as a yellow foam. MS M + H = 455. XH (CD30D) d 8.66 (2H), 7.71-7.65 (6H), 7.34-7.31 (4H), 5.93 (2H).

EXAMPLES 14 TO 48 The following examples were prepared according to the methods and procedure above: The compounds of set A below, in which R1 varies, R2 is 4-chlorofenyl, R3 is 2- (trifluoropethyl) pyridin-5-ylmethyl, R4 is methyl, R5 is O, n is a single bond and m is a bond double, can be prepared by one skilled in the art by the methods described above. Additionally, the variations of Rl shown here can be combined with R -R, n and m found in the above work examples. The compounds of step A are a medium that further illustrates the scope of the invention without limiting it in any way. Stage A: As noted above, set A consists of compounds that differ from each other only in the identity of R 1 with R 2 fixed as 4-chlorophenyl. The set A can be considered as a one-dimensional library of example compounds. If both R1 and R2 were varied, a two-dimensional library of example compounds would result. The set B is the two-dimensional library consisting of all the permutations of the variants of R1 represented in set A, the working examples, and a set of variants R2 listed below In set B, R3 is 2- (trifluoromethyl) pyridine -5-ylmethyl, R4 is methyl, R5 is 0, n is a single bond and m is a double bond. The compounds of set B can be prepared by one skilled in the art by the methods described above. The compounds of set B means that they further illustrate the scope of the invention without limiting it in any way.

Variants R2 of Stage B Furthermore, as noted above, set B is the two-dimensional library consisting of all the permutations of all the variants of R1 represented in set A and a set of variants R2 previously listed with fixed R3 as 2- (trifluoromethyl) pyridine- 5-ylmethyl. If R1 and R2 and R3 were to be varied, a three-dimensional library of example compounds would result. The set C is the three-dimensional library consisting of all the permutations of all the variants of Rl represented in set A, all the variants R2 previously listed for set B, and a set of variants R listed below. In set C, R4 is methyl, R5 is 0, n is a single bond and m is a double bond. The compounds of set C can be prepared by one skilled in the art by the methods described above. The compounds of set C means that they further illustrate the scope of the invention without limiting it in any way.

Variants of stage C: Furthermore, as noted above, the set C is the three-dimensional library consisting of all the permutations of all the variants of R1 represented in set A, all the variants of R2 represented in set B, and the variants listed above with R4 fixed as methyl, R5 is 0, n is a single bond and m is a double bond. If R and R and R were varied, a three-dimensional library of the example compounds would result. The set D is a four-dimensional library consisting of all the permutations of all the variants of R1 represented in set A, all the variants R2 listed above set B, all the variants of R3 listed above set C, and a set of R4, R5, the n and m variants listed above. The compounds of set D can be prepared by one skilled in the art by the methods described above. The compounds of set D means that they further illustrate the scope of the invention without limiting it in any way. The variants R4, R5 n and m of the set D are detailed as »a fragment of the formula I (for example, the description represents a compound of formula I wherein R is methyl, R is 0, n is a single bond and m is a double bond). Variants R4, R5 n and m of set D: Biological evaluation Binding assay of the Canabinoid Receptor Radioligand binding studies were conducted on membranes prepared from Chinese Hamster Ovary (CHO) cells overexpressing recombinant human CB-1 (CH0-CB cells -1) . The total assay volume for binding studies was 100 μl. 5 μg of membranes were taken to a final volume of 95 μl with an Enzyme Buffer Solution (25 mM H? PES, 150 mM NaCl, 2.5 mM CaCl2, 1 mM MgCl2, 0.25% BSA). The diluted membranes were pre-incubated with a DMSO compound or vehicle. The binding reaction was initiated by the addition of 2 nM final 3H-CP-55.940 (120 Ci / mmol) and proceeded for 2.5 hours at room temperature. The binding reaction was terminated by transferring the reaction to GF / B 96-well plates (pre-soaked with 0.3% polyethylenimine) using a Packard Cell Harvester. The filter was washed with 0.25x PBS, 30 μL MicroScint was added per well, and the linked radiolabel was quantified by scintillation counting in a Packard TopCount Scintillation Counter. The radioligand binding assay was conducted identically except that the membranes of the CHO-CB-2 cells were used. For a compound to be considered a CB-1 antagonist, the compound must possess a binding affinity of the CB-1 Ki receptor of less than 13,000 nM. As determined by the assay described above, the binding Ki values of CB-1 receptor of working examples 1-63 fall within the range of 0.01 nM to 10000 nM.

Functional Assay of the Canabinoid Receptor The functional CB-1 reverse agonist activity of the test compounds was determined in CHO-CB-1 cells using a cAMP accumulation assay. CHO-CB-1 cells grew in 96-well plates near confluence. On the day of the functional assay, the growth medium was aspirated and 100 of Shock Absorbing Solution (PBS plus 25mM HEPES / 0.1MM 3-isobutyl-1-methylxanthine / 0.1% BSA) were added. The compounds were added to the buffer solution of the 1: 100 diluted assay of 100% DMSO and allowed to preincubate for 10 minutes before the addition of 5 uM of forskolin. The mixture was allowed to proceed for 15 minutes at room temperature and was terminated by the addition of 0.1 N HCl. The total intracellular cAMP concentration was quantified using the SPA cAMP kit from Amersham.

Utilities and Combinations Utilities The compounds of the present invention are cannabinoid receptor modulators, and include compounds which are, for example, selective agonists, partial agonists, inverse agonists, antagonists or partial antagonists of the cannabinoid receptor. In consecuense, the compounds of the present invention may be useful for the treatment or prevention of diseases and disorders associated with the G-protein-coupled cannabinoid receptor activity. Preferably, the compounds of the present invention possess activity as antagonists or inverse agonists of the CB receptor. -1, and can be used in the treatment of diseases or disorders associated with CB-1 receptor activity. Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for treatment of a variety of conditions and disorders, including, but not limited to, metabolic and feeding disorders in addition to conditions associated with metabolic disorders, ( for example, obesity, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleeping disorders, hyperlipidemic conditions, bulimia nervosa and eating disorders compulsive) or psychiatric disorders, such as substance abuse, depression, anxiety, mania and schizophrenia. These compounds can also be used for the improvement of cognitive function (for example, the treatment of dementia, which includes Alzheimer's disease, short-term memory loss and attention deficit disorders).; neurodegenerative disorders (e.g. Parkinson's disease, cerebral stroke and craniocerebral trauma) and hypotension (e.g., hemorrhagic hypotension and endotoxin-induced). These compounds can also be used for the treatment of catabolism in connection with pulmonary dysfunction and ventilator dependence; treatment of cardiac dysfunction (eg, associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure); and I pray for general lung function; transplant rejection; rheumatoid arthritis; multiple sclerosis; inflammatory bowel disease; lupus, graft versus host disease; T-cell mediated hypersensitivity disease; psoriasis; asthma; Hashimoto's thyroiditis; Guillain Barre syndrome; Cancer; contact dermatitis; allergic rhinitis; and ischemic or reperfusion injury. The compounds used in the treatment of appetite or motivational disorders regulate the desire to consume sugars, carbohydrates, alcohol or drugs and more generally regulate the consumption of ingredients with a hedonic value. In the present description and in the claims, appetite disorders are understood as meaning: disorders associated with a substance and especially abuse of a substance and / or dependence on a substance, eating behavior disorders, especially those prone to cause excess of weight, without taking into account its origin, for example: bulimia nervosa, sugar cravings. The present invention therefore also relates to the use of a CB-1 receptor antagonist or inverse agonist for the treatment of bulimia and obesity, which includes obesity associated with type II diabetes (diabetes not dependent on insulin), or more generally any disease that results in the patient becoming overweight. Obesity, as described here, was defined by a body mass index (Kg / m2) of at least 26. This may be due to any cause, genetic or environmental that includes overfeeding and bulimia, ovarian disease polycystic, craniofaringeoma, Prader-Willi syndrome, Frohlich syndrome, type II diabetes, growth hormone deficiency, Turner syndrome and other pathological conditions characterized by reduced metabolic activity or reduced energy expenditure. As used with reference to the uses described herein, the term "treatment" encompasses prevention, partial relief, or cure of the disease or disorder. In addition, the treatment of obesity is expected to prevent progression of medical covariates of obesity, such as arteriosclerosis, Type II diabetes, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders. The compounds in the present invention may also be useful in the treatment of substance abuse disorders, which includes substance or abuse dependence without physiological dependence. Substances of abuse include alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis. , cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine (or compounds similar to phencyclidine), sedative hypnotics or benzodiazepines, and other substances (or not known) and combinations of the above. The terms "substance abuse disorders" also include drug or alcohol withdrawal syndromes and substance induced anxiety or mood disorder with onset during withdrawal. The compounds of the present invention may be useful in the treatment of cognitive disorders and memory damage. The condition of memory damage is manifested by damage of the ability to learn new information and / or the inability to remember information previously learned. Memory damage is a primary symptom of dementia and may also be a symptom associated with diseases such as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head trauma in addition to cognitive impairment related to age. Dementias are diseases that include memory loss and additional intellectual damage separated from memory. Cannabinoid receptor modulators may also be useful in the treatment of cognitive impairments related to attention deficits, such as attention deficit disorder. The compounds of the present invention can also be used in the treatment of diseases associated with dysfunction of brain dopaminergic systems, such as Parkinson's disease, and substance abuse disorders. Parkinson's disease is a neurodegenerative movement disorder characterized by bradykinesia and tremor. Like the cannabinoid receptor modulators, the compounds of the present invention are also useful for the treatment and prevention of respiratory diseases and disorders. Respiratory diseases for which cannabinoid receptor modulators are useful include, but are not limited to, chronic obstructive pulmonary disorder, emphysema, asthma, and bronchitis. In addition, cannabinoid receptor modulators block the activation of lung epithelial cells by portions such as allergic agents, inflammatory cytokines or smoke, thereby limiting the release of mucin, cytokines, and chemokines, or selective inhibition of cell activation epithelial lung. Moreover, the compounds used in the present invention can stimulate pathways of inhibition in cells, particularly in leukocytes, lung epithelial cells, or both, and thus are useful in the treatment of diseases. "Leukocyte activation" was defined herein as any or all of cell proliferation, cytosine production, adhesion protein expression, and production of inflammatory mediators. "Epithelial cell activation" was defined here as the production of any or all of mucins, cytokines, chemokines, and expression of addition protein. The use of the compounds of the present invention for the treatment of disorders associated with leukocyte activation is enforced by, but is not limited to, treatment of a range of disorders such as: transplant rejection (such as organ transplantation, acute transplantation , xenotransplant or heterograft or homograft (as used in the burn treatment)); protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes; transplant tolerance induction; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis, pulmonary and respiratory diseases that include but are not limited to chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, and acute respiratory distress syndrome (ARDS); Inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, lupus, (systemic lupus erythematosus); graft versus host disease; T-cell-mediated hypersensitive diseases, including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis, contact dermatitis (which includes that due to poison ivy); Hashimoto's thyroiditis, Sjogren's syndrome, Autoimmune Hyperthyroidism, such as Graves' disease; Addison's disease (autoimmune disease of the adrenal glands); Autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain Barre syndrome; other autoimmune diseases; glomerulonephritis; serum sickness; urticaria, allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute respiratory and inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease; palmoplanteris Pustulosis; Hypoderma gangrenosum; Sezary syndrome; atopic dermatitis; systemic sclerosis; and morphea. The term "disease associated with leukocyte activation" or "leukocyte activation-mediated" as used herein includes each of the diseases or disorders referenced above. In a particular embodiment, the compounds of the present invention are useful for the treatment of the exemplary disorders mentioned above without regard to their etiology. The combined activity of the compounds presented to monocytes, macrophages, T cells, etc., may be useful in the treatment of any of the aforementioned disorders. Cannabinoid receptors are important in the regulation of gamma-Fc receptor responses of monocytes and macrophages. The compounds of the present invention inhibit the gamma Fc-dependent production of alpha TNF in human monocytes / macrophages. The ability to inhibit monocyte and macrophage dependent responses of the gamma Fc receptor results in additional anti-inflammatory activity for the compounds present. This activity is especially valuable, for example, in the treatment of inflammatory diseases such as arthritis or inflammatory bowel disease. In particular, the present compounds are useful for the treatment of autoimmune glomerulonephritis and other examples of glomerulonephritis induced by deposition of immune complexes in the kidney that cause gamma-Fc receptor responses that lead to kidney damage.

Cannabinoid receptors are expressed in lung epithelial cells. These cells are responsible for the secretion of mucins and inflammatory cytokines / chemokines in the lung and thus are intrinsically involved in the generation and progression of respiratory diseases. Cannabinoid receptor modulators regulate both spontaneous and stimulated production of both mucins and cytokines. Thus, the compounds are useful in the treatment of respiratory and pulmonary diseases including, COPD, ARDS, and bronchitis. In addition, cannabinoid receptors can be expressed in intestinal epithelial cells and hence regulate the production of mucin and cytosine and can be of clinical use in the treatment of inflammatory diseases related to the intestine. Cannabinoid receptors are also expressed in lymphocytes, a subset of leukocytes. Thus the cannabinoid receptor modulators will inhibit the activation, proliferation and differentiation of the T and B cells. Thus, the compounds will be useful in the treatment of autoimmune diseases involving any antibody or cell-mediated response such as multiple sclerosis and lupus. In addition, cannabinoid receptors regulate the induced degranulation of chemokine and epsilon Fc receptor of connective tissue cells and basophils. These play important roles in asthma, allergic rhinitis, and other allergic diseases. The epsilon FC receptors are stimulated by IgE antigen complexes. The compounds of the present invention inhibit the Fc epsilon induced degranulation responses, which include the basophil cell line, RBL. The ability to inhibit the basophil and cell-dependent connective tissue responses of the epsilon FC receptor results in additional anti-inflammatory and anti-allergic activity for the compounds present. In particular, the present compounds are useful for the treatment of asthma, allergic rhinitis, and other examples of allergic disease. Combinations The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of the formula I, alone or in combination with a pharmaceutical carrier or diluent. Optionally, the compounds of the present invention can be used alone, in combination with other appropriate therapeutic agents useful in the treatment of the aforementioned disorders including anti-obesity agents; antidiabetic agents, appetite suppressants; cholesterol-lowering agents / lipids, HDL-raising agents, cognition-enhancing agents, agents used for neurodegeneration treatment, agents used for treatment of respiratory conditions, agents used to treat bowel disorders, anti-inflammatory agents; anti-anxiety agents; antidepressants; anti-hypertensive agents; cardiac glycosides; and anti tumor agents. Other therapeutic agents may be administered before, concurrent with, or followed by the administration of the cannabinoid receptor modulators according to the invention. Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include melanocortin receptor agonists (MC4R), elanine concentration hormone receptor antagonists (MCHR), growth hormone secretagogue receptor antagonists (GHSR ), galanin receptor modulators, orexin antagonists, CCK agonists, GLP-1 agonists, and other peptides derived from Pre-proglucagon; NPY1 or NPY5 antagonists, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, modulators of histamine 3 receptor (H3), aP2 inhibitors, PPAR range modulators, delta PPAR modulators, acetyl-CoA carboxylase inhibitors (ACC), 11-ß-HSD-1 inhibitors, adinopectin receptor modulators, beta 3 adrenergic agonists, such as AJ9677 (Takeda / Dainippon), L750355 (merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Patent Nos. 5,541,204, 5,770,615, 5,451,134, 5,776,983 and 5,488,064, a thyroid receptor beta modulator, such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO 99/00353 (KaroBio ) and GB98 / 284425 (KaroBio), a lipase inhibitor, such as orlistat or ATL-962 (Alzyme), serotonin receptor agonists, (e.g., BVT-933 (Biovitrum)), monoamine reuptake inhibitors or agents of release, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermin, picilorex, sibutramine, dexamfetamine, phentermine, phenylpropanolamine or mazindol, anorectic agents such as topiramate (Johnson & Johnson), CNTF (ciliary neurotrophic factor) / Axokine® (Regeneron), BDNF (brain derived neurotrophic factor), leptin modulators and leptin receptor, or cannabinoid-1 receptor antagonists, such as SR-141716 (Sanofi) or SLV-319 (Solvay).

