WO2007146761A2 - Diaryl pyrimidinones and related compounds - Google Patents

Diaryl pyrimidinones and related compounds Download PDF

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Publication number
WO2007146761A2
WO2007146761A2 PCT/US2007/070676 US2007070676W WO2007146761A2 WO 2007146761 A2 WO2007146761 A2 WO 2007146761A2 US 2007070676 W US2007070676 W US 2007070676W WO 2007146761 A2 WO2007146761 A2 WO 2007146761A2
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alkyl
oxo
mono
compound
phenyl
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PCT/US2007/070676
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French (fr)
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WO2007146761A3 (en
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Hongbin Li
Jun Yuan
David J. Wustrow
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Neurogen Corporation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates generally to diaryl pyrimidinones and related compounds, and to the use of such compounds to treat conditions responsive to cannabinoid receptor-1 (CB l ) modulation.
  • the invention further relates to the use of such compounds as reagents for the identification of other agents that bind to CB l , and as probes for the detection and localization of CB l .
  • Obesity is the most common nutritional problem in developed countries. This condition is often both harmful and costly, as it increases the likelihood of developing serious health conditions (such as cardiovascular diseases, stroke and diabetes) and complicates numerous chronic conditions such as respiratory diseases, osteoarthritis, osteoporosis, gall bladder disease and dyslipidemias. Fortunately, however, many of the conditions caused or exacerbated by obesity can be resolved or dramatically improved by weight loss.
  • obesity is now recognized as a complex multifactorial disease involving defective regulation of food intake, food-induced energy expenditure and the balance between lipid and lean body anabolism. Both environmental and genetic factors play a role in the development of obesity. As a result, treatment programs that focus entirely on behavior modification have limited efficacy and are associated with recidivism rates exceeding 95%. Pharmacotherapy is now seen as a critical component of weight loss and subsequent weight management.
  • the present invention provides diaryi pyrimidinones and related compounds that satisfy Formula 1:
  • Formula I are a pharmaceutically acceptable salt, solvate (e.g , hydrate) or ester of such a compound.
  • Ar, and Ar 2 are independently chosen from phenyl, naphthyl and 5- to IO-membered heteroary], each of which is optionally substituted, and each of which is preferably substituted with from 0 to 6 substituents independently chosen from R A ;
  • R 1 is:
  • R 2 is a non-hydrogen substituent; preferably R 2 is:
  • R 4 ;, and R 4I are independently: (i) hydrogen, halogen, cyano, -COOH or C r C 6 aIkyI;
  • R B taken together to form a 4- to 7-membered cycloalkyl or heterocycloalkyl that is optionally substituted, and is preferably substituted with from O to 4 substituents independently chosen from R B ;
  • R 5 and R 6 are independently (i) hydrogen; or
  • Each R B is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, -COOH, Ci-C 6 alkyl, d-C ⁇ afkenyl, C r C 6 alkynyI, Ci-Qhaloalkyl, C ,-C 6 alkoxy, C r C 6 haloalkoxy, Cj-C 6 alkylthio.
  • C r C 6 aIkanoyi Ci-C 6 alkoxycarbonyl, C]-C 6 alkanoyloxy, C 3 -
  • Cealkanone mono- or di-(C
  • diaryl pyrimidinones and related compounds of Formula 1, and other Formulas provided herein exhibit a K, of no greater than 2 micromolar, 1 micromolar, 500 nanomolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in a CB l ligand binding assay and/or have an IC 50 value of no greater than 2 micromolar, 1 micromolar, 500 nanomolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in an assay for determination of CB l antagonist activity,
  • diaryl pyrimidinones and related compounds provided herein exhibit no detectable agonist activity.
  • diaryl pyrimidinones and related compounds provided herein are labeled with a detectable marker (e.g., radiolabeled or fluorescein conjugated).
  • a detectable marker e.g., radiolabeled or fluorescein conjugated
  • the present invention further provides, within other aspects, pharmaceutical compositions comprising at least one diaryl pyrimidinone or related compound as described herein in combination with a physiologically acceptable carrier or excipient.
  • the present invention further provides methods for treating a condition responsive to CB l modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one diaryl pyrimidinone or related compound as described herein.
  • Such conditions include, for example, appetite disorders, obesity, dependency disorders such as alcohol dependency and nicotine dependency, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, memory disorders, cognitive disorders, movement disorders, metabolic disorders, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension and drug- induced hypotension.
  • compositions comprising (a) a first agent that is a diaryl pyrimidinone or related compound as described herein, (b) a second agent that is suitable for treating an appetite disorder, obesity, a dependency disorder such as alcohol dependency and nicotine dependency, asthma, liver cirrhosis, sepsis, irritable bowe!
  • the present invention also provides packaged pharmaceutical preparations, comprising: (a) a composition comprising a diaryl pyrimidinone or related compound as described herein in a container; and (b) instructions for using the composition to treat one or more conditions responsive to CB l modulation.
  • the present invention provides methods for determining the presence or absence of CB l in a sample, comprising: (a) contacting a sample with a diaryl pyrimidinone or related compound as described herein under conditions that permit binding of the compound to CB l ; and (b) detecting a signal indicative of a level of the diaryl pyrimidinone or related compound bound to CB l .
  • the invention provides methods of preparing the compounds disclosed herein, including the intermediates.
  • diaryl pyrimidinones and related compounds. Such compounds may be used in vitro or in vivo in a variety of contexts as described herein.
  • TERMINOLOGY Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. If a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass ail tautomeric forms. Certain compounds are described herein using a general formula that includes variables ⁇ e.g., X, A, Ar 1 ).
  • each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence.
  • the term "diaryl pyrimidinones and related compounds" encompasses all compounds of
  • Formula I includes pharmaceutically acceptable salts, solvates ⁇ e.g., hydrates) and esters of such compounds. It will be apparent that, unless otherwise specified herein, such formulas encompass compounds in which one or both of Ari and Ar 2 is a heterocycle, as well as compounds in which neither Ar 1 nor Ar 2 is a heterocycle. Such formulas further encompass compounds in which A is optionally substituted carbon (pyrimidinones) and compounds in which A is N (triazinones).
  • a "pharmaceutically acceptable salt" of a compound recited herein is an acid or base salt that is suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication.
  • Such salts include mineral and organic acid salts of basic residues such as amines, as wei) as alkali or organic salts of acidic residues such as carboxylic acids.
