# Patent

## Title
Azabicyclic heterocycles as cannabinoid receptor modulators

## 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 and Formula II:




including all prodrugs, pharmaceutically acceptable salts and stereoisomers, R1, R2, R3 and R4 are described herein.

## Background
RELATED APPLICATION
This application claims priority benefit under Title 35 § 119(e) of U.S. Provisional Application No. 60/692,034, filed Jun. 17, 2005, the contents of which are herein incorporated by reference.


BACKGROUND
Delta-9-tetrahydrocannabinol or Delta-9 THC, the principle active component of Cannabis sativa (marijuana), is a member of a large family of lipophilic compounds (i.e., cannabinoids) that mediate physiological and psychotropic effects including regulation of appetite, immunosuppression, analgesia, inflammation, emesis, anti-nocioception, sedation, and intraocular pressure. Other members of the cannabinoid family include the endogenous (arachidonic acid-derived) ligands, anandamide, 2-arachidonyl glycerol, and 2-arachidonyl glycerol ether. Cannabinoids work through selective binding to and activation of G-protein coupled cannabinoid receptors. Two types of cannabinoid receptors have been cloned including CB-1 (L. A. Matsuda, et al., Nature, 346, 561-564 (1990)), and CB-2 (S. Munro, et al., Nature, 365, 61-65 (1993)). The CB-1 receptor is highly expressed in the central and peripheral nervous systems (M. Glass, et al., Neuroscience, 77, 299-318 (1997)), while the CB-2 receptor is highly expressed in immune tissue, particularly in spleen and tonsils. The CB-2 receptor is also expressed on other immune system cells, such as lymphoid cells (S. Galiegue, et al., Eur J Biochem, 232, 54-61 (1995)). Agonist activation of cannabinoid receptors results in inhibition of cAMP accumulation, stimulation of MAP kinase activity, and closure of calcium channels.
There exists substantial evidence that cannabinoids regulate appetitive behavior. Stimulation of CB-1 activity by anandamide or Delta-9 THC results in increased food intake and weight gain in multiple species including humans (Williams and Kirkham, Psychopharm., 143, 315-317 (1999)). Genetic knock-out of CB-1 result in mice that were hypophagic and lean relative to wild-type litter mates (DiMarzo, et al., Nature, 410, 822-825 (2001)). Published studies with CB-1 small molecule antagonists have demonstrated decreased food intake and body weight in rats (Trillou, et. al., Am. J. Physiol. Regul. Integr. Comp. Physiol., R345—R353, (2003)). Chronic administration of the CB-1 antagonist AM-251 for two weeks resulted in substantial body weight reduction and decreased adipose tissue mass (Hildebrandt, et. al., Eur. J. Pharm, 462, 125-132 (2003)). There are multiple studies that have assessed the anorexic effect of the Sanofi CB-1 antagonist, SR-141716 (Rowland, et. al., Pyschopharm., 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 regulation of appetite, Sanofi's SR-141716 and Solvay's SLV-319. Published Phase IIb data reveal that SR-141716 dose-dependently reduced body weight in human subjects over a 16 week trial period. CB-1 antagonists have also been shown to promote cessation of smoking behavior. Phase II clinical data on smoking cessation were presented in September of 2002 at Sanofi-Synthelabo's Information meeting. This data showed that 30.2% of patients treated with the highest dose of SR-141716 stayed abstinent from cigarette smoke relative to 14.8% for placebo.


DETAILED DESCRIPTION
The present application describes compounds according to Formula I and Formula II, pharmaceutical compositions comprising at least one compound according to Formula I and Formula II, and optionally one or more additional therapeutic agents and methods of treatment using the compounds according to Formula I and Formula II both alone and in combination with one or more additional therapeutic agents. The compounds have the general Formula I and Formula II below:




including all prodrugs, pharmaceutically acceptable salts and stereoisomers, R1, R2, R3 and R4 are described herein.

DEFINITIONS
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
As used herein, the term “alkyl” denotes 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. Further, alkyl groups, as defined herein, may optionally be substituted on any available carbon atom with one or more functional groups commonly attached to such chains, such as, but not limited to hydroxyl, halo, haloalkyl, mercapto or thio, cyano, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, carbalkoyl, carboxamido, carbonyl, alkenyl, alkynyl, nitro, amino, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, amido, —OPO3H, —OSO3H, and the like to form alkyl groups such as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl and the like.
Unless otherwise indicated, 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 to 8 carbons with one or more double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 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, alkenyl groups, as defined herein, may optionally be substituted on 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, nitro, cyano, thiol, alkylthio and/or any of the alkyl substituents set out herein.
Unless otherwise indicated, 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-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like. Further, alkynyl groups, as defined herein, may optionally be substituted on 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, hydroxyl, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, alkylthio and/or any of the alkyl substituents set out herein.
Unless otherwise indicated, the term “cycloalkyl” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing one or more double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, appended or fused, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,




Further, any cycloalkyl may be optionally substituted through any 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 said “cycloalkyl” and/or “alkyl” groups may optionally be substituted as defined above.
Unless otherwise indicated, the term “aryl” as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic 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 one to three additional rings fused to a carbocyclic ring or a heterocyclic ring, for example




Further, “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, heteroarylheteroaryl, 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, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl and/or any of the alkyl substituents set out herein.
Unless otherwise indicated, the term “heteroaryl” as used herein alone or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms 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, A. R. and Rees, C. W., eds. Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, N.Y.; and Katritzky, A. R., Rees, C. W., Scriven, E. F., eds. Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, N.Y.; and references therein. Further, “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 “substituted aryl”. Examples of heteroaryl groups include the following:




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 said heteroaryl and/or alkyl groups may optionally be substituted as defined above.
The term “heterocyclo”, “heterocycle”, “heterocyclyl” or “heterocyclic ring”, as used herein, represents an unsubstituted or substituted stable 4 to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms, with one to four 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 may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but is 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, A. R. and Rees, C. W., eds. Comprehensive Heterocyclic Chemistry The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, N.Y.; and Katritzky, A. R., Rees, C. W., Scriven, E. F., eds. Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 1996, Elsevier Science, Inc., Tarrytown, N.Y.; and references therein.
The term “heterocycloalkyl” as used herein alone or as part of another group refers to alkyl groups as defined above having a heterocyclyl substituent, wherein said heterocyclyl and/or alkyl groups may optionally be substituted as defined above.
The terms “arylalkyl”, “arylalkenyl” and “arylalkynyl” as used alone or as part of another group refer to alkyl, alkenyl and alkynyl groups as described above having 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 term “alkoxy”, “aryloxy”, “heteroaryloxy” “arylalkyloxy”, or “heteroarylalkyloxy” as employed herein alone or as part of another group includes an alkyl or aryl group as defined above linked through an oxygen atom.
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 “methylene,” as used herein, refers to a —CH2— group.
The term “nitro,” as used herein, refers to a —NO2 group.
The compounds of Formula I and Formula II can be present as salts, which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred. If the compounds of Formula I and Formula II have, for example, at least one basic center, they can form acid addition 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 alkanecarboxylic acids of 1 to 4 carbon atoms, for example acetic acid, which are unsubstituted or substituted, for example, by halogen as chloroacetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methyl- or p-toluene-sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of Formula I and Formula II 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, such 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. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of Formula I and Formula II or their pharmaceutically acceptable salts, are also included.
Preferred salts of the compounds of Formula I and Formula II which contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate, nitrate or acetate.
Preferred salts of the compounds of Formula I and Formula II which contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
The term “modulator” refers to a chemical compound with capacity to either enhance (e.g., “agonist” activity) or partially enhance (e.g., “partial agonist” activity) or inhibit (e.g., “antagonist” activity or “inverse agonist” activity) a functional property of biological activity or process (e.g., enzyme activity or receptor binding); such enhancement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, and/or may be manifest only in particular cell types.
The term “bioactive metabolite” as employed herein refers to any functional group contained in a compound of Formula I and Formula II with an open valence for further substitution wherein such substitution can, upon biotransformation, generate a compound of Formula I and Formula II. Examples of 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 —PO3H2 for example, which, upon biotransformation generates an —OH or —NH functional group of a compound of Formula I and Formula II.
The term “prodrug esters” as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of Formula I and Formula II with alkyl, alkoxy, or aryl substituted 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 that confer a pharmaceutical advantage such as—but not limited to—favorable aqueous solubility or in vivo exposure to the bioactive component Formula I and Formula II.
The term “prodrug” as employed herein includes functionalization of bioactive amine- or hydroxyl-containing compounds of Formula I and Formula II to form alkyl-, acyl-, sulfonyl-, phosphoryl-, or carbohydrate-substituted derivatives. Such derivatives are formed by reacting compounds of Formula I and Formula II with alkylating-, acylating-, sulfonylating-, or phosphorylating reagents employing procedures known to those skilled in the art. Alkylation of amines of Formula I and Formula II may result in—but are not limited to—derivatives that include spacer units to other prodrug moieties such as substituted alkyoxymethyl-, acyloxymethyl-, phosphoryloxymethyl-, or sulfonyloxymethyl-groups. Alkylation of amines of Formula I and Formula II may result in the generation of quarternary amine salts that act in vivo to provide the bioactive agent (i.e., the compound of Formula I and Formula II).
Preferred prodrugs consist of a compound of Formula I and Formula II where a pendant hydroxyl is phosphorylated to generate a phosphate derivative. Such a prodrug may also include a spacer group between the compound of Formula I and Formula II and the phosphate group, such as a methyleneoxy-group. Methods to generate such a prodrug from a compound of Formula I and Formula II are known to those skilled in the art, and are listed in the references below.
Preferred prodrugs also consist of a compound of Formula I and Formula II where a pendant amine, such as a pyridine group, is alkylated with a group, such as methyl, to form a quarternary ammonium ion salt. Methods to generate such a prodrug from a compound of Formula I and Formula II are known to those skilled in the art, and are listed in the references below.
Any compound that can be converted in vivo to provide the bioactive agent (i.e., the compound of Formula I and Formula II) 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:

    a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch. 31, (Academic Press, 1996);
    b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);
    c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers, 1991);
    d) Hydrolysis in Drug and Prodrug Metabolism, B. Testa and J. M. Mayer, (Verlag Helvetica Chimica Acta A G, Zurich, Switzerland; Wiley-VCH, Weinheim, Federal Republic of Germany, 2003);
    e) Ettmayer, P.; Amidon, G. L.; Clement, B.; Testa, B. “Lessons Learned from Marketed and Investigational Prodrugs” J. Med. Chem. 2004, 47 (10), 2393-2404; and
    f) Davidsen, S. K. et al. “N-(Acyloxyalkyl)pyridinium Salts as Soluble Prodrugs of a Potent Platelet Activating Factor Antagonist” J. Med. Chem. 1994, 37 (26), 4423-4429.