Examples of anti-diabetic agents suitable for use in combination with the compounds of the present invention include: insulin secretagogues or insulin synthesizers, which may include biguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductase inhibitors, PPAR agonists. such as thiazolidinediones, PPAR agonists or i (such as fibric acid derivatives), PPAR d agonists or agonists, PPAR double agonists a / ?, 11-β-HSD-1 inhibitors, dipeptidyl IV (DP4) peptidase inhibitors, SGLT2 inhibitors, glycogen phosphorylase inhibitors, and / or meglitinides, in addition to insulin, and / or glucagon-like peptide-1 (GLP-1), GLP-1 agonist, and / or an inhibitor of PTP-1B (inhibitor of tyrosine protein phosphates-IB). The antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HCl. Where the antidiabetic agent is a biguanide, the compounds of the present invention will be employed in a weight ratio for biguanide in the range of about 0.001: 1 to about 10; 1, preferably from about 0.01: 1 to about 5: 1. The antidiabetic agent may also preferably be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (listed in US Patent No. 4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents that act in the ATP-dependent channel of the beta cells, with glyburide and glipizide are preferred, which can be administered in the same oral or separate dosage forms. The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Patent No. 4,904,769) or miglitol (disclosed in U.S. Patent No. 4,639,436), which may be administered in the same or a separate oral dosage form. The compounds of the present invention can be used in combination with a PPAR? Agonist. such as an oral antidiabetic agent thiazolidinedione or other insulin synthesizers (which have an insulin-sensitive effect in NIDDM patients) such as rosiglitazone (SKB), pioglitazone (Takeda), MCC-555 from Mitsubishi (disclosed in U.S. Pat. 5,594,016), GL-262570 by Glaxo-Welcome, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT / J &J), JTT-501 (JPNT / P &U), L -895645 (Merck), R-119702 (Sankyo / WL), NN-2344 (Dr. Reddy / NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone The compounds of the present invention can be used with a PPAR a /? double agonist such as MK-767 / KRP-297 (Merck / Kyorin; as described in, K. Yajima, et al., Am. J. Physiol. Endocrinol. Metab., 284: E966-E971 (2003 )), AZ-242 (tesaglitazar, Astra-Zeneca, as described in B. Ljung, et al., J. Lipid Res., 43, 1855-1863 (2002)), muraglitazar, or the compounds described in the US Pat. USA No. 6,414,002. The compounds of the present invention can be used in combination with antihyperlipidemia agents, or agents used to treat arteriosclerosis. An example of a hypolipidemic agent may be a reductase inhibitor of HMG CoA which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. Patent No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Patent No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Patent Nos. 4., 448,784 and 4,450,171. Other HMG CoA reductase inhibitors that may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Patent No. 5,354,772, cerivastatin disclosed in U.S. Patent Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. USA 4,681,893, 5,273,995, 5,385,929 and 5,686,104, pitavastatin (Nissan / Sankyo nisvastatin (NK-104) or itavastatin), broken down in U.S. Patent No. 5,011,930, Shionogi-Astra / Zeneca rosuvastatin (visastatin (ZD-4522)) broken down into U.S. Patent No. 5,260,440, and related statin compounds disclosed in U.S. Patent No. 5,753,675, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Patent No. 4,613,610. indene analogs of mevalonolactone derivatives as disclosed in the PCT application WO 86/03488, 6- [2- (substituted pyrrol-1-yl) -alkyl] pyran-2-ones and derivatives thereof as disclosed in U.S. Patent No. 4,647,576, SC-45355 from Searle (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3-carboxy-2-acid derivatives hydroxy-propan-phosphonic as disclosed in French Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives as disclosed in European Patent Application No. 0221025, analogs of mevalonolactone naphthyl as disclosed in US Pat. U.S. Patent No. 4,686,237, Octahydronaphthalenes as disclosed in U.S. Patent No. 4,499,289, Mevinolin Keto Analogs (lovastatin) as disclosed in the Patent Application European No. 0,142,146 A2, and quinoline and pyridine derivatives listed in U.S. Patent Nos. 5,506,219 and 5,691,322. In addition, the phosphinic acid compounds useful in inhibition of HMG CoA reductase appropriate for use herein were disclosed in GB 2205837. Squalene synthetase inhibitors suitable for use herein include, but are not limited to, α-phosphono-sulfonates broken down in the U.S. Patent No. 5,712,396, those broken down by Biller, et al., ". Med. Chem., 31, 1869-1871 (1998) including isoprenoid (phosphinyl-methyl) phosphonates in addition to other known squalene synthetase inhibitors, by example, as disclosed in U.S. Patent Nos. 4,871,721 and 4,924,024 and in Biller, SA, Neue schwander, K., Ponpipom, MM, and Poulter, CD, Current Pharmaceutical Design, 2, 1-40 (1996). , other squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano, et al., J. Med. Chem., 20, 243-249 (1977), the farnesyl diphosphate analogue A and analogs of p Prescualene irosphate (PSQ-PP) as disclosed by Corey and Volante, J. Am. Chem. Soc. , 98, 1291-1293 (1976), phosphinylphosphonates reported by McClard, RW et al., J ". Am. Chem. Soc., 109, 5544 (1987) and cyclopropans reported by Capson, TL, PhD dissertation, June, 1987, Dept. Med. Chem. U of UTA, Summary, Table of Contents, pp. 16, 17, 40-43, 48-51, Compendium.