  • Specific pharmaceutically acceptable anions for use in salt formation include, but are not limited to, acetate, 2-acetoxybenzoate, ascorbate, benzoate, bicarbonate, bromide, calcium edetate, carbonate, chloride, citrate, dihydrochioride, diphosphate, ditartrate, edetate, estolate (ethylsuccinate), formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylars anil ate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxymaleate, hydroxynaphthoate, iodide, isethionate, lactate, Iactobionate, malate, maleate, mandelate
  • pharmaceutically acceptable cations for use in salt formation include, but are not limited to ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethyl en ediamine, meglumine, procaine, and metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile, is preferred.
  • nonaqueous media such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile
  • prodrugs of the compounds provided herein are a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, amine or sulfhydryi groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, amino, or sulfhydryi group, respeclive ⁇ y.
  • Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon.
  • Alkyl groups include groups having from 1 to 8 carbon atoms (Cj-Cgalkyl), from 1 to 6 carbon atoms (CrQalkyl) and from 1 to 4 carbon atoms (C r C 4 alky[), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, rerf-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexy!, 2-hexyl, 3-hexyl or 3-methylpentyl.
  • Co-C 4 alkyr refers to a single covalent bond (C 0 ) or an alkyiene group having 1 ,
  • C 0 -C 6 aikyl refers to a single covalent bond or a d-C 6 alkyIene group; "C 0 -
  • C 8 alkyl refers to a single covalent bond or a C r C s alkylene group.
  • a substituent of an alkyl group is indicated, as in the term "C r C 4 hydroxyalkyl,” which refers to a C]-C 4 alkyl group that is substituted with one or more hydroxy groups, and "C r C 4 aminoaIkyl,” which refers to a C 1 -
  • Alkyiene refers to a divalent aSkyl group, as defined above.
  • C r C 4 alkyfene is an alkyiene group having 1 , 2, 3 or 4 carbon atoms.
  • Alkenyl refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C 2 -C 3 alkenyl, C 2 -C 6 afkenyl and C 2 -
  • Alkynyl refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond.
  • Alkynyi groups include
  • C 2 -C 3 alkynyl, C 2 -C 6 alkynyl and C r C 4 alkynyI groups which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
  • a “cycloalkyl” is a saturated or partially saturated cyclic group in which all ring members are carbon, such as cyclopropyl, cyclobutyi, cyclopentyl and cyclohexyl, as well as partially saturated variants thereof.
  • Certain cycloalkyl groups are C-,-C 3 cycloalkyl, in which the ring contains from 3 to
  • a "(C 3 -C 8 cycloalkyl)Co-C.jalkyl” is a C 3 -C 8 cycloalkyl group linked via a single covalent bond or a C r C 4 alkylene group.
  • alkoxy 1 ' as used herein, is meant an alkyl group attached via an oxygen bridge.
  • Alkoxy groups include C 3 -C 6 alkoxy and Cj-Qalkoxy groups, which have from 1 to 6 or 1 to 4 carbon atoms, respectively.
  • 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy are representative alkoxy groups.
  • Alkylthio refers to an alkyl group as described above attached via a sulfur bridge.
  • Alkylsulfinyl refers to groups of the formula -(SO)-alkyl, in which the sulfur atom is the point of attachment.
  • Alkylsulfinyl groups include C r C 6 alkylsulfinyl and C r C 4 alkyIsuIfmyl groups, which have from I to 6 or I to 4 carbon atoms, respectively.
  • Alkylsulfonyl refers to groups of the formula -(SO 2 )-aIkyl, in which the sulfur atom is the point of attachment. Alkylsulfonyl groups include C r Qalkylsu!fonyi and C r C 4 alkylsulfonyI groups, which have from 1 to 6 or 1 to 4 carbon atoms, respectively. "(C 1 -C 6 alkyl)sulfonyIC 0 -C 4 alkyl” is a C i-Cealkylsulfony! group linked via a single covalent bond or a C
  • Alkanoyl groups include C 2 -C 8 alkanoy 1, C 2 -C 6 alkanoyl and C 2 -
  • C 4 alkanoyl groups which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
  • Ethanoyi is C 2 alkanoyl.
  • alkanone is a ketone group in which carbon atoms are in a linear or branched alkyl arrangement.
  • C 3 -C 8 alkanone refers to an a ⁇ kanone having from 3 to 8, 6 or 4 carbon atoms, respectively.
  • alkyl ether refers to a linear or branched ether substituent.
  • Alkyl ether groups include C 2 -C 8 alkyl ether, C 2 -C 6 alkyl ether and C 2 -QaIkVl ether groups, which have 2 to 8, 6 or 4 carbon atoms, respectively.
  • a C 2 alkyl ether has the structure -CH 2 -O-CH 3 .
  • Alkoxycarbonyl groups include C)-C 8 , Cj-Ce and C,- Qalkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the alkyl portion of the group.
  • Alkanoyloxy groups include C 2 -C 8 , C 2 -C 6 and C 2 -C 4 alkanoyloxy groups, which have from 2 to 8, 6 or 4 carbon atoms, respectively.
  • Alkylamino refers to a secondary or tertiary amine that has the general structure -NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl is selected independently from alkyl, cycloalkyl and
  • (cycloalkyl)alkyl groups include, for example, mono- and di-(C r C s alkyl)amino groups, in which each Ci-C 8 alkyl may be the same or different, as well as mono- and ds-(Ci-C 6 alkyl)amino groups and mono- and di-(C r C 4 alkyl)amino groups.
  • Alkylaminoalkyl refers to an alkylamino group linked via an alkylene group (i.e., a group having the general structure -alkylene-NH-alkyl or -alkylene-N(alkyl)(alkyl)) in which each alkyl is selected independently from alkyl, cycSoalkyl and (cycloalkyl)alkyl groups.
  • Alkyiaminoalkyl groups include, for example, mono- and di-(C r C 8 alkyI)aminoCi-C 8 alkyl, mono- and di-(C 5 - C 6 alkyl)aminoCi-C fi alkyl and mono- and di-(Ci-C 3 alkyI)aminoCi -C 4 alkyl.
  • "Mono- or di-(C,- C 6 alkyl)aminoCo-C 4 alkyl” refers to a mono- or group linked via a single covalent bond or a C r C 4 aIkylene group. The following are representative alkylaminoalkyi groups:
  • alkyl as used in the terms “alkyiamino” and “alkyiaminoalkyl” differs from the definition of "alkyl” used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cyc[oaikyl)alkyl groups (e.g., (C 3 -C 8 cycloa[kyl)Co-C 4 alkyl).