Said 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 prevent a condition treatable by administration of a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect. The effect may include, for example, treatment or prevention of the conditions listed herein. The precise effective amount for a subject will depend upon the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration.
All stereoisomers of the compounds of the instant invention are contemplated, either in mixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of Formula I and Formula II can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for preparation can utilize 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 and Formula II of the invention can be prepared as shown in the following reaction schemes and description thereof, as well as relevant published literature procedures that may be used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples.
Abbreviations
The following abbreviations are employed in the Schemes, Examples and elsewhere herein:
Ac=acetyl
AcOH=acetic acid
Boc=tert-butoxycarbonyl
DCM=dichloromethane
DIPEA=N,N-diisopropylethylamine
DMF=N,N-dimethylformamide
EDAC=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtOAc=ethyl acetate
Et3N=triethylamine
Et2O=diethyl ether
HEX=hexanes
HOBt=1-hydroxybenzotriazole hydrate
HPLC=high performance liquid chromatography
LAH=lithium aluminum hydride
LCMS=liquid chromatography mass spectrometry
MeOH=methanol
MS or Mass Spec=mass spectrometry
NaOH=sodium hydroxide
PG=protecting group
rt=room temperature
TFA=trifluoroacetic acid
THF=tetrahydrofuran
min=minute(s)
hr(s)=hour(s)
L=liter
mL=milliliter
μL=microliter
g=gram(s)
mg=milligram(s)
mol=moles
mmol=millimole(s)
nM=nanomolar
Compounds of the present invention may be prepared by procedures illustrated in the accompanying schemes.
Methods of Preparation
The compounds of the present invention may be prepared by methods such as those illustrated in the following Scheme 1 to 3 and as described below in the preparation of the Example compounds. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods. For all of the schemes and compounds described below, R1, R2, R3, R4, X1 and X2 are as described for a compound of Formula I and Formula II.
The following are the definitions of symbols used throughout Schemes 1 to 3:

    PG independently selected from suitable nitrogen or oxygen protecting group, exemplified by benzyl, methoxymethyl-[MOM], benzyloxymethyl-[BOM], 2-(trimethylsilyl)ethoxymethyl-[SEM], methoxyethoxymethyl-[MEM], t-butyl groups, t-butyloxycarbonyl, or benzylcarbonyl;
    EE Sn2 or Sn1 leaving group exemplified by halogen (Cl, Br, I) and sulfonates (—OSO2-aryl (e.g., —OSO2Ph or —OSO2PhCH3), or —OSO2-alkyl (e.g., —OSO2CH3 or —OSO2CF3));
    MM boronate ester or boronic acid, or trialkylstannane; or metal atom such as zinc, magnesium or lithium as part of an organometallic compound used as an intermediate for coupling reactions that may be performed in the absence of presence of transition metals.






Compounds of formula i wherein EE is an activated group such as chlorine, bromine and the like are available by means known to one skilled in the art. Compounds of formula II are prepared from compounds of formula i by reacting compounds of formula i under basic conditions using potassium carbonate or sodium hydride or the like in a solvent such as DMF or THF at room temperature to elevated temperatures, with an appropriate protecting group such as a benzyl halide. Compounds of formula iii are prepared from compounds of formula II by reacting two or more equivalents of an aryl or heteroaryl boronic acid when R1 and R2 are equivalent. When R1 and R2 are different, compounds of formula II are reacted with one equivalent of an aryl or heteroaryl boronic acid. When the reaction is complete, the resulting intermediate is further reacted with a different aryl or heteroaryl boronic acid to give compounds of formula iii. Compounds of formula iv can be prepared from compounds of formula iii by removing the protecting group PG under reported conditions such as those found in T. W. Greene & P. G. M. Wuts, “Protecting Groups in Organic Synthesis”, 3rd Edition, Wiley, 1999. For example, if PG is benzyl, then compounds of formula iii are treated with aluminum chloride in toluene with heating to give compounds of formula iv. Compounds of formula v are formed from compounds of formula iv by treatment of compounds of formula v with a chlorinating reagent such as POCl3 under refluxing conditions. Compounds of formula v are then used to synthesize compounds of formula I and formula II.




Compounds of formula viii are prepared from compounds of formula v by reacting compounds of formula v with an acyl hydrazine. Compounds of formula ix are then formed by treatment of compounds of formula viii with a dehydrating reagent, such as POCl3 at elevated temperatures. Alternatively, compounds of formula ix are formed by treatment of compounds of formula v with hydrazine, followed by reaction with formic acid under refluxing conditions or with an acyl chloride under basic conditions. Compounds of formula x are prepared from compounds of formula ix by reacting compounds of formula ix with a source of hydroxide such as TMSOK or tetrabutyl ammonium hydroxide. Compounds of formula xi and xii are prepared from compounds of formula x by reaction of compounds of formula x with a base such as sodium hydride or potassium carbonate in a solvent such as acetonitrile or DMF in the presence of an alkylating agent such as a benzyl bromide, an alkyl halide and the like.




Alternatively compounds of formula xii can be prepared from compounds of formula ix by condensing with an alcohol under basic conditions.
Parallel synthesis may be employed in the preparation of compounds, for example, where the intermediates possess an activated reaction center: such as but not limited to a reactive heteroaryl chloride for Suzuki coupling chemistry or a carboxylic acid for amide coupling chemistry or a reactive halide for alkylation chemistry or an activated chloride for displacement chemistry by for example an alcohol.
EXAMPLES
The following examples serve to better illustrate, but not limit, some of the preferred embodiments of the invention.
Analytical HPLC Methods Employed in Characterization of Examples
Analytical HPLC/MS was performed on Shimadzu LC10AS liquid chromatography systems and Waters ZMD Mass Spectrometers using the following method:
Method A. Linear gradient of 0 to 100% solvent B over 4 min, with 1 min hold at 100% B;
UV visualization at 220 nm
Column: YMC S5 ODS Combiscreen C18, 4.6×50 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
Method B. Linear gradient of 0 to 100% solvent B over 4 min, with 1 min hold at 100% B; UV visualization at 220 nm
Column: Phenomenex Luna C18, 4.6×50 mm
Flow rate: 4 ml/min
Solvent A: 0.1% trifluoroacetic acid, 90% water, 10% methanol
Solvent B: 0.1% trifluoroacetic acid, 90% methanol, 10% water
Method C. Linear gradient of 40% to 95% solvent B over 15 min
UV visualization at 220 nm
Column: Phenomenex Luna Phenyl-hexyl 4.6×150 mm
Flow rate: 1.2 ml/min
Solvent A: 0.1% ammonium acetate, 100% water
Solvent B: 0.1% ammonium acetate, 100% Acetonitrile
NMR Employed in Characterization of Examples
1H NMR spectra were obtained with Bruker or JOEL fourier transform spectrometers operating at the following frequencies: 1H NMR: 400 MHz (Bruker), 400 MHz (JOEL), or 500 MHz (JOEL); 13C NMR: 100 MHz (Bruker), 100 MHz (JOEL) or 125 MHz (JOEL). Spectra data are reported as Chemical shift (multiplicity, number of hydrogens, coupling constants in Hz) and are reported in ppm(δ units) relative to either an internal standard (tetramethylsilane=ppm) for 1H NMR spectra, or are referenced to the residual solvent peak (2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2HOD, 7.24 ppm for CHCl3, 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, 77.0 ppm for CDCl3). All 13C NMR spectra were proton decoupled.
Example 1
Preparation of 3,6-Dichloro-4,5-bis(4-chlorophenyl)pyridazine