Other hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Patent No. 3,674,836, with probucol and gemfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (SECHOLEX, POLICEXIDE) and cholestagel (Sankyo / Geltex), in addition lipostabil (Rhone-Poulec), Eisai E-5050 (a N-substituted ethanolamine derivative), imanixyl (HOE-402), tetrahydrolipestatin. (THL), istigmastanilfos-forilcolina (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulen derivative), melinamide (Sumitomo), Sandoz (58-035, American Cyanamid CL-277.082 and CL-283,546 ( disubstituted urea derivatives), nicotinic acid (niacin), acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly (diallylmethylamine) derivatives as disclosed in U.S. Patent No. 4,759,923, poly (diallyldimethylammonium chloride) quaternary amine and ionene such as disclosed in US Patent No. 4,027,009, and other known serum cholesterol lowering agents.The other hypolipidemic agent may be an ACAT inhibitor (which also has anti-atherosclerosis activity) as it was broken down in, Drugs of the Future, 24, 9-15 (1999), (Avasimibe), "The ACAT inhibitor, Cl-1011 is effective in the prevention and regression of fatty acid streak area in hamsters", Nicolosi et al, Atherosclerosis ( Shannon, Go el), 137 (1), 77-85 (1998); "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoBlOO-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev., 16 (1), 16-30 (1998); "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor", Smith, C, et al., Bioorg. Med. Chem. Lett, 6 (1), 47-50 (1996); "ACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animáis", Karuse et al., Editor (s): Ruffolo, Robert R., Jr .; Hollinger, Mannfred A., Inflammation: Mediators Pathways, 173-98 (1995), Publisher: CRC, Boca Raton, Fia .; "ACAT inhibitors: potential anti-atherosclerotic agents", Sliskovic et al., Curr. Med Chem. , 1 (3), 204-25 (1994); "Inhibitors of acyl-CoA: Cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents 6. The first water-soluble ACAT inhibitor with lipid-regulating activity Inhibitors of acyl-CoA: Cholesterol acyltransferase (ACAT) 7. Development of a series of substituted N-phenyl-N'- [(1-phenylcyclopentyl) -methyl] ureas with enhanced hypocholesterolemic activity ", Stout et al., Chemtracts: Org. Chem., 8 (6), 359-62 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd), in addition to F-1394, CS-505, F-12511 ,. HL-004, K-10085 and YIC-C8-434. The hypolipidemic agent may be a higher regulator of LDL receptor activity such as MD-700 (Taisho Pharmaceutical Co., Ltd.) and LY295427 (Eli Lilly). The hypolipidemic agent can be a cholesterol absorption inhibitor preferably SCH48461 (ezetimibe) from Schering-Plow in addition to those broken down into Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998). The other lipid agent or lipid modulating agent can be a cholesteryl transfer protein (CETP) inhibitor such as CP-529,414 of Pfizer in addition to those disclosed in WO / 0038722 and EP 818448 (Bayer) and EP 992496, and SC-744 and SC-795 from Pharmacia, in addition to CETi-1 and JTT-705. The hypolipidemic agent may be a cotransporter inhibitor of NaVbiliar ileal acid as disclosed in Drugs of the Future, 24, 425-430 (1999). The ATP citrate lyase inhibitor which may be employed in the combination of the invention may include, for example, those disclosed in U.S. Patent No. 5,447,954. The other lipid agents also include a phytoestrogen compound as disclosed in WO 00/30665 - which includes isolated soy bean protein, concentrated soy protein and soybean meal in addition to an isoflavone such as genistein, daidzein, glycitein or equol, or phytosterols, phytostanol, or tocotrienol as disclosed in WO 200/015201; a beta-lactam cholesterol absorption inhibitor as broken down in EP 675714; an HDL top regulator such as an LXR agonist, a PPAR-OI agonist and / or an FXR agonist; an LDL catabolism promoter as broken down in EP 1022272; a sodium proton exchange inhibitor as disclosed in DE 19622222; an LDL receptor inducer or a spheroidal glycoside as disclosed in U.S. Patent No. 5,698,527 and GB 2304106; an antioxidant such as beta-carotene, ascorbic acid, α-tocopherol or retinol as disclosed in WO 94/15592 in addition to Vitamin C and antihomocysteine agent such as folic acid, a folate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid as disclosed in WO 97/35576; a cholesterol absorption inhibitor, a HMG-CoA synthase inhibitor, or a denostylase inhibitor of lanosterol as disclosed in WO 97/48701; a PPAR d agonist for treatment of dyslipidemia; or a sterol regulatory element that binds protein I (SREBP-1) as broken down in WO 2000/050574, for example, a sphingolipid, such as ceramide, or neutral sphingomyelinase (N-SMase) or fragment thereof. Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin and rosuvatatin, in addition to niacin and / or cholestagel. The compounds of the present invention can be used in combination with anti-hypertensive agents. Examples of suitable antihypertensive agents for use in combination with the compounds of the present invention include beta adrenergic blockers, calcium channel blockers (type L and / or type T, for example diltiazem, verapamil, nifedipine, amoldipine and mibefradil), diuretics (for example, chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid, tricinafen, chlorthalidone, furosemide, musolimine, bumetanide, triamthrenone, amiloride, spironolactone), renin inhibitors, ACE inhibitors (for example, captopril, zofenpril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (eg losartan, irbesartan, valsartan), ET receptor antagonists (eg, sitaxsentan) , backs and compounds disclosed in U.S. Patent Nos. 5,612,359 and 6,043,265), The double ET / AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptide inhibitors (NEP), vasopepsidase inhibitors (dual inhibitors) NEP-ACE) (for example, omapatrilat and gemopatrilat), and nitrates.

Cannabinoid receptor modulators may be useful in the treatment of other diseases associated with obesity, including sleep disorders. Therefore, the compounds described in the present invention can be used in combination with therapeutics for the treatment of sleep disorders. Examples of suitable therapies for the treatment of sleep disorders for use in combination with the compounds of the present invention include melatonin analogs, melatonin receptor antagonists, M 1 B agonists, GABA receptor modulators; modulators of NMDA receptor, histamine-3 (H3) receptor modulators, dopamine agonists and orexin receptor modulators. Cannabinoid receptor modulators can reduce or lessen substance abuse or addictive disorders. Therefore, the combination of cannabinoid receptor modulators with agents used to treat addictive disorders may reduce the dose requirement or improve the efficacy of current addictive disorder therapeutics. Examples of agents used to treat substance abuse or addictive disorders are: selective serotonin reuptake inhibitors (SSRI), methadone, buprenorphine, nicotine and bupropion. Cannabinoid receptor modulators can reduce anxiety or depression; therefore, the compounds described in this application can be used in combination with anti-anxiety agents or antidepressants. Examples of anti-anxiety agents suitable for use in combination with the compounds of the present invention include benzodiazepines (eg, diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam, clorazepate, halazepam and prazepam), 5HT1A receptor agonists (e.g. , buspirone, flesinoxan, gepirone and ipsapirone), and corticotropin releasing factor (CRF) antagonists. Examples of appropriate classes of antidepressants for use in combination with the compounds of the present invention include norepinephrine reuptake inhibitors. (tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRI) (Fluoxetine, fluvoxamine, paroxetine and sertraline), monoamine oxidase inhibitors (MAOI) (isocarboxazid, phenelzine, tranylcipromine, selegiline), reversible oxidase inhibitors of monoamine (RIMA) (oclobemide), reuptake inhibitors of serotonin and norepinephrine (SNRI) (venlafaxine), corticotropin-releasing factor receptor (CRF) antagonists, alpha-adrenoreceptor antagonists, and atypical antidepressants (bupropion, lithium, nefazodone , trazodone and viloxazine). The combination of a conventional antipsychotic drug with a CB-1 receptor antagonist can also improve the reduction of the symptom in the treatment of psychosis or mania. In addition, such a combination can make possible the reduction of the rapid symptom, reducing the need for chronic treatment with antipsychotic agents. Such a combination may also reduce the requirement for effective antipsychotic dose, resulting in reduced likelihood of development of the common motor dysfunction of chronic antipsychotic treatment. Examples of suitable antipsychotic agents for use in combination with the compounds of the present invention include the phenothiazine classes (chlorpromazine, mesoridazine, thioridazine, acetophenazine, fulfenazine, perphenazine and trifluoperazine), thioxanthine (chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine, olanzepine). and aripiprazole), butyrophenone (haloperidol), diphenylbutylpiperidine (pimozide) and indole (molindolone) of antipsychotic agents. Other antipsychotic agents with potential therapeutic value in combination with the compounds of the present invention include loxapine, sulpiride and risperidone. The combination of the compounds in the present invention with conventional antipsychotic drugs may also provide an improved therapeutic effect for the treatment of schizophrenic disorders, as described above for manic disorders. As used herein, schizophrenic disorders include paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia, schizophreniform disorder, schizoaffective disorder, disilusional disorder, brief psychotic