  • Ci-Cealkanoylammo refers to a mono- or di-(CrC 6 aIkyl)amino group in which at least one C
  • (Ci-C 6 alkanoy])aminoC ⁇ rC 4 alkyi refers to a mono- or di-(Ci-Qalkyl)aminoCo-C 4 a]kyI moiety in which at least one C
  • the following are representative (CrC 6 alkanoyl)ammoC 0 -C 4 alkyl groups:
  • "Mono- or di-(Ci- C 6 alkyI)aminocarbonyIC 0 -C 4 aIkyr refers to an aminocarbonyl group in which one or both hydrogens are replaced with an independently selected C r C 6 alkyl group, and which is linked via a single covalent bond or a Cj-C 4 alkylene group.
  • aminonosulfonyl refers to a sulfonamide group (i.e., -SO 2 NH 2 ).
  • C 6 alkyl)aminosulfonylCo-C 4 alkyl refers to an aminosulfonyl group in which one or both hydrogens are replaced with an independently selected C]-C 6 alkyl group, and which is linked via a single covalent bond or a C r C 4 aikylene group.
  • -C fl alkyI)sulfony[aminoC 0 -C 4 alkyl” refers to a group of the formula -(Co-C 4 alkyl)-N(R ⁇ )S ⁇ 2 (R ⁇ ), in which R x is hydrogen or C r C 6 aIkyi and Ry is an independently selected C r C 6 alkyl group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalky ⁇ is an alkyl group that is substituted with I or more independently chosen halogens (e.g., "Cj ⁇ C s haioalkyl” groups have from 1 to 8 carbon atoms; "C r C 6 haloalkyl” groups have from 1 to 6 carbon atoms).
  • haloalkyl groups include, but are not limited to, mono-, di- or tri-f ⁇ uoromethyl; mono-, di- or tri-chbromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; and 1 ,2,2,2-tetrafluoro-l -trifluoromethyl-ethyl.
  • Typical haloalkyl groups are trifluoromethyl and difluoromethyl.
  • haloalkoxy refers to a hatoalky! group as defined above attached via an oxygen bridge.
  • Ci-C 8 haloalkoxy have 1 to S carbon atoms.
  • a "carbocycle” has from 1 to 3 fused, pendant or spiro rings, each of which has oniy carbon ring members. Typically, a carbocycle that has a single ring contains from 3 to S ring members (i.e., C 3 -Cgcarbocycles); rings having from 4 or 5 to 7 ring members (i.e., CrCvcarbocycles or C 5 - C7carbocycles) are recited in certain embodiments.
  • Carbocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Carbocycles may be optionally substituted with a I O variety of substituents, as indicated. Unless otherwise specified, a carbocycle may be a cycloalkyl group (i. e., each ring is saturated or partially saturated as described above) or an aryl group (i.e., at least one ring within the group is aromatic). Representative aromatic carbocycles are phenyl, naphthyl and biphenyl. In certain embodiments preferred carbocycles have a single ring, such as phenyl and C 3 -C 3 cycloa!kyl groups.
  • a “heterocycle” (also referred to herein as a “heterocyclic group”) has from 1 to 3 fused, pendant or spiro rings, at least one of which is a heterocyclic ring (i.e , one or more ring atoms is a heteroatom independently chosen from oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon).
  • a heterocyclic ring comprises 1 , 2, 3 or 4 heteroatoms; within certain embodiments each heterocyclic ring has 1 or 2 heteroatoms per ring.
  • Each heterocyclic ring generally 0 contains from 3 to 8 ring members (rings having from 4 or 5 to 7 ring members are recited in certain embodiments) and heterocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members.
  • Certain heterocycles comprise a suif ⁇ r atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SO 2 .
  • Heterocycles may be optionally substituted with a variety of substituents, as indicated.
  • heterocycles are 4- to 10-membered or 5- to 30- 5 membered, which comprise one or two rings - in certain embodiments, such heterocycles are monocyclic (e.g., 4- to 8-membered, 5- to 8-membered, 5- to 7-membered, or 5- or 6-membered); in other embodiments, such heterocycles are 9- or 10-membered bicyclic heterocycles.
  • heterocycles are heteroaryl groups (i.e., at least one heterocyclic ring within the group is aromatic), such as a 5- to 10-membered heteroaryl (which may be monocyclic or bicyclic) or a 6- 0 membered heteroaryl (e.g., pyridyl or pyrimidyl).
  • Other heterocycles are heterocycloalkyl groups.
  • heterocycles may be linked by a single covalent bond or via an alkylene group, as indicated, for example, by the term "(4- to 8-membered heterocycloaikyl)Co-C 4 alkyl.”
  • a “substituent,” as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest.
  • a “ring substituent” may be a moiety such as a 5 halogen, alkyl group, haloaikyl group or other group discussed herein that is covalently bonded to an atom (such as a carbon or nitrogen atom) that is a ring member.
  • substitution refers to replacing a hydrogen atom in a molecular structure with a substituent as described above, such that the valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.
  • Groups that are "optionally substituted” are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically 1 , 2, 3, 4 or 5 positions, by one or more suitable groups (which may be the same or different).
  • Optional substitution is also indicated by the phrase
  • Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substitutents).
  • CB l refers to the human cannabinoid receptor reported by Hoeche et al. (1991 ) New Biol. J(9j:88G-85, as well as allelic variants thereof and homologues thereof found in other species.
  • a "CB l antagonist” is a compound that detectably inhibits signal transduction mediated by CB 1. Such inhibition may be determined using the representative agonist-induced GTP binding assay provided in Example 12.
  • Preferred CB I antagonists have an IC 50 Of 2 ⁇ M or less in this assay, more preferably 1 ⁇ M or less, and still more preferably 500 nM or less or 100 nJvl or less.
  • the CB l antagonist is specific for CB I ⁇ i.e., the IC 50 value in a similar assay performed using the predominantly peripheral cannabinoid receptor CB2 is greater than 2 ⁇ M and/or the 1C JO ratio (CB2/CB I ) is at least 10, preferably 100, and more preferably at least 1000).
  • CB l antagonists preferably have minimal agonist activity (i.e., induce an increase in the basal activity of CB l that is less than 5% of the increase that would be induced by one EC 50 of the agonist CP55.940, and more preferably have no detectable agonist activity within the assay described in Example 12).