1A. Preparation of 4,5-Dichloro-1,2-dihydropyridazine-3,6-dione




To a round bottom flask was added water (170 ml) and hydrazine dihydrochloride salt (41.9 gm, 398.8 mmol). The solution was brought to reflux and dichloromandelic anhydride (66.6 gm, 398.9 mmol) was added portionwise. The reaction was stirred at reflux for 30 min. After this time, the solution was cooled to rt 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+H)=181.0.
1B. Preparation of 2-Benzyl-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 hrs and then stirred at rt overnight. After this time, the reaction was poured into a 1:1 water: hexane mixture (2000 mL). The resultant mixture was stirred at rt for 1 h. A solid precipitate formed and the precipitate was collected by filtration to give the title compound, 2-benzyl-6-(benzyloxy)-4,5-dichloropyridazin-3(2H)-one (23.9 gm, 90% yield) as light yellow solid. 1(DMSO-D6): 7.45 (m, 2H), 7.35 (m, 4H), 7.30 (m, 4H), 5.26 (s, 2H), 5.17 (s, 2H).
1C. Preparation of 2-Benzyl-(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)4 (3.2 gm, 2.77 mmol). The reaction was stirred at 100° C. for 36 hrs. After this time, the solution was cooled to rt 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 (MgSO4), 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 light yellow solid. MS (M+H)=513.1.
1D. Preparation of 4,5-Bis(4-chlorophenyl)-1,2-dihydropyridazine-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 aluminum chloride (10.08 gm, 75.54 mmol). The reaction was stirred at 90° C. for 2 h. 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 (MgSO4), filtered and concentrated. The title compound, 4,5-bis(4-chlorophenyl)-1,2-dihydropyridazine-3,6-dione, was obtained as a solid and used in next reaction without further purification. MS (M+H)=330.9, 333.0.
1E. Preparation of 3,6-Dichloro-4,5-bis(4-chlorophenyl)pyridazine




To the 4,5-bis(4-chlorophenyl)-1,2-dihydropyridazine-3,6-dione was added POCl3 (50 ml), dropwise. The resultant reaction mixture was heated reflux for 2 hrs. The reaction turned black. After this time, POCl3 was removed under reduced pressure. To the residue was slowly added ice (250 gm) followed by the slow addition of water (250 ml). A solid precipitate was formed which was then collected by filtration to give product as a dark solid. The crude product was dissolved in CH2Cl2 (250 ml) and the solution was filtered through Celite (30 ml). The collected filtrate was concentrate to give brown solid. The crude solid was recystallized from CH2Cl2 (30 ml) and hexanes (500 mL) to give the title compound, 3,5-dichloro-4,5-bis(4-chlorophenyl)pyridazine as beige solid (5.0 gm, 45% for the 2 steps). MS; (M+H)=368.5, 370.5.
Example 2
Synthesis of 7,8-bis(4-chlorophenyl)-3-methyl-5-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one




2A. Synthesis of 6-Chloro-4,5-bis(4-chlorophenyl)pyridazin-3-ol




To a round bottom flask was added 3,6-dichloro-4,5-bis(4-chlorophenyl)pyridazine (1000 mg, 2.710 mmol), THF (20 ml) and TMSOK (869 mg, 6.775 mmol). The reaction was stirred at 80° C. for 8 hrs. After this time, the reaction mixture was concentrated. The residue was diluted with water (15 ml). The pH of the resulting solution was adjusted to 4 using 1N HCl. During addition, a solid precipitated. The solid was collected by filtration to give product 6-chloro-4,5-bis(4-chlorophenyl)pyridazin-3-ol as white solid (760 mg, 80% yield). HPLC retention time (method A) 3.535 min; LCMS (M+H)=351.1.
2B. Synthesis of 6-chloro-4,5-bis(4-chlorophenyl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one




To a round bottom flask was added 6-chloro-4,5-bis(4-chlorophenyl)pyridazin-3-ol (1.5 gm, 4.26 mmol), DMF (15 ml) and K2CO3 (1.17 gm, 8.52 mmol). The reaction was stirred at rt for 30 min. After this time, 4-trifluoromethylbenzyl bromide (1.2 gm, 5.19 mmol) was added to the reaction and the reaction was stirred at rt for an additional 8 hrs. The reaction mixture was then diluted with water (40 ml). The reaction mixture was poured into a separatory funnel and extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (4×30 ml) and saturated aqueous NaCl (30 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give product 6-chloro-4,5-bis(4-chlorophenyl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one as off white solid (1.5 gm, 65.1% yield).
2C. Synthesis of 7,8-bis(4-chlorophenyl)-3-methyl-5-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one




To a round bottom flask was added 6-chloro-4,5-bis(4-chlorophenyl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one (0.1 gm, 0.196 mmol), n-butanol (1 ml) and hydrazine hydrate (0.5 ml). The reaction heated to 135° C. and stirred at that temperature for 24 hrs. After this time, the solution was cooled to rt and then concentrated to dryness to give a yellow solid. To the resultant yellow solid was added CH2Cl2 (3 ml) followed by Et3N (0.1 ml, 0.594 mmol). To the resultant reaction mixture was then added slowly acetic anhydride (24 mg, 0.236 mmol). The reaction was then stirred for an additional 6 hrs at rt. After this time, the reaction mixture was diluted with water (10 ml). The solution was poured into a separatory funnel and extracted with CH2Cl2 (2×15 ml). The combined organic layers were washed with water (10 ml) and saturated aqueous NaCl (10 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the reaction product as an off-white solid. To this solid was added POCl3 (3 ml) and resulting solution was heated to 85° C. and stirred at this temperature for 2 hrs. After this time, the reaction was cooled in ice-water bath and slowly ice-water was added to the reaction mixture. A solid precipitated. The solid was collected by filtration to give product 7,8-bis(4-chlorophenyl)-3-methyl-5-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one as a white solid 70 mg (67% yield). HPLC retention time (method A) 3.783 min; LCMS (M+H)=529.1; 1HNMR (MeOD, 400 Hz): 7.75 (2H, d), 7.56 (2H, d), 7.39 (4H, s), 7.30 (2H, d), 7.21 (2H, d), 5.85 (2H, s), 2.61 (3H, s).
Example 3
Synthesis of 8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one




3A. Synthesis of 6-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3-ol




To a round bottom flask was added 3,6-dichloro-4-(4-chlorophenyl)-5-(pyridin-4-yl)pyridazine (1.5 gm, 4.464 mmol), CH3CN (5 ml), water (1 ml) and LiOH monohydrate (0.938 gm, 22.32 mmol). The reaction was heated to 80° C. and stirred at this temperature for 4 hrs. After this time, the reaction was colled to rt and concentrated under reduced pressure. The residue was diluted with water (30 ml). The pH of the aqueous solution was adjusted to 7 with 1N HCl. The resulting solution was poured into a separatory funnel and extract with EtOAc (4×20 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give a white solid residue. The residue was stirred in CH2Cl2 (10 ml) for 15 min. The solution was then filter and the solid was collected to give product 6-chloro-5-(4-chlorophenyl)-4-(pyridin-4-yl)pyridazin-3-ol as white solid (0.70 gm, 48% yield). HPLC retention time (method A) 1.332 min.
3B. Synthesis of 6-chloro-5-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one




To a round bottom flask was added 6-chloro-5-(4-chlorophenyl)-4-(pyridinyl)pyridazin-3-ol (1.1 gm, 3.47 mmol), DMF (10 ml), K2CO3 (0.958 gm, 6.94 mmol), and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (0.798 gm, 3.817 mmol). The reaction was heated to 80° C. and stirred at that temperature for 2 hrs. The reaction was then cooled to rt and diluted with EtOAc (75 ml). The resulting mixture was poured into a separatory funnel, washed with water (4×10 ml) and with saturated aqueous NaCl (15 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated. The crude product was purified using an automated column chromatography system (ISCO, 40 gm silica gel) eluting with a gradient of 40%-100% EtOAc/Hex to give product 6-chloro-5-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one as beige solid (1.35 gm, 79% yield). HPLC retention time (method A)3.140 min; LCMS (M+H)=491.1.
3C. Synthesis of 5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one




To a round bottom flask was added 6-chloro-5-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (900 mg, 1.833 mmol), 1-BuOH (2 ml) and hydrazine hydrate (5 ml). The reaction was heated to 130° C. and stirred at that temperature for 8 hrs. After this time the reaction was cooled to rt and concentrated under reduced pressure. The reaction was poured into a separatory funnel and partitioned between EtOAc (50 ml) and water (20 ml). The layers were separated and the organic layer was washed with water (20 ml) and saturated aqueous NaCl (20 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the product 5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one as yellow solid. HPLC retention time (method A) 1.138 min; LCMS (M+H)=487.1.
3D. Synthesis of 5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one




To a round bottom flask was added 5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (200 mg, 0.41 mmol), THF (5 ml), Et3N (124 mg, 1.232 mmol) followed by propionyl chloride (57 mg, 0.616 mmol). The reaction was then stirred at rt for 20 min. The reaction mixture was diluted with EtOAc (30 ml). The resulting solution was wash with water (2×10 ml) and saturated aqueous NaCl (10 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 12 gm silica gel) eluting with 100% EtOAc for 10 min, then 5% MeOH in CH2Cl2 to give product N′-(4-(4-chlorophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridazin-3-yl)propionohydrazide as light yellow solid 140 mg(63% yield). HPLC retention time (method A)1.892 min; LCMS (M+1)=543.3.
3E. Synthesis of 8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one