disorder and psychotic disorder not otherwise specified. Examples of antipsychotic drugs suitable for combination with the compounds of the present invention include the antipsychotics mentioned above, in addition to dopamine receptor antagonists, muscarinic receptor agonists, 5HT2A receptor antagonists and 5HT2A / dopamine receptor antagonists or partial agonists (eg, example, olanzepine, aripiprazole, risperidone, ziprasidone). The compounds described in the present invention can be used to improve the effects of cognition enhancing agents, such as acetylcholinesterase inhibitors (e.g., tacrine), muscarinic receptor-1 agonists (e.g., milamelin), nicotinic agonists, modulators of glutamic acid receptor (AMPA and NMDA), and nootropic agents (for example, piracetam, levetiracetam). Examples of appropriate therapies for the treatment of Alzheimer's disease and cognitive disorders for use in combination with the compounds of the present invention include donepezil, tacrine, revastigraine, 5HT6, gamma secretase inhibitors, beta secretase inhibitors, SK channel blockers, Maxi blockers. -K, and KCNQ blockers. The compounds described in the present invention can be used to improve the effects of agents used in the treatment of Parkinson's disease. Examples of agents used to treat Parkinson's disease include: levadote with or without a COMT inhibitor, anti-glutamatergic drugs (amantadite, riluzole), alpha-2 adrenergic antagonists such as idazoxan, opioid antagonists, such as naltrexone, other dopamine agonists or modulators of carrier, such as ropinirole, or pramipexole or neurotrophic factors such as glial derived neurotrophic factor (GDNF). The compounds described in the present invention can be. used in combination with appropriate anti-inflammatory agents. Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include prednisone, dexamethasone, cyclooxygenase inhibitors (i.e., COX-1 and / or COX-2 inhibitors such as NSAID, aspirin, indomethacin, ibuprofen , piroxicam, Naproxen®, Celebrex®, Vioxx®), CTLA4-Ig agonists / antagonists, CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate (CellCept®), integrin antagonists, integrin alpha-4 beta-7 antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, tumor necrosis factor (TNF) antagonists (eg, infliximab, OR1384, which includes TNF-alpha inhibitors, such as tenidap, anti-TNF antibodies or Soluble TNF such as etanercept (Enbrel®), rapamycin (sirolimus or Rapamune) and lefunomide (Arava)), synthesis inhibitors of prostaglandin, budesonide, clofazimine, CNI-1493, CD4 antagonists (eg, priliximab), inhibitor is of activated p38 mitogen protein kinase, protein tyrosine kinase (PTK) inhibitors, and therapies for the treatment of irritable bowel syndrome (e.g., Zelnorm ® and MAxi-K® openers such as those disclosed in the patent) of US No. 6,184,231 Bl). Examples of such other therapeutic agents that can be used in combination with cannabinoid receptor modulators include the following: cyclosporins (eg, cyclosporin A), anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti- CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody 0KT3, agents that block the interaction between CD40 and gp39, such as antibodies specific for CD40 and / or gp39 (this is , CD154), fusion proteins constructed of CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), gold compounds, antiproliferative agents such as meotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathiprine and cyclophosphamide, anticytokines such as anti-IL-4 or IL-4 receptor fusion proteins and PDE inhibitors 4 such as Ariflo, and the PTK inhibitors broken down in the following U.S. Patent Applications incorporated herein by reference in their entirety: Ser. No. 09 / 097,338, filed June 15, 1998; Ser. No. 09 / 094,797, filed on June 15, 1998; Ser. No. 09 / 173,413, filed on October 15, 1998; and Ser. No. 09 / 262,525, filed March 4, 1999. See also the following documents and references cited therein and incorporated herein by reference: Hollengaugh, D., et al., "Cleavable CD40lg Fusion Proteins and the Binding to Sgp39", J. Immunol. Methods (Netherlands), 188 (1), pp. 1-7 (Dec. 15, 1995); Hollengaugh, D. et al., "The Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Is a Ligand for the CD40 Recipient: Expression of a Soluble Form of GP39 with B Cell Co-Stimulatory Activity", EMBO J ( England), 11 (12), pp. 4313-4321 (December 1992); and Moreland, L. W. et al., "Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Receptor Factor (P75) -Fc Fusion Protein," New England J. or f Medicine, 337 (3), pp. 141-147 (1997). The other therapeutic agents above, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physician's Desk Referrer (PDR) or as otherwise determined by an expert. ordinary in the art. The compounds of the formula (I) of the invention can be administered orally or parenterally, as well as subcutaneously or intravenously, in addition to by nasal application, rectally or sublingually to various mammalian species known to be subject to such conditions, for example, humans. , in an effective amount of up to 1 gram, preferably up to 200 mg, more preferably up to 100 mg in a regimen of one, two or four divided doses during the day. The compounds of the formula (I) can be administered by any of the uses described herein by any appropriate means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally parenterally, as well as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, as well as by inhalation of spray; externally, such as in the form of a cream or ointment; or rectally as in the form of suppositories; in dosage unit formulations containing pharmaceutically acceptable, non-toxic vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of pharmaceutically appropriate compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomally. Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose to impart volume, alginic acid or sodium alignate as a suspending agent, methylcellulose as a viscosity improver, and sweetening or flavoring agents such as those known in the art. The technique; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and / or lactose and / or other excipients, binders, builders, disintegrants, diluents and lubricants such as those known in the art. The compounds of the formula (I) can also be delivered through the oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms that can be used. Exemplary compositions include those formulations of the present compounds with fast dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. High molecular weight excipients such as celluloses (avicel) or propylene glycols (PEG) may also be included in such formulations. Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g. , Gantrez), and agents to control the release such as polyacrylic copolymer (e.g., Carbopol 934). Lubricating agents, glidants, seasonings, colorants and stabilizers can also be added for ease of manufacture and use. Exemplary compositions for nasal spray or administration by inhalation include saline solutions which may contain, for example, benzyl alcohol and other suitable preservatives, absorption promoters to improve biocapacity, and / or other solubilization or dispersing agents such as those known in the technique. Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution , or other suitable dispersing or humidifying and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including fatty acids, or Cremafor. Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at normal temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug. Exemplary compositions for external administration include an external carrier such as Plastibase (mineral oil gelled with polyethylene). It will be understood that the specific dose level and frequency of dosing for any particular subject may be varied and will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and the period of action of that compound, the species , age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, combination of the drug, and severity of the particular condition. It should be understood that while this invention has been described herein in terms of specific embodiments set forth in detail, such embodiments are presented by way of illustration of the general principles of the invention, and the invention is not necessarily limited thereto. Certain modifications and variations in any given material, process step or chemical formula will be readily apparent to those skilled in the art without departing from the true spirit and scope of the present invention, and all modifications and variations should be considered within the scope of claims that follow. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (73)