  • CBl antagonists for use as described herein are generally non-toxic.
  • CB l antagonists include neutral antagonists and inverse agonists.
  • a "neutral antagonist" of CBl is a compound that inhibits the activity of CBl agonist (e.g., endocannabinoids) at CB l , but does not significantly change the basal activity of the receptor (i.e., within a GTP binding assay as described in Example 12 performed in the absence of agonist, CB l activity is reduced by no more than 10%, more preferably by no more than 5%, and even more preferably by no more than 2%; most preferably, there is no detectable reduction in activity).
  • CBl agonist e.g., endocannabinoids
  • An "inverse agonist" of CB l is a compound that reduces the activity of CB I below its basal activity level in the absence of activating concentrations of agonist. Inverse agonists may also inhibit the activity of agonist at CB l , and/or may inhibit binding of CB l agonist to CB l .
  • the ability of a compound to inhibit the binding of CB l agonists to the CB I receptor may be measured by a binding assay, such as the radioligand binding assay given in Example 1 1 .
  • the reduction in basal activity of CBl produced by an inverse agonist may be determined from a GTP binding assay, such as the assay of Example 12.
  • a “non-competitive CB l antagonist” is a CB l antagonist that (1 ) does not detectably inhibit binding of CB l agonist (e.g., CP55,940) to CBl at antagonist concentrations up to 10 ⁇ M and (2) reduces the maxima! functional response elicited by agonist.
  • CB l agonist e.g., CP55,940
  • Compounds that satisfy these two conditions may be identified using the assays provided herein. Such compounds generally do not display detectable activity in the competition binding assay described in Example 1 1.
  • a non-competitive antagonist concentration -dependently reduces the maxima! functional response elicited by agonist without altering agonist EC 50 .
  • the suppression of functional activity by a non-competitive antagonist cannot be overcome by increasing agonist concentrations (i. e., the antagonist activity is insurmountable).
  • a “therapeutically effective amount” is an amount that, upon administration to a patient, results in a discernible patient benefit (e.g., provides detectable relief from a condition being treated). Such relief may be detected using any appropriate criteria, including the alleviation of one or more symptoms of dependency or an appetite disorder, or the promotion of weight loss. In the case of appetite suppression, a therapeutically effective amount is sufficient to decrease patient appetite, as assessed using patient reporting or actual food intake.
  • a therapeutically effective amount or dose generally results in a concentration of compound in a body fluid (such as blood, plasma, serum, CSF, synovial fluid, lymph, cellular interstitial fluid, tears or urine) that is sufficient to result in detectable alteration in CB l - mediated signal transduction (using an assay provided herein).
  • a body fluid such as blood, plasma, serum, CSF, synovial fluid, lymph, cellular interstitial fluid, tears or urine
  • the discernible patient benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a predetermined regimen, depending upon the indication for which the compound is administered.
  • a "patient” is any individual treated with a compound as provided herein. Patients include humans, as well as other animals such as companion animals (e.g , dogs and cats) and livestock.
  • Patients may be experiencing one or more symptoms of a condition responsive to CB l modulation or may be free of such symptom(s) (i.e., treatment may be prophylactic in a patient considered to be at risk for the development of such symptoms).
  • diary! pyrimidinones and related compounds that may be used in a variety of contexts, including in the treatment of appetite disorders, obesity and dependency disorders (addictive disorders). Such compounds may also be used within ui assays
  • Diary! pyrimidinones and related compounds provided herein generally satisfy Formula I: Formula I or are a pharmaceutical Jy acceptable salt, solvate or ester of such a compound, in which variables are a described above.
  • Formula IA the variables within Formula I carry the following definitions: A is CR, or N;
  • Ar, and Ar 2 are independently chosen from phenyl, naphthyl and 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from R A ;
  • R 2 is:
  • R 7 is hydrogen, C r C s aIkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C,-C 3 cycloalkyl)Co-C 4 alkyl or (4- to 8- membered heterocycloalkyl)Co-C 4 alkyl, each of which is substituted with from O to 6 substituents independently chosen from R B ;
  • Each R A is independently chosen from:
  • Each RB is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro. aminocarbonyl, aminosulfonyl, -COOH, C ⁇ -C 6 alkyl, C r C 6 a!kenyl, C,-C 6 alkynyl, (C 3 -C 3 cycloalkyl)Co-C 4 alky],
  • CrC f ihaloalkyl Ci-C 6 alkoxy, C,-C 6 haloalkoxy. C r C 6 alkylthio. C r C 6 alkanoy ⁇ , C 1 -
  • Arj and Ar 2 are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 1 to 5 substituents independently chosen from R A ; such that Ar 2 is substituted para to the point of attachment ⁇ i.e., if Ar 2 is phenyl, then the phenyl ring is substituted at the 4-position, and may (but need not) be additionally substituted at from 1 to 4 other ring carbon atoms); R 1 is:
  • Ci-C f ,alkyl C 2 -C 6 alkenyi, C 2 -C 6 alkynyl, C 2 -C 6 alkyl ether, C r C 6 aikoxy, Q-Qalkoxycarbonyl, mono- or di-fCi-Cealky ⁇ aminocarbonylCo-Qalkyl, mono- or di-(CrC6a!kyl)aminoC 0 -
  • R. 5 and R 6 are independently: (i) hydrogen; or
  • R 7 is hydrogen, C r C 6 alkyI, C 2 -C 6 alkenyl s C 2 -C 6 alkynyl, (C 3 -C8cycloalkyl)Co-C 4 alkyl or (4- to 8- membcred heterocycloalky!C 0 -C 4 alkyl, each of which is substituted with from O to 6 substituents independently chosen from R B ;
  • Each R A is independently chosen from:
  • C 4 alkyl mono- or di-(C r C 6 alkyl)aminoCo-C 4 alkyl, mono- or di-(C,- C 6 alkyl)aminosulfonylCo-C 4 alkyl, mono- or di-tCrQalky ⁇ aminocarbonylCo ⁇ alkyl, phenyl C 0 -C 4 alkyl, (4- to 8-membered heterocycle)C 0 -C. ( alkyl and (4- to 8-membered heterocycle)Ci-C 4 alkoxy: each of which is substituted with from O to 4 substituents independently chosen from R B ; and
  • Each R B is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl. aminosulfonyl, -COOH, C r C 6 alkyl, C,-C 6 alkenyl, C r C 6 alkynyl, (C 3 -C 3 cycloalkyI)C 0 -C,alkyl. C r C 6 haloafkyL Ci-Calkoxy, C,-C 6 haloalkoxy, C,-C r ,alkylthio, C,-C 6 alkanoyL C 1 - C fi alkoxycarbonyl.