To a round bottom flask was added N′-(4-(4-chlorophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridazin-3-yl)propionohydrazide (130 mg, 0.239 mmol) and toluene (5 ml). The reaction was heated at 130° C. and stirred at this temperature for 1 hr. After this time, POCl3 (1.3 ml) was added and the reaction was stirred at 130° C. for additional 4 hrs. The reaction mixture was then cooled to rt and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 ml). The resulting solution was poured into a separatory funnel and wash with 0.5N NaOH (10 ml), water (15 ml) and saturated aqueous NaCl (10 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 4 gm silica gel) eluting 65%-100% EtOAc/Hex to give product 8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (80 mg) as off-white solid in 64% yield. HPLC retention time (method A) 2.110 min; LCMS (M+H)=525.2; 1HNMR (CDCl3, 500 Hz): 8.59 (2H, d, J=4.4 Hz), 7.56 (1H, d, J=7.7 Hz), 7.44, (1H, d, J=7.7 Hz), 7.3417 (4H, m), 7.18 (2H, d, J=4.4 Hz), 5.64 (2H, s), 2.82 (2H, q), 2.79 (3H, s), 1.46 (3H, t). 13C-NMR (CDCl3, 500 Hz) 158.3, 154.4, 148.9, 144.0, 140.8, 138.2, 136.2, 133.3, 131.8, 131.6, 129.0, 128.8, 126.8, 125.8, 118.3, 49.1, 22.4, 20.8, 12.3.
Example 4
Synthesis of 4-(8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile




4A. Synthesis of 2-benzyl-4,5-dichloropyridazin-3(2H)-one




To a round bottom flask was added 4,5-dichloropyridazin-3(2H)-one (50 gm, 303.03 mmol), DMF (150 ml), K2CO3 (46 gm, 333.33) and benzyl bromide (51.83 gm, 303.03 mmol). The reaction was stirred at rt for 16 hrs. After this time, the reaction mixture was slowly poured into water (500 ml) and a solid precipitate formed. The slurry was stirred at rt for 1 hr. After this time, the reaction mixture was filtered and the solid was collected. The solid was dried under vacuum to give product 2-benzyl-4,5-dichloropyridazin-3(2H)-one as tan-colored solid (74 gm, 97% yield). HPLC retention time (method A)2.788 min; LCMS (M+1)=255.1.
4B. Synthesis of 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one




To a round bottom flask was added 2-benzyl-4,5-dichloropyridazin-3(2H)-one (7.14 gm, 27.99 mmol), dioxane (125 ml, anhydrous). To the resulting reaction mixture was slowly added 25%/NaOMe in MeOH solution (6.98 ml, 30.51 mmol). The reaction was stirred at rt for 70 min. After this time, the reaction mixture was diluted with water (200 ml). The resulting solution was poured into a separatory funnel and extracted with CH2Cl2 (2×100 ml). The combined organic layers were washed with saturated aqueous NaCl (10 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 120 gm silica gel) eluting with 0-5% MeOH/CH2Cl2 to give product 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one as colorless oil (6.5 gm, 93% yield). HPLC retention time (method A) 3.090 min; LCMS (M+H)=251.2.
4C. Synthesis of 2-benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one




To a round bottom flask was added 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one (25.1 gm, 0.1 mmol), 4-chlorophenyl boronic acid (17.215 gm, 0.11 mmol), Pd(PPh3)4(9.24 gm, 0.008 mmol), toluene (200 ml), EtOH (200 ml) and 2.0N Na2CO3 (200 ml, 0.4 mmol). The reaction was purged with argon for 10 min. The reaction was then heated to 120° C. and stirred at this temperature for 18 hrs. After this time, the reaction was cooled to rt, poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (50 ml). The combined organic layers were washed with 1N NaOH (200 ml), water (200 ml) and saturated aqueous NaCl (200 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 330 gm silica gel) eluting with a gradient of 0-30% EtOAc/CH2Cl2 to give product 2-benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one (33 gm, 99% yield) as light yellow solid. HPLC retention time (method A) 3.740 min; LCMS (M+H)=327.2.
4D. Synthesis of 2-benzyl-4-chloro-5-4-chlorophenyl)pyridazin-3(2H)-one




To a round bottom flask was added 2-benzyl-5-(4-chlorophenyl)-4-methoxypyridazin-3(2H)-one (32.7 gm, 0.1 mmol) and POCl3 (80 ml). The reaction heated to 80° C. and stirred at this temperature for 3 hrs. The solution was cooled to rt and concentrated under reduced pressure to remove the POCl3. The resulting residue was cooled using and ice-water bath and slowly, ice-water (50 ml) was added to the reaction flask residue over 15 min. Water (400 mL) was then added to the reaction and a solid precipitated. The reaction mixture was filtered and the solid was collected. The crude product was purified using an automated column chromatography system (ISCO, 330 gm silica gel) eluting with a gradient of 0-40% EtOAC/Hex to give product as beige solid (30 gm, 91% yield). HPLC retention time (method A) 3.491 min; LCMS (M+H)=331.2.
4E. Synthesis of 4-(2-benzyl-5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile




To a sealed tube was added 2-benzyl-4-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one (3.31 gm, 110.0 mmol), 4-cyanophenyl boronic acid (2.94 gm, 20 mmol), Pd(dppf)Cl2 dichloromethane complex (0.817 gm, 1.0 mmol), potassium phosphate (6.36 gm, 30 mmol) and THF (10 ml). The reaction solution was degassed with argon for 5 min and then sealed in a reaction tube. The reaction was then heated to 90° C. and keeped at this temperature for 4 hrs. The reaction was then cooled to rt and diluted with EtOAc (50 ml). The reaction mixture was then poured into a separatory funnel and the layers were separated. The organic layer was washed with water (20 ml) and saturated aqueous NaCl (20 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 330 gm silica gel) eluting with a gradient of 0-70% EtOAc/Hex to give 3.65 gm (92% yield) 4-(2-benzyl-5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile. HPLC retention time (method B) 3.81 min; LCMS (M+H)=398.0.
4F. Synthesis of 4-(2-benzyl-5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile




To the suspension of 4-(2-benzyl-5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (3.62 gm, 9.12 mmol) in toluene (50 ml) at rt under argon was added AlCl3 (3.65 gm, 27.4 mmol). The reaction was heated to 80° C. and stirred at this temperature for 4 hrs. After this time, the solution was cooled to rt and concentrated under reduced pressure. Ice water (100 ml) was added to the reaction residue and the resulting slurry was stirred for 20 min. The solution was then diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 ml). The combined organic layers were washed with 1N NaOH (50 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was triturated with EtOAc/Hex to give 2.21 gm (79% yield) 4-(5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile. HPLC retention time (method B) 3.22 min; LCMS (M+H)=308.0.
4G. Synthesis of 4-(6-bromo-5-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile




To a suspension of 4-(5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (2.21 gm, 7.2 mmol) in 30 ml of methanol at rt was added LiOH monohydrate (0.45, 10.8 mmol). The resulting mixture was heated to 70° C. and stirred at this temperature for 15 min. Br2 (2.3 g, 14.4 mmol) was then carefully added dropwise to the reaction mixture. After addition was complete, the color of Br2 disappeared after 2 minutes. HPLC indicated that the reaction had proceeded to 40% completion. Additional Br2 ( ̃0.8 g, 5 mmol) was then added followed by additional LiOH monohydrate (0.21 g, 5 mmol). The Br2 was consumed within 2 minutes after addition. The reaction was then cooled to rt and the solvent was removed under reduced pressure. The resulting residue was reconcentrated from acetone (2×20 ml). To the resulting light brown residue was added 20 mL DMF, followed by addition of LiOH monohydrate (0.612 g, 14.40 mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (1.65 gm, 7.91 mmol) at rt under Ar. The reaction mixture was heated to 70° C. and stirred at this temperature for 1 hr. After this time, the solution was cooled to rt and diluted with water (50 ml) and EtOAc (50 ml) and stirred for 10 minutes. The layers were separated and organic phase was washed with saturated aqueous NaCl (100 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 120 gm silica gel) eluting with a gradient of 20%-80% EtOAc/Hex to give product as off-white solid (3.27 gm, 81% yield). HPLC retention time (method B) 3.91 min; LCMS (M+H)=561.0.
4H. Synthesis of 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile




To a microwave flask was added 4-(6-bromo-5-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (105 mg, 0.187 mmol), pyridine (10 ml) and anhydrous hydrazine (60 mg, 1.87 mmol). The reaction was subjected to microwaves with heating to 200° C. and the conditions were continued at that temperature for 1.5 hr. After this time, the reaction was cooled to rt and the solvent was removed to give product as yellow solid. The product was used in the next reaction without further purification.
41. Synthesis of N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propionohydrazide




To a round bottom flask was added 4-(5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (96 mg, 0.187 mmol), THF (31 ml), Et3N (37.8 mg, 0.374 mmol) and propionyl chloride (17.3 mg, 0.187 mmol). The resulting reaction mixture was stirred at rt for 20 min. After this time, the reaction mixture was diluted with EtOAc (30 ml). The resulting solution was poured into a separatory funnel and the layers were separated. The organic layer was washed with water (2×10 ml) and saturated aqueous NaCl (10 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 4 gm silica gel) eluting with a gradient of 20-80% EtOAc/Hex to give product N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propionohydrazide as light yellow solid 50 mg (47% yield, for 2 steps). HPLC retention time (method A) 2.941 min; LCMS (M+H)=567.3.
4J. Synthesis of 4-(8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile




To a round bottom flask was added N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propionohydrazide (45 mg, 0.0794 mmol) and toluene (3 ml). The reaction was heated to 130° C. and stirred at this temperature for 1 hr. After this time, POCl3 (1 ml) was added and the reaction mixture was stirred at 130° C. for additional 4 hrs. The reaction was then cooled to rt and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 ml) and the resulting solution was washed with 0.5N NaOH (10 ml), water (15 ml), saturated aqueous NaCl (10 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 4 gm silica gel) eluting with a gradient of 65%-100% EtOAc/Hex to give product 4-(8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (30 mg) as off-white solid. 69% yield. HPLC retention time (method A) 3.110 min; LCMS (M+H)=549.4. 1HNMR (CDCl3, 500 Hz): 7.49-7.53 (3H, m), 7.35-7.37 (1H, m), 7.22-7.24 (6H, m), 5.57 (2H, s), 2.73 (2H, q), 2.65 (3H, s), 1.38 (3H, t); 13CNMR (CDCl3, 500 Hz) 159.8, 155.7, 148.6, 147.5(q), 143.9, 138.0, 137.1, 136.6, 133.5, 131.9, 131.8, 128.9, 120.8(q), 118.6, 118.2, 112.6, 49.2, 22.2, 20.5, 12.4.
Example 5
Synthesis of 7,8-bis(4-chlorophenyl)-6-(4-methoxybenzyloxy)-[1,2,4]triazolo[4,3-b]pyridazine




5A. Synthesis of 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine




To a round bottom flask was added 3,6-dichloro-4,5-bis(4-chlorophenyl)pyridazine (1.55 gm, 4.201 mmol), pyridine(10 ml) and hydrazine hydrate (617 mg, 12.602 mmol). The reaction was stirred at 120° C. for 4 hrs. After this time, the reaction mixture was concentrated to near dryness. To the resulting residue was added water (50 ml) and a solid formed. The solid was collected by filtration to give product -chloro-4,5-bis(4-chlorophenyl)-6-hydrazinylpyridazine as a beige solid (1.53 gm, 99% yield). HPLC retention time (method A) 2.740 min; LCMS (M+H)=365.1.
5B. Synthesis of 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine




To a round bottom flask was added 3-chloro-4,5-bis(4-chlorophenyl)-6-hydrazinylpyridazine (3.0 gm, 8.2 mmol) and formic acid (15 ml). The reaction was heated at 120° C. for 2 hrs. The reaction mixture was cooled to rt, poured into water (100 ml) and solid precipitated. The solid was collected by filtration to give product 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine as a grey solid (2.8 gm, 91% yield). LCMS (M+H)=376.9; 1HNMR (CDCl3, 400 Hz): 9.16 (1H, s), 7.38-7.40 (4H, m), 7.37 (2H, d), 7.15 (2H, d).
5C. Synthesis of 7,8-bis(4-chlorophenyl)-6-(4-methoxybenzyloxy)-[1,2,4]triazolo[4,3-b]pyridazine




To round bottom flask was added 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (37.6 mg, 0.10 mmol), 4-methyoxybenzyl alcohol (0.15 mmol), THF (1 ml) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) (30 mg, 0.11 mmol). The reaction was heated to 50° C. and stirred at this temperature for 40 hrs. The solvent was removed and the residue was purified using preparative HPLC to give pure product 7,8-bis(4-chlorophenyl)-6-(4-methoxybenzyloxy)-[1,2,4]triazolo[4,3-b]pyridazine as a solid. HPLC retention time (method C) 7.91 min; LCMS (M+H)=477.10.
Example 6
Synthesis of 7,8-bis(4-chlorophenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one




The title compound was synthesized by reacting 6-chloro-7,8-bis(4-chlorophenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with TMSOK using the procedures described above. 1HNMR (DMSO, 400 Hz): 7.48 (2H, d), 7.38-7.7.42 (4H, m), 7.25 (2H, d). 13CNMR (DMSO, 400 Hz) 160.88, 145.91, 137.00, 135.11, 133.90, 132.94, 132.10, 131.07, 129.98, 128.00 127.13, 118.30(q).
The following compounds were synthesized using procedures similar to those described for the synthesis of 7,8-bis(4-chlorophenyl)-3-methyl-5-(4-(trifluoromethyl)benzyl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one, Example 2.




HPLC retention time (method A) 3.836 min LCMS (M+H)=515.0





HPLC retention time (method A) 3.580 min LCMS (M+H)=516.2





HPLC retention time (method A) 3.783 min LCMS (M+H)=529.1





HPLC retention time (method A) 3.918 min LCMS (M+H)=583.1





HPLC retention time (method A) 3.856 min LCMS (M+H)=543.2





HPLC retention time (method A) 3.886 min LCMS (M+H)=557.1

The following compounds were synthesized using procedures similar to those described for the synthesis of 8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-7-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one, Example 3.




HPLC retention time (method A) 2.27 min LCMS (M+H)=497.2





HPLC retention time (method A) 2.26 min LCMS (M+H)=511.2





HPLC retention time (method A) 2.32 min LCMS (M+H)=511.3





HPLC retention time (method A) 2.41 min HRMS (M+H)=476.1283





HPLC retention time (method A) 2.680 min LCMS (M+H)=525.2





HPLC retention time (method A) 2.110 min LCMS (M+H)=525.2





HPLC retention time (method A) 2.295 min LCMS (M+H)=539.3





HPLC retention time (method A) 2.363 min LCMS (M+H)=511.2





HPLC retention time (method A) 2.603 min LCMS (M+H)=520.1





HPLC retention time (method A) 1.816 min LCMS (M+H)=467.2





HPLC retention time (method A) 1.625 min LCMS (M+H)=453.2





HPLC retention time (method A) 2.548 min LCMS (M+H)=593.3

The following compounds were synthesized using procedures similar to those described for the synthesis of 7,8-bis(4-chlorophenyl)-6-(4-methoxybenzyloxy)-[1,2,4]triazolo[4,3-b]pyridazine, Example 5.