1. R E I V I N D I C A I N N E S Having described the invention as above, the content of the following claims is claimed as property: 1. The compound of the formula I I including all pharmaceutically acceptable salts and stereoisomers, characterized in that: R1 is selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy , NR8R9, C02R8, -CONR8R9, -OR8, NR8COR9, -NR8CONR8R9, -NR8C02R9, -OCONR8R9, -NR8S (0) pR9, -NR8S (0) pNR8R9, -NR8S (0) pOR9 and -OS (0) pNR8R9; R2 is selected from the group consisting of halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, NR8R9, C02R8, -CONR8R9, -OR8, NR8COR9, -NR8CONR8R9, -NR8C02R9, -OCONR8R9, -NR8S (0) pR9, -NR8S (0) pNR8R9, -NR8S (0) pOR9 and -OS (0) pNR8R9; R3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R4 is absent when n is a double bond; R 4 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, when n is a single bond; R5 is selected from the group consisting of halogen, -OR8, -NR8R9, -0C0NR8R9, -NCR8, -NC02R8 and -NR8S (0) pR9 when m is a double bond. wherein the group R5 has a molecular weight of less than 200 atomic mass units; R5 is O when m is a double bond; R8 and R9 are independently selected from H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl; R8 and R9 taken together can form a 4, 5, 6 or 7-membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; and m is a single or double bond n is a single or double bond; when m is a simple link, n is a double bond; when m is a double bond, n is a single bond; and p is an integer of 1 or 2. The compound according to claim 1, characterized in that: R1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy , heteroaryloxy, -OR8 and -NR8R9; R2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R 4 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R5 is O and R are independently selected from H, alkyl, arylalkyl, cycloalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl; R8 and R9 taken together can form a 4, 5, 6 or 1 membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; and m is a double bond and n is a single bond. 3. The compound according to claim 2 characterized in that: R1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R 2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, OR8 and NR8R9. R3 is selected from the group consisting of H alkyl, cycloalkyl, and heterocyclyl R4 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R5 is O; R8 and R9 are independently selected from H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl; R8 and R9 taken together can optionally form a 4, 5, 6 or 7-membered heterocyclyl ring or a 5- or 6-membered heteroaryl ring; and m is a double bond and n is a single bond; 4. The compound according to claim 3, characterized in that: R2 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, OR8 and NR8R9. 5. The compound according to claim 4, characterized in that: R1 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, OR8 and NR8R9. 6. The compound according to claim 5, characterized in that: R4 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. The compound according to claim 1, characterized in that: R1 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, OR8 and NR8R9; R2 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, OR8 and NR8R9; R3 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; R 4 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroalkyl and heteroarylalkyl; R5 is O; R8 and R9 are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, and heteroarylalkyl; R8 and R9 can together form a heterocyclyl ring of 4, 5, 6 or 7 members or a 5 or 6 membered heteroaryl ring; m is a double bond; and n is a simple link. 8. The compound according to claim 1, characterized in that: R1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R2 is selected from the group consisting of cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R 4 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl; R5 is O; R8 and R9 are independently selected from H, alkyl, arylalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl and heteroarylalkyl; R8 and R9 can together form a heterocyclyl ring of 4, 5, 6 or 7 members or a 5 or 6 membered heteroaryl ring; m is a double bond; and n is a simple link. 9. The compound according to claim 8, characterized in that: R 2 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR 8, and -NR 8 R 9. The compound according to claim 9, characterized in that: R1 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9. The compound according to claim 10, characterized in that: R3 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. The compound according to claim 1, characterized in that: R1 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R2 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R3 is selected from the group consisting of H, alkyl. cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; R 4 is selected from the group consisting of H and alkyl, R 5 is 0; R8 and R9 are independently selected from H, alkyl, arylalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl and heteroarylalkyl; R8 and R9 can together form a heterocyclyl ring of 4, 5, 6 or 7 members or a 5 or 6 membered heteroaryl ring; m is a double bond; and n is a simple link. The compound according to claim 1, characterized in that: R1 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R2 is selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R4 is absent; R5 is selected from the group consisting of halogen, -OR8, -NR8R9, -OCONR8R9, -NCR8, -NC02R8, -NR8S (0) PR9 when m is a single bond, wherein the group R5 has a molecular weight of less than 200 units of atomic mass; R8 and R9 are independently selected from H, alkyl, arylalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl and heteroarylalkyl; R8 and R9 can together form a heterocyclyl ring of 4, 5, 6 or 7 members or a 5 or 6 membered heteroaryl ring; m is a double bond; and i n is a simple link. 14. The compound in accordance with the claim 13, characterized in that: R2 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8, and -NR8R9. 15. The compound in accordance with the claim 14, characterized in that: R1 is selected from the group consisting of heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxy, heteroaryloxy, -OR8, and -NR8R9. 16. The compound according to claim 15, characterized in that: R3 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. 17. The compound according to claim 16, characterized in that: R5 is selected from the group consisting of -OR8 and -NR8R9; wherein the group R5 has a molecular weight of less than 200 atomic mass units. 18. The compound according to claim 1 characterized in that: R1 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R2 is selected from the group consisting of aryl, heteroaryl, aryloxy, heteroaryloxy, -OR8 and -NR8R9; R3 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl; R5 is selected from the group consisting of -OR8, -NR8R9, wherein the group R5 has a molecular weight of less than 200 atomic mass units; R8 and R9 are independently selected from the group consisting of H, alkyl, arylalkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl and heteroarylalkyl; R8 and R9 can together form a heterocyclyl ring of 4, 5, 6 or 7 members or a 5 or 6 membered heteroaryl ring; m is a double bond; and n is a simple link. 19. The compound according to claim 1, characterized in that it is selected from: 25 25 20. The compound according to claim 1, characterized in that: 25 25 21. The compound according to claim 1, characterized in that: 22. A pharmaceutical composition, characterized in that it comprises: at least one compound according to claim 1; and at least one pharmaceutically acceptable diluent or carrier. 23. A pharmaceutical composition, characterized in that it comprises: at least one compound according to claim 1; at least one other therapeutic agent; and at least one pharmaceutically acceptable diluent or carrier 24. A method for treating a cannabinoid receptor-mediated disease or disorder, characterized in that it comprises: administering to the patient in need of treatment a therapeutically effective amount of the compound according to claim 1. A pharmaceutical combination, characterized in that it comprises a pharmaceutical composition according to claim 22 and a therapeutic agent selected from anti-obesity agents; appetite suppressants; antidiabetic agents; anti-hyperlipidemia agents; hypolipidemic agents; hypocholesterolemic agents; lipid modulating agents; cholesterol reducing agents; lipid reducing agents; agents that raise HDL; agents • anti-hypertension; agents used to treat sleeping disorders; agents used to treat substance abuse and addictive disorders; anti-anxiety agents; anti-depressants; anti-psychotic agents; agents that increase cognition; agents used to treat cognitive disorders; agents used to treat Alzheimer's disease; agents used to treat Parkinson's disease; anti-inflammatory agents; agents used to treat neurodegeneration; agents used to treat atherosclerosis; agents used to treat respiratory conditions; agents used to treat bowel disorders; cardiac glycosides; and anti-tumor agents. 26. The pharmaceutical combination according to claim 25, characterized in that the other therapeutic agent can be administered before, simultaneously with, or after administration of the pharmaceutical composition of claim 22. 27. The pharmaceutical combination according to the claim 25, characterized in that the anti-obesity agent is selected from melanocortin receptor agonists (MC4R); antagonists of the hormone receptor that concentrates melanin (MCHR); antagonists of the growth hormone secretagogue receptor (GHSR); Galanin receptor modulators; orexin antagonists; CCK agonists; GLP-1 agonists and other peptides derived from pPre-proglucagon; NPY1 or NPY5 antagonists; modulators NPY2 and NPY4; agonists of the corticotropin releasing factor; modulators of histamine-3 receptor (H3); aP2 inhibitors; PPAR gamma modulators; PPAR delta modulators; acetyl carboxylase inhibitors CoA (ACC); 11-ß-HSD-1 inhibitors; adiponectin receptor modulators; β 3 adrenergic agonists, including AJ9677, L750355 and CP331648 or other known beta 3 agonists; beta modulator of the thyroid receptor; lipase inhibitors, which include orlistat and ATL-962; serotonin receptor agonists, including BVT-933; inhibitors or moniamine resorption-releasing agents, including fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermin, picilorex, sibutrmine, dexamfeta ina, phentermine, phenylpropanolamine and mazindol; anorectic agents, including topiramate; ciliary neurotrophic factor, including Axokina; neurotrophic factor derived from the brain; modulators of leptin and leptin receptor and other cannabinoid-1 receptor antagonists, including SR-141716 and SLV-319. 