  • C r C 6 alkanoyloxy C 3 -C 6 alkanone, mono- or di ⁇ (C
  • each R A is independently chosen from halogen, cyano, C 3 -C 6 alkyi, CVQalkenyl, C 2 -C 6 alkynyl, C,-C 6 haloalkyl, (C 3 -C 8 cycloalkyl)C 0 -C 4 alkyl and C 1 - C 6 alkoxy.
  • variable "A" in Formulas ⁇ , IA and IB is N or CR 1 .
  • A is CRj and R 1 is hydrogen or Ci- C f ialkyl,
  • R 1 is C 3 -C 6 alkanone, C r C 6 aIkoxycarbonyl, mono- or di-(Cj- C fi alkyl)aminoCo-C 4 alkyl, mono- or di-(C r C 6 alkyi)aminocarbonylC 0 -C 4 alkyi, (C 1 - C ⁇ alkanoyl)aminoCo-C, t alkyl, mono- or di-(Ci-C 6 alkyl)aminosulfony!Co-C 4 aIkyl, (Ci- C 6 a!kyl)suIfonylCo-C 4 aIkyl, mono- or
  • R 2 moieties include groups of the . wherein R 5 is C r
  • N N-R 3 include groups of the formula ⁇ ' — ' ; in certain such groups R 3 is C 3 -C 3 cycloaikyl, Cp C 6 alkanoyl, or mono- or di-(C]-C 6 alkyl)aminocarbonyi.
  • R 2 is Ci-Cealkanov ⁇ amino, mono- or di-(C r C 5 alkyl)sulfonylamino, C r C 6 a]koxycarbonyl, mono- or di-(C r C 6 alkyl)aminocarbonyl. or a group of the formula O , wherein n is O or 1 and q is O or 1 ; each of which is substituted with from
  • R 2 is C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, (C 3 -C 8 cyc[oalkyI)Co-C 4 alkyI, C r C 6 aIkanoyI, C 3 -C 6 alkanone, or C 2 - Cealkyl ether, each of which is substituted with from 0 to 6 substituents independently chosen from R B .
  • Rj is preferably C 3 -C 6 alkanone, Ci-C 6 alkoxycarbonyl, mono- or CU-(C 1 - C 6 alkyl)aminoC ⁇ rC 4 aikyl, mono- or di-(CrC 6 alkyI)aminocarbonylCo-C 4 alkyl, (C 1 - C 6 a ⁇ kanoyl)aminoCo-C 4 alkyl, mono- or di ⁇ (Ci-C 6 alkyl)aminosulfonylCo-C 4 alky[, (Cp C 6 alkyl)sulfonylCo-C 4 alkyl, or mono- or di-(Ci ⁇ C 6 alkyl)su!fonylaminoCo-C 4 alkyl, each of which is substituted with from O to 6 substituents independently chosen from R B .
  • R 2 of Formulas I and IB is, within certain embodiments:
  • R 5 is C r C 6 alkanoyl, Ci-Cealkoxycarbonyl or mono-or di-(C r
  • R 1 is preferabiy hydrogen or CpCealkyl within such compounds.
  • R 2 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -
  • R is preferably C 3 -Cs;alkanone, C r C 6 alkoxycarbonyl, mono- or di-(Ci-C b alkyi)aminoCo-C 2 alkyl, mono- or di-(Cr C 6 alkyl)aminocarbonylC 0 -C 2 alkyl.
  • R 2 moieties for Formulas I, IA and IB include mono- or di-(C r C 6 alky 1) amino, C r C 6 alkanoy!amino, mono- or di-(C r C 6 alkyl)sulfonylamino, C r C 6 alkoxycarbonyl, mono- or (Ji-(Q -C 6 alkyl)aminocarbonyl, and groups of the formula O 5 wherein n is O or
  • R 2 groups for Formulas ⁇ , IA and IB include bicyclic, N-linked
  • Formula IV wherein: B and D are independently CR n or N; R 1 is hydrogen or C r C(,alkyl; R 2 for compounds of Formulas I and IA is:
  • R 2 for compounds of Formulas I and IB is:
  • R 8 is halogen, cyano, C r C 6 alkyl. C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C,-C 6 haloalkyl, (C 3 -C 8 cycIoalkyl)C 0 -
  • R 5 , Rio and R n are independently hydrogen, halogen, cyano, C r C 6 alkyl, C 2 -C 6 alkenyl, Ca-Cealkynyl, Ci-CehaloalkyS, (C 3 -C 8 cycloalkyl)Co-C 4 alkyl or C r C 6 alkoxy; in certain such compounds, at least one ofR 9 and R 10 (where present) is not hydrogen, Certain diary] pyrimidinones and related compounds of Formula I, IA or IB further satisfy
  • R 9 and R) 0 is other than hydrogen
  • X is N(R 1 ) or CH(R 4a )
  • R 3 is C 3 -C 8 cycloalkyl, Ci-Qalkanoyl, Ci-C 6 alko ⁇ ycarbonyl, or mono- or di-(C r C ⁇ alky!)aminocarbonyl;
  • R( d is a group of the formula ' , wherein R 5 is Ci-C 6 alkanoyl, C r C 6 alkoxycarbonyl or mono-or di-(C i -C 6 alky f)aminocarbonyi .
  • diaryl pyrimidinones and related compounds provided herein are generally CB l antagonists. Certain such compounds are non-competitive CB l antagonists.
  • certain compounds provided herein display CB l specificity. CB l antagonist activity may be confirmed using an agonist-induced GTP binding assay, such as the assay described in Example 12, herein.
  • Such assays employ a CB 1 -containing cell membrane preparation (e.g., a preparation of membranes of insect cells that recombinantly express CB l ) to determine the effect of a test compound on CB l agonist-induced GTP binding to CB l .
  • a first cell membrane preparation comprising CB l is contacted with: (i) labeled GTP; (ii) a CB l agonist; and (iii) a test compound to yield a test membrane preparation.
  • a second cell membrane preparation comprising CB l is contacted with: (i) labeled GTP; and (ii) a CB l agonist to yield a control membrane preparation.