HPLC retention time (method A) 4.11 min LCMS (M+H)=529.0





HPLC retention time (method A) 4.09 min LCMS (M+H)=515.1





HPLC retention time (method A) 2.84 min LCMS (M+H)=497.2





HPLC retention time (method A) 4.16 min LCMS (M+H)=543.1





HPLC retention time (method A) 4.21 min LCMS (M+H)=557.0





HPLC retention time (method A) 3.75 min LCMS (M+H)=516.1





HPLC retention time (method A) 4.19 min LCMS (M+H)=583.1





HPLC retention time (method C) 7.91 min MS (M+H)=477.10





HPLC retention time (method C) 8.71 min MS (M+H)=531.09





HPLC retention time (method C) 7.97 min MS (M+H)=500.13





HPLC retention time (method C) 6.72 min MS (M+H)=471.13





HPLC retention time (method C) 8.33 min MS (M+H)=511.16





HPLC retention time (method C) 6.09 min MS (M+H)=488.10





HPLC retention time (method C) 8.04 min MS (M+H)=477.10





HPLC retention time (method C) 5.57 min MS (M+H)=448.11





HPLC retention time (method C) 5.50 min MS (M+H)=448.11





HPLC retention time (method C) 6.25 min MS (M+H)=476.14





HPLC retention time (method C) 6.53 min MS (M+H)=462.13





HPLC retention time (method C) 9.01 min MS (M+H)=544.22





HPLC retention time (method C) 7.75 min MS (M+H)=491.10





HPLC retention time (method C) 8.31 min MS (M+H)=505.13

Biological Evaluation
Cannabinoid Receptor Binding Assay
Radioligand binding studies were conducted in membranes prepared from Chinese Hamster Ovary (CHO) cells that over-express recombinant human CB-1 (CHO-CB-1 cells). Total assay volume for the binding studies was 100 μl. 5 μg of membranes were brought up to a final volume of 95 μl with Binding Buffer (25 mM HEPES, 150 mM NaCl, 2.5 mM CaCl2, 1 mM MgCl2, 0.25% BSA). The diluted membranes were preincubated with a compound or DMSO 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 (presoaked with 0.3% polyethylenimine) using a Packard Cell Harvester. The filter was washed with 0.25×PBS, 30 μl MicroScint was added per well, and the bound radiolabel was quantitated by scintillation counting on a Packard TopCount Scintillation Counter. The CB-2 radioligand binding assay was conducted identically except that the membranes from CHO-CB-2 cells were used.
For a compound to be considered a CB-1 antagonist, the compound must possess a CB-1 receptor binding affinity Ki less than 13000 nM. As determined by the assay described above, the CB-1 receptor binding Ki values of working Examples 1-63 fall within the range of 0.01 nM to 10000 nM.
Cannabinoid Receptor Functional Activity Assay
Functional CB-1 inverse agonist activity of test compounds was determined in CHO-CB-1 cells using a cAMP accumulation assay. CHO-CB-1 cells were grown in 96 well plates to near confluence. On the day of the functional assay, growth medium was aspirated and 100 of Assay Buffer (PBS plus 25 mM HEPES/0.1 mM 3-isobutyl-1-methylxanthine/0.1% BSA) was added. Compounds were added to the Assay buffer diluted 1:100 from 100% DMSO and allowed to preincubate for 10 minutes prior to addition of 5 uM 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 quantitated using the Amersham cAMP SPA kit.
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. Accordingly, the compounds of the present invention may be useful for the treatment or prevention of diseases and disorders associated with G-protein coupled cannabinoid receptor activity. Preferably, compounds of the present invention possess activity as antagonists or inverse agonists of the CB-1 receptor, and may be used in the treatment of diseases or disorders associated with the activity of the CB-1 receptor.
Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to metabolic and eating disorders as well as conditions associated with metabolic disorders, (e.g., obesity, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, cholelithiasis and sleep disorders, hyperlipidemic conditions, bulimia nervosa and compulsive eating disorders) or psychiatric disorders, such as substance abuse, depression, anxiety, mania and schizophrenia. These compounds could also be used for the improvement of cognitive function (e.g., the treatment of dementia, including Alzheimer's disease, short term memory loss and attention deficit disorders); neurodegenerative disorders (e.g., Parkinson's Disease, cerebral apoplexy and craniocerebral trauma) and hypotension (e.g., hemorrhagic and endotoxin-induced hypotension). These compounds could also be used for treatment of catabolism in connection with pulmonary dysfunction and ventilator dependency; treatment of cardiac dysfunction (e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure); and improvement of the overall pulmonary function; transplant rejection; rheumatoid arthritis; multiple sclerosis; inflammatory bowel disease; lupus; graft vs. 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.
Compounds useful in the treatment of appetitive or motivational disorders regulate desires to consume sugars, carbohydrates, alcohol or drugs and more generally to regulate the consumption of ingredients with hedonic value. In the present description and in the claims, appetitive disorders are understood as meaning: disorders associated with a substance and especially abuse of a substance and/or dependency on a substance, disorders of eating behaviors, especially those liable to cause excess weight, irrespective of its origin, for example: bulimia nervosa, craving for sugars. The present invention therefore further relates to the use of a CB-1 receptor antagonist or inverse agonist for the treatment of bulimia and obesity, including obesity associated with type II diabetes (non-insulin-dependent diabetes), or more generally any disease resulting in the patient becoming overweight. Obesity, as described herein, is defined by a body mass index (k g/m2) of at least 26. It may be due to any cause, whether genetic or environmental, including overeating and bulemia, polycycstic ovary disease, craniopharyngeoma, Prader-Willi Syndrome, Frohlich's Syndrome, Type II diabetes, growth hormone deficiency, Turner's Syndrome and other pathological states characterized by reduced metabolic activity or reduced energy expenditure. As used with reference to the utilities described herein, the term “treating” or “treatment” encompasses prevention, partial alleviation, or cure of the disease or disorder. Further, treatment of obesity is expected to prevent progression of medical covariants 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.
Compounds in the present invention may also be useful in treating substance abuse disorders, including substance dependence or abuse without physiological dependence. Substances of abuse include alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalents, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of the above. The terms “substance abuse disorders” also includes drug or alcohol withdrawal syndromes and substance-induced anxiety or mood disorder with onset during withdrawal.
Compounds in the present invention may be useful in treating memory impairment and cognitive disorders. The condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information. Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline. Dementias are diseases that include memory loss and additional intellectual impairment separate from memory. Cannabinoid receptor modulators may also be useful in treating cognitive impairments related to attentional deficits, such as attention deficit disorder.
Compounds in the present invention may also be useful in treating diseases associated with dysfunction of brain dopaminergic systems, such as Parkinson's Disease and substance abuse disorders. Parkinsons's Disease is a neurodenerative movement disorder characterized by bradykinesia and tremor.
As modulators of the cannabinoid receptor, the compounds of the present invention are further 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 pulmonary obstructive disorder, emphysema, asthma, and bronchitis. In addition, cannabinoid receptor modulators block the activation of lung epithelial cells by moeties such as allergic agents, inflammatory cytokines or smoke, thereby limiting release of mucin, cytokines, and chemokines, or selectively inhibiting lung epithelial cell activation.
Moreover, the compounds employed in the present invention may stimulate inhibitory pathways in cells, particularly in leukocytes, lung epithelial cells, or both, and are thus useful in treating such diseases. “Leukocyte activation” is defined herein as any or all of cell proliferation, cytokine production, adhesion protein expression, and production of inflammatory mediators. “Epithelial cell activation” is defined herein as the production of any or all of mucins, cytokines, chemokines, and adhesion protein expression.
Use of the compounds of the present invention for treating leukocyte activation-associated disorders is exemplified by, but is not limited to, treating a range of disorders such as: transplant (such as organ transplant, acute transplant, xenotransplant or heterograft or homograft (such as is employed in burn treatment)) rejection; protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes; transplantation tolerance induction; arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; respiratory and pulmonary diseases including but not limited to chronic obstructive pulmonary disease (COPD), emphysema, bronchitis, and acute respiratory distress syndrome (ARDS); inflammatory bowel disease, including ulcerative colitis and Crohn's disease; lupus (systemic lupus erythematosis); graft vs. host disease; T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis; contact dermatitis (including 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); Autoimrnune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome; other autoimmune diseases; glomerulonephritis; serum sickness; uticaria; allergic diseases such as respiratory allergies (asthma, hayfever, allergic rhinitis) or skin allergies; scleracierma; mycosis fungoides; acute inflammatory and respiratory responses (such as acute respiratory distress syndrome and ishchemia/reperfusion injury); dermatomyositis; alopecia greata; chronic actinic dermatitis; eczema; Behcet's disease; Pustulosis palmoplanteris; Pyoderma gangrenum; Sezary's syndrome; atopic dermatitis; systemic schlerosis; and morphea. The term “leukocyte activation-associated” or “leukocyte-activation mediated” disease as used herein includes each of the above referenced diseases or disorders. In a particular embodiment, the compounds of the present invention are useful for treating the aforementioned exemplary disorders irrespective of their etiology. The combined activity of the present compounds towards monocytes, macrophages, T-cells, etc. may be useful in treating any of the above-mentioned disorders.
Cannabinoid receptors are important in the regulation of Fc gamma receptor responses of monocytes and macrophages. Compounds of the present invention inhibit the Fc gamma dependent production of TNF alpha in human monocytes/macrophages. The ability to inhibit Fc gamma receptor dependent monocyte and macrophage responses results in additional anti-inflammatory activity for the present compounds. This activity is especially of value, for example, in treating inflammatory diseases such as arthritis or inflammatory bowel disease. In particular, the present compounds are useful for treating autoimmune glomerulonephritis and other instances of glomerulonephritis induced by deposition of immune complexes in the kidney that trigger Fc gamma receptor responses leading to kidney damage.
Cannabinoid receptors are expressed on lung epithelial cells. These cells are responsible for the secretion of mucins and inflammatory cytokines/chemokines in the lung and are thus intricately involved in the generation and progression of respiratory diseases. Cannabinoid receptor modulators regulate both the spontaneous and the stimulated production of both mucins and cytokines. Thus, such compounds are useful in treating respiratory and pulmonary diseases including, COPD, ARDS, and bronchitis.
Further, cannabinoid receptors may be expressed on gut epithelial cells and hence regulate cytokine and mucin production and may be of clinical use in treating inflammatory diseases related to the gut. Cannabinoid receptors are also expressed on lymphocytes, a subset of leukocytes. Thus, cannabinoid receptor modulators will inhibit B and T-cell activation, proliferation and differentiation. Thus, such compounds will be useful in treating autoimmune diseases that involve either antibody or cell mediated responses such as multiple sclerosis and lupus.
In addition, cannabinoid receptors regulate the Fc epsilon receptor and chemokine induced degranulation of mast cells and basophils. These play important roles in asthma, allergic rhinitis, and other allergic disease. Fc epsilon receptors are stimulated by IgE-antigen complexes. Compounds of the present invention inhibit the Fc epsilon induced degranulation responses, including the basophil cell line, RBL. The ability to inhibit Fc epsilon receptor dependent mast cell and basophil responses results in additional anti-inflammatory and anti-allergic activity for the present compounds. In particular, the present compounds are useful for treating asthma, allergic rhinitis, and other instances 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 formula I, alone or in combination with a pharmaceutical carrier or diluent. Optionally, compounds of the present invention can be used alone, in combination with other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-obesity agents; anti-diabetic agents, appetite suppressants; cholesterol/lipid-lowering agents, HDL-raising agents, cognition enhancing agents, agents used to treat neurodegeneration, agents used to treat respiratory conditions, agents used to treat bowel disorders, anti-inflammatory agents; anti-anxiety agents; anti-depressants; anti-hypertensive agents; cardiac glycosides; and anti-tumor agents.
Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the cannabinoid receptor modulators in accordance with the invention.
Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include melanocortin receptor (MC4R) agonists, melanin-concentrating hormone receptor (MCHR) antagonists, growth hormone secretagogue receptor (GHSR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-1 agonists, and other Pre-proglucagon-derived peptides; NPY1 or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC) inihibitors, 11-β-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. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 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 WO 00/039077 (KaroBio), a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), serotonin receptor agonists, (e.g., BVT-933 (Biovitrum)), monoamine reuptake inhibitors or releasing agents, such as fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentennine, phenylpropanolamine or mazindol, anorectic agents such as topiramate (Johnson & Johnson), CNTF (ciliary neurotrophic factor)/Axokine® (Regeneron), BDNF (brain-derived neurotrophic factor), leptin and leptin receptor modulators, or cannabinoid-1 receptor antagonists, such as SR-141716 (Sanofi) or SLV-319 (Solvay).
Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include: insulin secretagogues or insulin sensitizers, which may include biguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductase inhibitors, PPAR γ agonists such as thiazolidinediones, PPAR α agonists (such as fibric acid derivatives), PPAR δ antagonists or agonists, PPAR α/γ dual agonists, 11-β-HSD-1 inhibitors, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors, glycogen phosphorylase inhibitors, and/or meglitinides, as well as insulin, and/or glucagon-like peptide-1 (GLP-1), GLP-1 agonist, and/or a PTP-1B inhibitor (protein tyrosine phosphatase-1B inhibitor).
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 to biguanide within the range from 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 (disclosed in U.S. Pat. No. 4,379,785), glipizide, gliclazide or chlorpropamide, other known sulfonylureas or other antihyperglycemic agents which act on the ATP-dependent channel of the beta-cells, with glyburide and glipizide being preferred, which may be administered in the same or in separate oral dosage forms. The oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Pat. No. 4,904,769) or miglitol (disclosed in U.S. Pat. No. 4,639,436), which may be administered in the same or in a separate oral dosage forms.
The compounds of the present invention may be employed in combination with a PPAR γ agonist such as a thiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Pat. No. 5,594,016), Glaxo-Wellcome's GL-262570, 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), N,N-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.
The compounds of the present invention may be employed with a PPARα/γ dual 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 U.S. Pat. No. 6,414,002.
The compounds of the present invention may be employed in combination with anti-hyperlipidemia agents, or agents used to treat arteriosclerosis. An example of an hypolipidemic agent would be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, pitavastatin (Nissan/Sankyo's nisvastatin (NK-104) or itavastatin), disclosed in U.S. Pat. No. 5,011,930, Shionogi-Astra/Zeneca rosuvastatin (visastatin (ZD-4522)) disclosed in U.S. Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat. No. 5,753,675, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives as disclosed in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivatives thereof as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone as disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives 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, naphthyl analogs of mevalonolactone as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes such as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin) as disclosed in European Patent Application No. 0,142,146 A2, and quinoline and pyridine derivatives disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. In addition, phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.
The squalene synthetase inhibitors suitable for use herein include, but are not limited to, α-phosphono-sulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller, et al., J. Med. Chem., 31, 1869-1871 (1998) including isoprenoid (phosphinyl-methyl)phosphonates as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Pat. Nos. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).
In addition, 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 analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 98, 1291-1293 (1976), phosphinylphosphonates reported by McClard, R. W. et al., J. Am. Chem. Soc., 109, 5544 (1987) and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, Summary.
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. Pat. No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex (SECHOLEX, POLICEXIDE) and cholestagel (Sankyo/Geltex), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene 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 such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Pat. 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) such as disclosed in, Drugs of the Future, 24, 9-15 (1999), (Avasimibe); “The ACAT inhibitor, C1-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters”, Nicolosi et al., Atherosclerosis (Shannon, Irel), 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 ApoB100-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 animals”, Krause et al., Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways, 173-98 (1995), Publisher: CRC, Boca Raton, Fla.; “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), as well as F-1394, CS-505, F-12511, HL-004, K-10085 and YIC-C8-434.
The hypolipidemic agent may be an upregulator of LDL receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly). The hypolipidemic agent may be a cholesterol absorption inhibitor preferably Schering-Plough's SCH48461 (ezetimibe) as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
The other lipid agent or lipid-modulating agent may be a cholesteryl transfer protein inhibitor (CETP) such as Pfizer's CP-529,414 as well as those disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496, and Pharmacia's SC-744 and SC-795, as well as CETi-1 and JTT-705.
The hypolipidemic agent may be an ileal Na+/bile acid cotransporter inhibitor such 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. Pat. No. 5,447,954.
The other lipid agent also includes a phytoestrogen compound such as disclosed in WO 00/30665 including isolated soy bean protein, soy protein concentrate or soy flour as well as an isoflavone such as genistein, daidzein, glycitein or equol, or phytosterols, phytostanol or tocotrienol as disclosed in WO 2000/015201; a beta-lactam cholesterol absorption inhibitor such as disclosed in EP 675714; an HDL upregulator such as an LXR agonist, a PPAR α-agonist and/or an FXR agonist; an LDL catabolism promoter such as disclosed in EP 1022272; a sodium-proton exchange inhibitor such as disclosed in DE 19622222; an LDL-receptor inducer or a steroidal glycoside such as disclosed in U.S. Pat. No. 5,698,527 and GB 2304106; an anti-oxidant such as beta-carotene, ascorbic acid, α-tocopherol or retinol as disclosed in WO 94/15592 as well as Vitamin C and an 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, an HMG-CoA synthase inhibitor, or a lanosterol demethylase inhibitor as disclosed in WO 97/48701; a PPAR δ agonist for treating dyslipidemia; or a sterol regulating element binding protein-I (SREBP-1) as disclosed in WO 2000/050574, for example, a sphingolipid, such as ceramide, or neutral sphingomyelenase (N-SMase) or fragment thereof. Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin and rosuvastatin, as well as niacin and/or cholestagel.
The compounds of the present invention may be employed in combination with anti-hypertensive agents. Examples of suitable anti-hypertensive agents for use in combination with the compounds of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and/or T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/A11 antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.
Cannbinoid receptor modulators could be useful in treating other diseases associated with obesity, including sleep disorders. Therefore, the compounds described in the present invention could be used in combination with therapeutics for treating sleep disorders. Examples of suitable therapies for treatment of sleeping disorders for use in combination with the compounds of the present invention include melatonin analogs, melatonin receptor antagonists, ML 1 B agonists, GABA receptor modulators; NMDA receptor modulators, histamine-3 (H3) receptor modulators, dopamine agonists and orexin receptor modulators.
Cannabinoid receptor modulators may reduce or ameliorate substance abuse or addictive disorders. Therefore, 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 may reduce anxiety or depression; therefore, the compounds described in this application may be used in combination with anti-anxiety agents or antidepressants. Examples of suitable anti-anxiety agents for use in combination with the compounds of the present invention include benzodiazepines (e.g., diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazepate, halazepam and prazepam), 5HT1A receptor agonists (e.g., buspirone, flesinoxan, gepirone and ipsapirone), and corticotropin releasing factor (CRF) antagonists.
Examples of suitable classes of anti-depressants for use in combination with the compounds of the present invention include norepinephrine reuptake inhibitors (tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine and sertraline), monoamine oxidase inhibitors (MAOIs) (isocarboxazid, phenelzine, tranylcypromine, selegiline), reversible inhibitors of monoamine oxidase (RIMAs) (moclobemide), serotonin and norepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropin releasing factor (CRF) receptor 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 could also enhance symptom reduction in the treatment of psychosis or mania. Further, such a combination could enable rapid symptom reduction, reducing the need for chronic treatment with antipsychotic agents. Such a combination could also reduce the effective antipsychotic dose requirement, resulting in reduced probability of developing the motor dysfunction typical of chronic antipsychotic treatment.
Examples of suitable antipsychotic agents for use in combination with the compounds of the present invention include the phenothiazine (chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine), thioxanthine (chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine, olanzepine and aripiprazole), butyrophenone (haloperidol), dipheyylbutylpiperidine (pimozide) and indolone (molindolone) classes of antipsychotic agents. Other antipsychotic agents with potential therapeutic value in combination with the compounds in the present invention include loxapine, sulpiride and risperidone.
Combination of the compounds in the present invention with conventional antipsychotic drugs could also provide an enhanced therapeutic effect for the treatment of schizophrenic disorders, as described above for manic disorders. As used here, schizophrenic disorders include paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia, schizophreniform disorder, shcizoaffective disorder, delusional disorder, brief psychotic disorder and psychotic disorder not specified. Examples of suitable antipsychotic drugs for combination with the compounds in the present invention include the antipsychotics mentioned above, as well as dopamine receptor antagonists, muscarinic receptor agonists, 5HT2A receptor antagonists and 5HT2A/dopamine receptor antagonists or partial agonists (e.g., olanzepine, aripiprazole, risperidone, ziprasidone).
The compounds described in the present invention could be used to enhance the effects of cognition-enhancing agents, such as acetylcholinesterase inhibitors (e.g., tacrine), muscarinic receptor-1 agonists (e.g., milameline), nicotinic agonists, glutamic acid receptor (AMPA and NMDA) modulators, and nootropic agents (e.g., piracetam, levetiracetam). Examples of suitable therapies for 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-K blockers, and KCNQs blockers.
The compounds described in the present invention could be used to enhance the effects of agents used in the treatment of Parkinson's Disease. Examples of agents used to treat Parkinson's Disease include: levadopa with or without a COMT inhibitor, antiglutamatergic drugs (amantadine, riluzole), alpha-2 adrenergic antagonists such as idazoxan, opiate antagonists, such as naltrexone, other dopamine agonists or transportor modulators, such as ropinirole, or pramipexole or neurotrophic factors such as glial derived neurotrophic factor (GDNF).
The compounds described in the present invention could be used in combination with suitable 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 NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen®, Celebrex®, Vioxx®), CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate (CellCept®), integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, tumor necrosis factor (TNF) antagonists (e.g., infliximab, OR1384, including TNF-alpha inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptor such as etanercept (Enbrel®), rapamycin (sirolimus or Rapamune) and leflunomide (Arava)), prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors, and therapies for the treatment of irritable bowel syndrome (e.g., Zelnorm® and Maxi-K® openers such as those disclosed in U.S. Pat. No. 6,184,231 B1).
Exemplary of such other therapeutic agents which may be used in combination with cannabinoid receptor modulators include the following: cyclosporins (e.g., cyclosporin A), anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from 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 methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathiprine and cyclophosphamide, anticytokines such as antiIL-4 or IL-4 receptor fusion proteins and PDE 4 inhibitors such as Ariflo, and the PTK inhibitors disclosed in the following U.S. patent applications, incorporated herein by reference in their entirety: Ser. No. 09/097,338, filed Jun. 15, 1998; Ser. No. 09/094,797, filed Jun. 15, 1998; Ser. No. 09/173,413, filed Oct. 15, 1998; and Ser. No. 09/262,525, filed Mar. 4, 1999. See also the following documents and references cited therein and incorporated herein by reference: Hollenbaugh, D., et al., “Cleavable CD40Ig Fusion Proteins and the Binding to Sgp39”, J. Immunol. Methods (Netherlands), 188 (1), pp. 1-7 (Dec. 15, 1995); Hollenbaugh, D., et al., “The Human T Cell Antigen Gp39, A Member of the TNF Gene Family, Is a Ligand for the CD40 Receptor: 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 Factor Receptor (P75)-Fc Fusion Protein,” New England J. of Medicine, 337 (3), pp. 141-147 (1997).
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
The compounds of formula (I) of the invention can be administered orally or parenterally, such as subcutaneously or intravenously, as well as by nasal application, rectally or sublingually to various mammalian species known to be subject to such maladies, e.g., humans, in an effective amount up to 1 gram, preferably up to 200 mg, more preferably up to 100 mg in a regimen of single, two or four divided daily doses.
The compounds of the formula (I) can be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such 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, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds can, 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 suitable pharmaceutical 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 can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of 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 which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can 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 release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable 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 wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
Exemplary compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
It will be understood that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length 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, drug combination, 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 such modifications and variations should be considered within the scope of the claims that follow.