28. The pharmaceutical combination according to claim 25, characterized in that the antidiabetic agent is selected from insulin secretagogues; insulin sensitizers; anti-hypeglycemic agents; biguanides; sulfonyl ureas; glucosidase inhibitors; inhibitors of aldose reductase; PPAR agonist? which include thiazolidinediones; PPAR agonists or, including fibric acid derivatives; PPAR agonists or PPAR agonists PPAR a / ?; inhibitors 11-ß-HSD-l dipeptidyl peptidase IV inhibitors; SGLT2 inhibitors of glycogen phosphorylase inhibitors; meglitidines; insulin peptide 1 type glucagon; glucagon type 1 peptide agonists; and inhibitors of protein tyrosine phosphatase-IB. 29. The pharmaceutical combination according to claim 28, characterized in that the anti-diabetic agent is an oral anti-hyperglycemic agent selected from biguanides, metformin, performin, metformin HCl and other salts thereof. 30. The pharmaceutical combination according to claim 29, characterized in that the other therapeutic agent is the biguanide and the compound of claim 1 will be administered in a weight ratio to the biguanide in the range from about 0.001: 1 to about 10: 1 The pharmaceutical combination according to claim 28, characterized in that the sulfonyl urea is selected from glyburide, glibenclamide, glimepiride, glipizide, glycoside, chlorpropamide, other known sulfonylureas or other antihyperglycemic agents that act on the ATP-dependent channel of the cells beta. 32. The pharmaceutical combination according to claim 31, characterized in that the combination of the compound of claim 1 and the sulfonyl urea is administered in the same or in separate oral dosage forms. 33. The pharmaceutical combination according to claim 28, characterized in that the glucosidase inhibitor is selected from acarbose and miglitol. 34. The pharmaceutical combination according to claim 33, characterized in that the combination of the compound of claim 1 and the glucosidase inhibitor is administered in the same or in separate oral dosage forms. 35. The pharmaceutical combination according to claim 28, characterized in that the PPAR? Agonist. is an oral anti-diabetic agent of thiazolidinedione. 36. The pharmaceutical combination according to claim 28, characterized in that the insulin sensitizer is selected from rosiglitazone, pioglitazone, MCC-555, GL-262570, englitazone, darglitazone, isaglitazone; JTT-501, L-895645, -R119702, NN-2344 and YM-440. 37. The pharmaceutical combination according to claim 28, characterized in that the dual PPAR agonists a /? they are selected from MK-767 / KRP-297, tesaglitazar and muraglitazar. 38. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an inhibitor of the HMG CoA reductase selected from mevastatin; compounds related to mevastatin; lovastatin; Mevinolin; compounds related to lovastatin and mevinolin; pravastatin and compounds related to pravastatin; simvastatin and compounds related to simvastatin; fluvastatin; cerivastatin; atorvastatin; pitavastatin; nisvatatin; itavastatin; rosuvastatin; visastatin; compounds related to rosuvastatin and visastine; pyrazole analogues derived from mevalonolactone; indene analogues; mevalonolactone derivatives; 6 [-2-substituted-pyrrol-1-yl) alkyl) iran-2-ones- and derivatives thereof; SC-45355; substituted pentandioic acid derivatives 3; dichloroacetate; imidazole analogues of mevalonolactone; 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives; 2,3-substituted pyrrolo, furan and thiophene derivatives; mevalonolactane naphthyl analogs; octahydronaphthalenes; keto analogs of lovastatin and mevinolin; quinoline and pyridine derivatives; and phosphinic acid compounds. 39. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an inhibitor of the squalene synthetase selected from α-phosphono-sulfonate; isoprenoid phosphates (phosphinyl-methyl); Analog A of famesyl of disphosphate and pyrophosphate analogues prescualen; phosphinyl phosphonates; and cyclopropanes. 40. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is a fibric acid derivative selected from fenofibrate; gemfibrozil; clofibrate; bezafibrate; ciprofibrate; clinofibrate; probucol; and compounds related to probucol. 41. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is a bile acid sequestrant selected from cholestyramine; colestipol; DEAE-Sephadex; Secholex; Policexido; cholestagel; lipostabil; E-5050; N-substituted ethanolamine derivatives; imanixil; tetrahydrolipstatin; istagmastanilfos-porylcholine; aminocyclodextrin; AJ-814; azulena derivatives; melinamide; 58-035; CL-277,082; CL-283,546; disubstituted urine derivatives; nicotinic acid; niacin; acipi ox; acifran; neomycin; p-aminosalicylic acid; aspirin; poly (diallylmethylamine) derivatives; poly (diallylmethylammonium) chloride of quaternary amine; ionones; and other known serum cholesterol lowering agents. 42. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an acyl CoA-Cholesterol 0-acyl transferase inhibitor selected from substituted N-phenyl-N '- [(1-phenylcyclopentyl) ethyl] ureas; TS-962; F-1394; CS-505; F-12511; HL-004; K-10085; and YIC-C8-434. 43. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an up-regulator of LDL receptor activity that includes MD-700. 44. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an inhibitor of cholesterol absorption that includes ezetimibe. 45. The pharmaceutical combination according to claim 25, characterized in that the lipid modulating agent is an inhibitor of the transferase cholesterol protein selected from CP-529,414; SC-744; SC-795; CETi-1; and JTT-705. 46. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an inhibitor of the co-transport of Na + ileal / biliary acid. 47. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is an inhibitor of citrate lyase ATP. 48. The pharmaceutical combination according to claim 25, characterized in that the lipid-modulating agents are selected from the selected phytoestrogen compound of isolated soy bean protein, soy protein concentrate, soybean meal, isoflavone, genistein, daidzain, glycitein or ecol, or phytosterols, phytostanol and tocotrienol; an inhibitor of beta-lactam cholesterol absorption; a regulated HDL envelope selected from an LXR agonist, a PPAR agonist and an FXR agonist; a promoter of LDL catabolism; an inhibitor of sodium-proton exchange; an inducer of the LDL receptor; steroidal glycoside; an antioxidant selected from beta-carotene, ascorbic acid, α-tocopherol, ret ol, vitamin C antihomocysteine agent, folic acid, folate, vitamin B6, vitamin B12 and vitamin E; isoniazid; an inhibitor of cholesterol absorption; an HMG-CoA synthase inhibitor; a lanosterol demethylase inhibitor; a PPAR d agonist to treat dyslipidemia; a regulatory element of the sterol linked to protein I selected from neutral espingolipid, ceramide, espingomyellenase or fragments thereof. 49. The pharmaceutical combination according to claim 25, characterized in that the hypolipidemic agent is selected from pravastatin; lovastatin; simvastatin; atorvastatin; Flovastatin; pitavastatin; rosuvastatin; niacin and cholestagel. 50. The pharmaceutical combination according to claim 25, characterized in that the anti-hypertensive agents are selected from beta-adrenergic blockers; blockers of L-type channels selected from diltiazem, verapamil, nifedipine, amlodipine and mibefradil; T-type calcium blockers selected from diltiazem, verapamil, nifedipine, amlodipine and mibefradil; diuretics selected from chlorothiazide, hydrochlorothiazide, flumetiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricinafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride and spironolactone, renin inhibitors; ACE inhibitors selected from captopril, zofenopril, nopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril and lisinopril; AT-1 receptor antagonists selected from losartan, irbesartan and valsartan; ET receptor antagonist selected from sitaxsentan and atrsentan; Dual ET / AII antagonists; inhibitors of the neutral endopeptidase; vasopeptidase inhibitors and dual NEP-ACE inhibitors selected from omapatrilat and gemopatrilat; and nitrates.- 51. The pharmaceutical combination according to claim 25, characterized in that the agent used to treat sleeping disorders is selected from melatonin analogues; Melatonin receptor antagonists; ML 1 B agonists; modulators of the GABA receptor; NMDA receptor modulators; modulators of the histamine-3 receptor (H3); Dopamine agonists and orexin receptor modulators. 52. The pharmaceutical combination according to claim 25, characterized in that the agent used to treat the abuse of addictive substances and disorders is selected from selective serotonin reuptake inhibitors; methadone; buprenofine; nicotine and bupropion. 53. The pharmaceutical combination according to claim 25, characterized in that the anti-anxiety agent is selected from benzodiazepines selected from diazepam, lorazepam, oxazepam, alprazolam, chlordiazapoxide, clonazepam, halazepam and prazepam; 5HT1A receptor agonists selected from buspirone, flesinoxan, gepirone and ipsapirone; and antagonists of the factor that releases corticotropin. 54. The pharmaceutical combination according to claim 25, characterized in that the antidepressant agent is selected from norepinephrine reuptake inhibitors selected from tertiary and secondary tricyclic amines; selective serotonin reuptake inhibitors selected from fluoxetine, fluvoxamine, paroxetine and sertalin; monoamine oxidase inhibitors selected from isocarboxiazide, phenee, tranylcypromine and selegiline; reversible inhibitors of monoamine oxidase including moclobemide; serotonin and norepinephrine reuptake inhibitors including venlafaxine; antagonists of the factor receptor that releases corticotropin; alpha-adrenoreceptor antagonists; and selected atypical antidepressants of bupropion, lithium, nefazodone, trazodone and viloxazine. 