  • the iabeled GTP is preferably GTPy 35 S; a representative CBl agonist is CP55,940.
  • Such contact is performed under conditions that are suitable for GTP binding to CBl , such as the conditions described in Example 12.
  • the concentrations of labeled GTP and CBl agonist used are generally concentrations that are sufficient to result in a detectable increase in the amount of labeled GTP bound to the membrane preparation in the presence of CB l agonist. Such concentrations may be determined by routine experimentation; representative suitable concentrations are provided in Example 12. Generally, a range of test compound concentrations is used (e.g., ranging from 10 "i0 m to 10 "5 M).
  • a signal that corresponds to (represents) the amount of bound, labeled GTP is detected (typically, unbound labeled GTP is first removed via a washing step).
  • a test signal that represents an amount of bound, labeled GTP in the test membrane preparation is detected; and
  • a control signal that represents an amount of bound, labeled GTP in the control membrane preparation is detected.
  • the nature of the signal detected is determined by the type of label used. For example, if the GTP is radioactively labeled, the signal detected is radioactive decay (e.g., via liquid scintillation spectrometry).
  • the CB l antagonist activity of the test compound is then determined by comparing the test signal with the control signal. A test signal that is lower than the control signal indicates that the test compound is a CB 1 antagonist.
  • preferred compounds are cannabinoid receptor-specific. This means that they only bind to, activate, or inhibit the activity of certain receptors other than cannabinoid receptors (preferably other than CB l) with affinity constants of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 4 micromolar. Alternatively, or in addition, such compounds exhibit 200-foid greater affinity for CB l than for other cellular receptors.
  • Such other non-cannabinoid cellular receptors include histamine receptors, bioactive peptide receptors (including NPY receptors such as NPY Y5), and hormone receptors (e.g., melanin-concentrating hormone receptors).
  • Assays for evaluating binding to such receptors are well known, and include those disclosed in US patent 6,566,367, which is incorporated herein by reference for its disclosure of NPY receptor binding assays in Example 676 columns 82-83; and in PCT International Application Publication No. WO 02/094799 which is incorporated herein by reference for its disclosure of an MCH receptor binding assay in Example 2, pages 108-109.
  • compounds provided herein may be evaluated for certain pharmacological properties including, but not limited to, oral bioavailability (preferred compounds are orally bioavailable to an extent allowing for therapeutically effective doses of less than 140 mg/kg, preferably less than 50 mg/kg, more preferably less than 30 mg/kg, even more preferably less than 10 mg/kg, still more preferably less than 1 mg/kg and most preferably less than 0.1 mg/kg), toxicity (a preferred compound is nontoxic when a therapeutically effective amount is administered to a subject), side effects (a preferred compound produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject), serum protein binding and in vitro and in vivo half-life (a preferred compound exhibits an in vivo half-life allowing for Q.
  • oral bioavailability preferred compounds are orally bioavailable to an extent allowing for therapeutically effective doses of less than 140 mg/kg, preferably less than 50 mg/kg, more preferably less than 30 mg/kg, even more preferably less than 10 mg/kg
  • LD dosing
  • T.LD. dosing preferably B. I. D. dosing, and most preferably once-a- day dosing
  • differentia! penetration of the blood brain barrier may be desirable.
  • Routine assays that are well known in the art may be used to assess these properties, and identify superior compounds for a particular use.
  • assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers.
  • Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound (e.g., intravenously).
  • Serum protein binding may be predicted from albumin binding assays.
  • Compound half-life is inversely proportional to the frequency of dosage of a compound, In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described herein.
  • nontoxic compounds are nontoxic.
  • the term "nontoxic” as used herein sha ⁇ be understood in a relative sense and is intended to refer to any substance that has been approved by the United States Food and Drug Administration (“FDA”) for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans).
  • FDA United States Food and Drug Administration
  • a highly preferred nontoxic compound generally satisfies one or more of the following criteria: (1 ) does not substantially inhibit cellular ATP production; (2) does not significantly prolong heart QT intervals; (3) does not cause substantial liver enlargement, or (4) does not cause substantial release of liver enzymes.
  • a compound that does not substantially inhibit cellular ATP production is a compound that satisfies the criteria set forth in Example 14, herein.
  • cells treated as described in Example 14 with 100 ⁇ M of such a compound exhibit ATP levels that are at least 50% of the ATP levels detected in untreated cells.
  • such cells exhibit
  • ATP levels that are at least 80% of the ATP levels detected in untreated cells.
  • a compound that does not significantly prolong heart QT intervals is a compound that does not result in a statistically significant prolongation of heart QT intervals (as determined by electrocardiography) in guinea pigs, minipigs or dogs upon administration of a dose that yields a serum concentration equal to the EC S0 or IC 50 for the compound.
  • a dose of 0.01 , 0.05, 0.1 , 0.5, 1 , 5, 10, 40 or 50 mg/kg administered parenterally or orally does not result in a statistically significant prolongation of heart QT intervals.
  • 'statistically significant is meant results varying from control at the p ⁇ 0.1 level or more preferably at the p ⁇ 0.05 level of significance as measured using a standard parametric assay of statistical significance such as a student's T test.
  • a compound does not cause substantial liver enlargement if daily treatment of laboratory rodents (e.g., mice or rats) for 5-10 days with a dose that yields a serum concentration equal to the EC 50 or IC 50 for the compound results in an increase in liver to body weight ratio that is no more than 100% over matched controls. In more highly preferred embodiments, such doses do not cause liver enlargement of more than 75% or 50% over matched controls. If non-rodent mammals (e g., dogs) are used, such doses should not result in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated controls. Preferred doses within such assays include 0.01 , 0.05.
  • a compound does not promote substantial release of liver enzymes if administration of twice the minimum dose that yields a serum concentration equal to the EC 50 or IC 50 for the compound does not elevate serum levels of ALT, LDH or AST in laboratory rodents by more than 100% over matched mock-treated controls. In more highly preferred embodiments, such doses do not elevate such serum levels by more than 75% or 50% over matched controls.
  • a compound does not promote substantial release of liver enzymes if, in an in vitro hepatocyte assay, concentrations (in culture media or other such solutions that are contacted and incubated with hepatocytes in vitro) that are equal to the EC 50 or IC 50 for the compound do not cause detectable release of any of such liver enzymes into culture medium above baseline levels seen in media from matched mock-treated control cells.