## Claims

1. A compound according to formula I:




or a pharmaceutically acceptable salt or a stereoisomer thereof wherein:
R1 and R2 are independently selected from the group consisting of aryl and heteroaryl;
R3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and —(CH2)nC(O)NR5R6;
n is 1 or 2;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; and R5 and R6 may be taken together to form a 4-7 membered ring; and
R4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl.

2. The compound according to claim 1, wherein:
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl and —(CH2)nC(O)NR5R6;
n is 1 or 2;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; and R5 and R6 may be taken together to form a 4-7 membered ring.

3. The compound according to claim 1, wherein:
R4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and heterocyclyl.

4. The compound according to claim 1, wherein:
R1 and R2 are independently selected from the group consisting of aryl and heteroaryl;
R3 is selected from the group consisting of hydrogen, alkyl cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl and —(CH2)nC(O)NR5R6;
n is 1 or 2;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; and R5 and R6 may be taken together to form a 4-7 membered ring; and
R4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and heterocyclyl.

5. The compound according to claim 1, wherein:
R1 is selected from the group consisting of phenyl, 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyano-3-pyridyl and 4-methyl-3-pyridyl;
R2 is selected from the group consisting of 4-chlorophenyl, 4-cyanophenyl, 4-fluorophenyl, 4-pyridyl, 3-methyl-4-pyridyl, 3-ethyl-4-pyridyl, 4-methyl-3-pyridyl, 4-ethyl-3-pyridyl, 4-isopropyl-3-pyridyl, 4-chloro-2-pyridyl, 4-methyl-2-pyridyl and 4-cyano-3-pyridyl;
R3 is selected from the group consisting of 4-cyanobenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethyl-3-pyridylmethyl, 2-methyl-4-trifluoromethyl-3-pyridylmethyl, 2-ethyl-4-trifluoromethyl-3-pyridylmethyl, 2-isopropyl-4-trifluoromethyl-3-pyridylmethyl, 2-cyclopropyl-4-trifluoromethyl-3-pyridylmethyl, 2-cyano-4-trifluoromethyl-3-pyridylmethyl, 2-trifluoromethyl-3-pyridylmethyl, 2-methyl-3-pyridylmethyl, 2-isopropyl-3-pyridylmethyl, 2-cyano-3-pyridylmethyl and 4-trifluoromethyl-2-pyridylmethyl; and
R4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl and trifluoroethyl.

6. A compound according to formula II




or a pharmaceutically acceptable salt or a stereoisomer thereof wherein:
R1 and R2 are independently selected from the group consisting of aryl and heteroaryl;
R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and —(CH2)nC(O)NR5R6;
n is 1 or 2;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl; and R5 and R6 may be taken together to form a 4-7 membered ring; and
R4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroaryl, aryl, heteroaryl, arylalkyl and heteroarylalkyl.

7. The compound according to claim 6, wherein:
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl —(CH2)nC(O)NR5R6;
n is 1 or 2;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; and R5 and R6 may be taken together to form a 4-7 membered ring.

8. The compound according to claim 6, wherein:
R4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and heterocyclyl.

9. The compound according to claim 6, wherein:
R1 and R2 are independently selected from the group consisting of aryl and heteroaryl;
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl and —(CH2%)C(O)NR5R6;
n is 1 or 2;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; and R5 and R6 may be taken together to form a 4-7 membered ring; and
R4 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and heterocyclyl.

10. The compound according to claim 6, wherein:
R1 is selected from the group consisting of phenyl, 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyano-3-pyridyl and 4-methyl-3-pyridyl;
R2 is selected from the group consisting of 4-chlorophenyl, 4-cyanophenyl, 4-fluorophenyl, 4-pyridyl, 3-methyl-4-pyridyl, 3-ethyl-4-pyridyl, 4-methyl-3-pyridyl, 4-ethyl-3-pyridyl, 4-isopropyl-3-pyridyl, 4-chloro-2-pyridyl, 4-methyl-2-pyridyl and 4-cyano-3-pyridyl;
R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl and —(CH2)nC(O)NR5R6;
n is 1 or 2;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; and R5 and R6 may be taken together to form a 4-7 membered ring; and
R4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, trifluoromethyl, and trifluoroethyl.

11. The compound according to claim 1, wherein the compound is selected from the group consisting of:

12. The compound according to claim 6, wherein the compound is selected from the group consisting of:

13. A pharmaceutical composition, comprising: at least one compound according to claim 1; and at least one pharmaceutically acceptable carrier or diluent.

14. The pharmaceutical composition according to claim 13, further comprising: at least one additional therapeutic agent selected from:
anti-obesity agents, appetite suppressants, anti-diabetic agents, anti-hyperlipidemia agents, hypolipidemic agents, hypocholesterolemic agents, lipid-modulating agents which are cholesteryl transfer protein inhibitors (CETP), cholesterol-lowering agents, lipid-lowering agents, HDL-raising agent and anti-hypertensive agents;
agents used to treat sleep disorders which are selected from melatonin analogs, melatonin receptor antagonists, ML1B agonists, GABA receptor modulators, NMDA receptor modulators, histamine-3 (H3) receptor modulators, dopamine agonists and orexin receptor modulators;
agents used to treat substance abuse and addictive disorders selected from serotonin reuptake inhibitors (SSRI), methadone, buprenorphine, nicotine and bupropion;
anti-anxiety agents selected from diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazepate, halazepam and prazepam, 5HT1A receptor agonists, and corticotropin releasing factor (CRF) antagonists;
anti-depressants selected from norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) receptor antagonists, alpha-adrenoreceptor antagonists, bupropion, lithium, nefazodone, trazodone and viloxazine;
anti-psychotic agents selected from chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chlorprothixene, thiothixene, clozapine, olanzepine, aripiprazole, haloperidol, pimozide, molindolone, loxapine, sulpiride, risperidone, dopamine receptor antagonists, muscarinic receptor agonists, 5HT2A receptor antagonists and 5HT2A/dopamine receptor antagonists or ziprasidone;
agents used to treat Parkinson's disease selected from levadopa with or without a COMT inhibitor, antiglutamatergic drugs, alpha-2 adrenergic antagonists, opiate antagonists, ropinirole, pramipexole or glial derived neurotrophic factor (GDNE).

15. A method for treating obesity, comprising: administering a therapeutically effective amount of a compound according to claim 1 to a patient in need.

16. A method for smoking cessation, comprising: administering a therapeutically effective amount of a compound according to claim 1 to a patient in need.

17. A pharmaceutical composition, comprising: at least one compound according to claim 6; and at least one pharmaceutically acceptable carrier or diluent.

18. The pharmaceutical composition according to claim 17, further comprising: at least one additional therapeutic agent selected from:
anti-obesity agents, appetite suppressants, anti-diabetic agents, anti-hyperlipidemia agents, hypolipidemic agents, hypocholesterolemic agents, lipid-modulating agents which are cholesteryl transfer protein inhibitors (CETP), cholesterol-lowering agents, lipid-lowering agents, HDL-raising agent and anti-hypertensive agents;
agents used to treat sleep disorders which are selected from melatonin analogs, melatonin receptor antagonists, ML1B agonists, GABA receptor modulators, NMDA receptor modulators, histamine-3 (H3) receptor modulators, dopamine agonists and orexin receptor modulators;
agents used to treat substance abuse and addictive disorders selected from serotonin reuptake inhibitors (SSRI), methadone, buprenorphine, nicotine and bupropion;
anti-anxiety agents selected from diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazepate, halazepam and prazepam, 5HT1A receptor agonists, and corticotropin releasing factor (CRF) antagonists;
anti-depressants selected from norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) receptor antagonists, alpha-adrenoreceptor antagonists, bupropion, lithium, nefazodone, trazodone and viloxazine;
anti-psychotic agents selected from chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chlorprothixene, thiothixene, clozapine, olanzepine, aripiprazole, haloperidol, pimozide, molindolone, loxapine, sulpiride, risperidone, dopamine receptor antagonists, muscarinic receptor agonists, 5HT2A receptor antagonists and 5HT2A/dopamine receptor antagonists or ziprasidone;
agents used to treat Parkinson's disease selected from levadopa with or without a COMT inhibitor, antiglutamatergic drugs, alpha-2 adrenergic antagonists, opiate antagonists, ropinirole, pramipexole or glial derived neurotrophic factor (GDNF).

19. A method for treating obesity, comprising: administering a therapeutically effective amount of a compound according to claim 6 to a patient in need.

20. A method for smoking cessation, comprising: administering a therapeutically effective amount of a compound according to claim 6 to a patient in need.