55. The pharmaceutical combination according to claim 25, characterized in that the antipsychotic agent is selected from phenothiazine selected from chloropromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine; thioxanthin selected from chlorprothixene and thiothixene; heterocyclic dibenzazepine selected from clozapine, alanzepine and aripiprazole; butyrophenone, including haloperidol; dif enylbutylpiperidine, including pimazide; indole and molindolone classes of anti-psychotic agents; loxapine; sulpiride; risperidone; Dopamine receptor antagonists; muscarinic receptor agonists; 5HT2A receptor antagonists, 5HT2A / dopamine receptor antagonists and partial agonists are selected from olanzepine, aripiprazole, risperidone and ziprasidone. 56. The pharmaceutical combination according to claim 25, characterized in that the cognition enhancing agent is selected from acetylcholinesterase inhibitors, including tacrine; muscarinic receptor 1 agonists, including milamelin; nicotinic agonists; modulators of the glutamic acid receptor; and selected nootropic agents of piraceta and levetiracetam. 57 The pharmaceutical combination according to claim 25, characterized in that the agent used to treat Alzheimer's disease and the agent used to treat cognitive disorders are selected from donepezil; tacrine; revastigraine; 5HT6; inhibitors of gamma secretase; inhibitors of beta secretase; SK channel blockers; Maxi-K blockers; and KCNQ blockers. 58 The pharmaceutical combination according to claim 25, characterized in that the agent used to treat Parkinson's disease is selected from levadopa with or without a COMT inhibitor; antiglutamatergic drugs selected from amantadine and riluzole; alpha-2 adrenergic antagonists including idazoxan; opiate antagonists including naltrexone; other dopamine agonists and carrier modulators including ropinirole; and pramipexole or neutrophilic factors that include the neutrophilic factor derived from the gial. 59. The pharmaceutical combination according to claim 25, characterized in that the anti-inflammatory agent is selected from prednisone; dexamethasone; cyclooxygenase inhibitors including COX-1 and COX-2 inhibitors selected from NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen, Celebrex and Vioxx; CTLA4-Ig agonists and antagonists; antagonists of the CD40 ligand; IMPDH inhibitors that include mycophenolate; integrin antagonists; alpha-4 beta-7 integrin antagonists; inhibitors of cell adhesion; interferon gamma antagonists; ICAM-1; tumor necrosis factor antagonists selected from infliximab, OR1384, TNF-alpha inhibitors including tenidap, anti-TNF antibodies or solvable TNF receptors including etanercept; Rapacinin selected from Sirolimus and Rapamune; eflunomide; inhibitors of prostaglandin synthesis; budesonide; clofazimine; CNI-1493; CD4 antagonists that include priliximab; protein kinase inhibitors activated by the p38 mitogen; - protein tyrosine kinase inhibitors; IKK inhibitors; and agents for the treatment of irritable bowel syndrome selected from Zelnorm and Maxi-K openers. 60. The pharmaceutical combination according to claim 25, characterized in that the other therapeutic agent is selected from cyclosporins; cyclosporin A; anti-IL-2 receptor; anti-CD45RB; anti-CD2; anti-CD3 (OKT-3); anti-CD4; anti-CD80; anti-CD86; monoclonal antibody OKT3; agents that block the interaction between CD40 and gp39; antibodies specific for CD40 and / or gp39; CD154; fusion proteins constructed of CD40 and gp39; CD40lg; CD8gp39; inhibitors of the nuclear translocation of the NF-kappa B function; deoxyspergualin; gold compounds; antiproliferantse agents selected from methotrexate, FK506, tacrolimus, prograf and mycophenolate mofetil; cytotoxic drugs selected from azathiprine and cyclophosphamide; anticytokines selected from fusion proteins of the anti-IL-4 or IL-4 receptor; PDE 4 inhibitors including Ariflo and PTK inhibitors. 61. The method according to claim 24, characterized in that the disease or disorders are associated with CB-1 receptor activity. 62. The method according to claim 61, characterized in that the diseases or disorders are bulimia, obesity or any disease that results in the patient belonging to overweight. 63. The method according to claim 61, characterized in that the diseases or disorders are metabolic disorders, eating disorders and appetite disorders, which includes the treatment of conditions associated with those disorders, such as obesity, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disease, hypertension, insulin resistance, hypercholesterolemia, hyperglyceridemia, cholelithiasis and sleep disorders, hyperlipidemic conditions, bulimia nervosa and compulsive eating disorders. 64. The method according to claim 61, characterized in that the diseases or disorders are obesity due to genetic or environmental causes, including bulemia and excess food, polycystic disease of the ovaries, craniopharynxoma, Prader-Willi syndrome, Frohlich syndrome , type II diabetes, growth hormone deficiency, Turner syndrome and other pathological conditions characterized by reduced metabolic activity or reduced energy expenditure. 65. The method according to claim 61, characterized in that the diseases or disorders are psychiatric disorders selected from substance abuse, addictive disorders, depression, anxiety, mania and schizophrenia. 66. A method for the improvement of cognitive function and memory deficiency, including the treatment of selected diseases of dementia, Alzheimer's disease, short-term memory loss and disorders in attention deficit, neurodegenerative disorders, malignancy Parkinson's, cerebral apoplexy and craniocerebral trauma, hypotension, endotoxin-induced and hemorrhagic hypotension, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, head trauma, and cognitive decline related to age, characterized because comprises administering to a mammal species in need of treatment, a therapeutically effective amount of a compound as defined in claim 24. 67. A method for the treatment of diseases associated with dysfunction of brain dopaminergic systems including Parkinson's and substance abuse disorders, characterized by which comprises administering to a mammalian species in need of treatment, a therapeutically effective amount of a compound as defined in accordance with claim 24. 68. A method for the treatment of diseases selected from catabolism in connection with pulmonary dysfunction and ventilator dependence, cardiac dysfunction, valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure; transplant rejection, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, lupus, graft-versus-host disease, T cell-mediated hypersensitivity disease, psoriasis, asthma, Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic rhinitis and ischemic or reperfusion injury, characterized in that it comprises administering to a mammalian species in need of treatment, a therapeutically effective amount of a compound as defined in accordance with claim 24. 69. A method for the treatment of abuse of substances or disorders of dependence in which substances of abuse or dependence include alcohol, amphetamines, amphetamine-like substances, caffeine, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, phencyclidine-type compounds, sedative hypnotics, benzodiazepines, other substances known or unknown, or combines Substances of abuse, characterized in that it comprises administering to a species of mammals in need of treatment, a therapeutically effective amount of a compound as defined in accordance with claim 24. 70. The method according to claim 69 , characterized in that substance abuse or dependence can occur without physiological dependence. 71. A method of treating withdrawal symptoms of alcohol or drugs and anxiety induced by mood substances or disorders with onset during withdrawal, characterized in that it comprises administering to a species of mammals in need of treatment, a therapeutically effective amount of a compound as defined in accordance with claim 24. 72. A method for the treatment of disorders associated with the activation of leukocytes, including rejection due to organ transplants, acute transplantation, xenotransplantation, heterograft or homograft; protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes; transplant tolerance induction; rheumatoid arthritis, psoriatic arthritis or osteoarthritis; multiple sclerosis, chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, and acute respiratory distress syndrome (ARDS); Inflammatory bowel disease, ulcerative colitis and Crohn's disease, systemic lupus erythematosus; graft versus host disease; T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, gluten-sensitive enteropathy and Celiac disease; psoriasis, contact dermatitis; Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, such as Graves' disease; Addison's disease, polyglandular autoimmune disease or syndrome; autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain Barre syndrome; other autoimmune diseases; glomerulonephritis; serum sickness; hives, asthma, hay fever, allergic rhinitis and skin allergies; scleracierma; mycosis fungoides; acute respiratory and inflammatory responses, including acute respiratory distress syndrome and ischemia / reperfusion injury; dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease; palmoplanteris Pustulosis; Pyoderma gangrenum; Sezary syndrome; atopic dermatitis; systemic sclerosis; and morphea, characterized in that it comprises administering to a mammalian species a therapeutically effective amount of a compound as defined in claim 24. 73. A method for the treatment of inflammatory diseases, including arthritis, inflammatory bowel disease and autoimmune glomerulonephritis. , characterized in that it comprises administering to a mammalian species in need of treatment, a therapeutically effective amount of a compound as defined in accordance with claim 24.