  • concentrations in culture media or other such solutions that are contacted and incubated with hepatocytes in vitro
  • concentrations in culture media or other such solutions that are contacted and incubated with hepatocytes in vitro
  • certain preferred compounds do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to the EC 50 or IC 50 for the compound.
  • microsomal cytochrome P450 enzyme activities such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to the EC 50 or IC 50 for the compound.
  • Certain preferred compounds are not clastogenic ⁇ e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucieus assay or the like) at a concentration equal the EC 5 0 or IC 5 0 for the compound.
  • certain preferred compounds do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells) at such concentrations.
  • compounds provided herein may be isotopically-labeled or radiolabeled.
  • such compounds may have one or more atoms replaced by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be present in the compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, ! I C, 13 C, M C, 15 N, 18 O, !7 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • substitution with heavy isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-fife or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • TMS trimethyisilyl Scheme I illustrates a method for preparing diaryl pyrimidinones of Formula (I) in which R 2 is a nitrogen-linked moiety (amine).
  • Amide 1 is prepared by any of a variety of methods known in the art. such as by converting an acid to its acid chloride with, for example, thionyl chloride, followed by addition of the aniline in the presence of a base; or by using a coupling agent such as BOP in an inert solvent such as methylene chloride.
  • Corresponding carboximidoyl chloride 2 is prepared using standard procedures, such as by heating compound 1 in thionyl chloride (SOCl 2 ) or phosphorus oxychloride (POCl 3 ).
  • Intermediate 5 is generated in a single pot from 2.
  • reaction of carboximidoyl chloride 2 with potassium thiocyanate in an inert solvent such as acetone at O 0 C produces the carb ⁇ ximidoyl isothiocyanate 3, which reacts further w ith the desired amine under the same temperature to give the intermediate 4.
  • Compound 4 is further methylated using a reagent such as iodomethane or dimethyl sulfate to afford 5.
  • Compound 6 (e g , compounds of Formula I where A is C-H) is prepared by reacting 5 with (trimethyisilyl)ketene or Reformatsky reagent (essentially as described by Mazumdar et al. (1990) Tetrahedron Letters, 31(29):A2 ⁇ 5- ⁇ %) at an elevated temperature in an inert solvent such as DCE.
  • Compound 7 ⁇ e.g., compounds of Formula I where A is N) is prepared by reacting 5 with (trimethylsilyl)isocyanate at an elevated temperature in an inert solvent such as DCE.
  • Compound 8 (e.g., compounds of Formula I where A is C-Rj) is prepared by reacting 5 with the appropriately substituted acetic acid or acetyl chloride in the presence of a base such as TEA in an inert solvent such as chloroform (essentially as described by Mazumdar et al. (1991 ) Tetrahedron 47(8): ⁇ 473-84 and Mazumdar et al. (1994) Tetrahedron 50(25):1579-S8), or with the appropriately substituted (trimethylsilyl)ketene at an elevated temperature in an inert solvent such as DCE.
  • a base such as TEA
  • an inert solvent such as chloroform
  • Benzarnidine 9 is prepared by reacting intermediate with ammonia in a solvent such as DMF at room or elevated temperature, or is prepared from the corresponding benzonitrile and aniline essentially as described by Ramsden et al, (1997) J. Chem. Soc. Perkin Trans. ](J6):23 [9-232&.
  • Acid I I is prepared by reacting benzamidine 9 with acetyienedicarboxylate or the appropriately substituted oxaloacetate in a solvent such as DMF at elevated temperature, followed by hydrolysis of the ester 10.
  • Amide 12 is prepared by any of the various methods known in the art, such as by converting the acid to its acid chloride with, for example, thionyl chloride, followed by reacting with amine in the presence of a base, or by reacting with the amine in the presence of a coupling agent such as BOP in an inert solvent such as methylene chloride.
  • Scheme III illustrates a method for preparing diaryl pyrimidinones of Formula I in which R 2 is other than an amine or carboxamide.
  • Compound 13 is prepared by reacting benzamidine 9 with the appropriately substituted ketoester in a solvent such as DMF at elevated temperature.
  • a compound provided herein may contain one or more asymmetric carbon atoms, so that the compound can exist in different stereoisomeric forms.
  • Such forms can be, for example, racemates or optically active forms.
  • All stereoisomers are encompassed by the present invention. Nonetheless, it may be desirable to obtain single enantiomers (i.e., optically active forms).
  • Standard methods for preparing single enantiomers include asymmetric synthesis and resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography using, for example a chiral HPLC column.
  • Compounds may be radiolabeled by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.
  • Each radioisotope is preferably carbon (e.g., 14 C), hydrogen (e.g., ⁇ ), sulfur (e.g., 35 S) or iodine (e.g., 125 I).
  • Tritium labeled compounds may also be prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas using the compound as substrate.
  • certain precursors may be subjected to tritium-halogen exchange with tritium gas.
  • Preparation of radiolabeled compounds may be conveniently performed by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • compositions comprising one or more compounds provided herein, together with at least one physiologically acceptable carrier or excipient
  • Pharmaceutical compositions may comprise, for example, one or more of water, buffers (e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethylsuifoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.
  • other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein.
  • compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral (including, but not limited to, sublingual), nasal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique.
  • compositions suitable for oral use are preferred.
  • Such compositions include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions of the present invention may be formulated as a lyophilizate.
  • Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations.
  • Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
  • exdpienls include, for example, inert di ⁇ uents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or talc).
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be empioyed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).
  • an inert solid diluent e.g., calcium carbonate, calcium phosphate or kaolin
  • an oil medium e.g., peanut oil, liquid paraffin or olive oil
  • Aqueous suspensions contain the active material(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents (e g., sodium carboxymethy!ce!lulose, methylcellulose, hydropropyimethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitoi such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitoi anhydrides such as polyethylene
  • Aqueous suspensions may also comprise one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil
  • the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide paiatabJe oral preparations. Such suspensions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • compositions may also be fo ⁇ nulated as oil-in-water emulsions.
  • the oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums (e.g , gum acacia or gum tragacanth).
  • An emulsion may also comprise one or more sweetening and/or flavoring agents.
  • phosphatides e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitoi
  • anhydrides e.g., sorbitan monoleate
  • condensation products of partial esters derived from fatty acids and hexitoi with ethylene oxide e.g., polyoxyethylene sorbitan monoleate.
  • An emulsion may also comprise one or more sweetening and/or flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components.
  • Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery.
  • Topical vehicles include water; organic solvents such as alcohols (e.g., ethanoi or isopropyl alcohol) or glycerin; glycols (e g , butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices.
  • organic solvents such as alcohols (e.g., ethanoi or isopropyl alcohol) or glycerin
  • glycols e g , butylene,
  • a composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
  • stabilizing agents such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsuies.
  • a topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions.
  • Typical modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush: spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing. Controlled release vehicles can also be used.
  • a pharmaceutical composition may be prepared as a sterile injectible aqueous or oleaginous suspension. The compound(s) provided herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • Such a composition may be formulated according to the known art using suitable dispersing, wetting and-Or suspending agents such as those mentioned above.
  • suitable dispersing, wetting and-Or suspending agents such as those mentioned above.
  • the acceptable vehicles and solvents that may be employed are water, 1 ,3-butanediol, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectible compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.
  • compositions may also be formulated as suppositories (e.g., for rectal administration).
  • Such compositions can be prepared by mixing the drug with a suitable non-irritating cxcipient that is so ⁇ id at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofluoromethane).
  • a conventional propellant e.g., dichlorodifluoromethane or trichlorofluoromethane.
  • Pharmaceutical compositions may be formulated for release at a pre-determined rate.
  • Instantaneous release may be achieved, for example, via sublingual administration (i.e., administration by mouth in such a way that the active ingredient(s) are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract).
  • Controlled release formulations (/ e., formulations such as a capsule, tablet or coated tablet that slows and/or delays release of active ingredient(s) following administration) may be administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at a target site.
  • a controlled release formulation comprises a matrix and/or coating that delays disintegration and absorption in the gastrointestinal tract (or implantation site) and thereby provides a delayed action or a sustained action over a longer period.
  • One type of controlled-release formulation is a sustained-release formulation, in which at least one active ingredient is continuously released over a period of time at a constant rate.
  • the therapeutic agent is released at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic levels, over a period of time that is at least 4 hours, preferably at least 8 hours, and more preferably at least 12 hours.
  • blood e.g., plasma
  • Such formulations may generally be prepared using weli known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • Controlled release may be achieved by combining the active ingredient(s) with a matrix material that itself alters release rate and/or through the use of a controlled-reiease coating.
  • the release rate can be varied using methods well known in the art, including (a) varying the thickness or composition of coating, fb) altering the amount or manner of addition of plasticizer in a coating, (c) including additional ingredients, such as release-modifying agents, (d) altering the composition, particle size or particle shape of the matrix, and (e) providing one or more passageways through the coating.
  • the amount of modulator contained within a sustained release formulation depends upon, for example, the method of administration (e.g., the site of implantation), the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • the matrix material which itself may or may not serve a controlled-release function, is generally any material that supports the active ingredient(s).
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Active ingredient(s) may be combined with matrix material prior to formation of the dosage form (e g., a tablet).
  • active ingredient(s) may be coated on the surface of a particle, granule, sphere, microsphere, bead or pellet that comprises the matrix material. Such coating may be achieved by conventional means, such as by dissolving the active ingredient(s) in water or other suitable solvent and spraying.
  • additional ingredients are added prior to coating (e.g., to assist binding of the active ingredient(s) to the matrix material or to color the solution).
  • the matrix may then be coated with a barrier agent prior to application of contra lled-release coating.
  • Multiple coated matrix units may, if desired, be encapsulated to generate the final dosage fo ⁇ n.
  • a controlled release is achieved through the use of a controlled release coating (i.e., a coating that permits release of active ingredient(s) at a controlled rate in aqueous medium).
  • the controlled release coating should be a strong, continuous film that is smooth, capable of supporting pigments and other additives, non-toxic, inert and tack-free.
  • Coatings that regulate release of the modulator include pH -independent coatings, pH-dependent coatings (which may be used to release modulator in the stomach) and enteric coatings (which allow the formulation to pass intact through the stomach and into the small intestine, where the coating dissolves and the contents are absorbed by the body).
  • pH dependent coatings include, for example, shellac, cellulose acetate phthalate, polyvinyl acetate phthaiate, hydroxypropylmethylcellulose phthalate, methacrylic acid ester copolymers and zein.
  • the coating is a hydrophobic material, preferably used in an amount effective to slow the hydration of the gelling agent following administration.
  • Suitable hydrophobic materials include alkyl celluloses (e.g., ethylcellulose or carboxymethylcellulose), cellulose ethers, cellulose esters, acrylic polymers (e.g., poly(acrylic acid), poly(methacrylic acid), acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxy ethyl methacrylates, cyanoethyl methacrylate, methacrylic acid alkamide copolymer, polyfmethyl methacrylate), polyacrylamide, ammonio methacrylate copolymers, aminoalky!
  • aqueous dispersions of ethylcellulose include, for example,
  • AQUACOAT® FMC Corp., Philadelphia, PA
  • SURELEASE® Colorcon, Inc., West Point, PA
  • Representative acrylic polymers include, for example, the various EUDRAGIT® (Rohm America, Piscataway, NJ) polymers, which may be used singly or in combination depending on the desired release profile, according to the manufacturer's instructions.
  • EUDRAGIT® Rohm America, Piscataway, NJ
  • the physical properties of coatings that comprise an aqueous dispersion of a hydrophobic material may be improved by the addition or one or more plasticizers.
  • Suitable plasticizers for alkyl celluloses include, for example, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin.
  • Suitable plasticizers for acrylic polymers include, for example, citric acid esters such as triethyl citrate and tributyl citrate, dibutyl phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin.
  • Controlled-reiease coatings are generally applied using conventional techniques, such as by spraying in the form of an aqueous dispersion.
  • the coating may comprise pores or channels or to facilitate release of active ingredient. Pores and channels may be generated by well known methods, including the addition of organic or inorganic materia! that is dissolved, extracted or leached from the coating in the environment of use.
  • pore-forming materials include hydrophilic polymers, such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose), cellulose ethers, synthetic water-soluble polymers (e.g., polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone and polyethylene oxide), water-soluble polydextrose, saccharides and polysaccharides and alkali metal salts.
  • a controlled release coating may include one or more orifices, which may be formed my methods such as those described in US Patent Nos. 3,845,770; 4,034,758; 4,077,407; 4,088,864; 4,783,337 and 5,071 ,607. Controlled-release may also be achieved through the use of transdermal patches, using conventional technology (see, e.g., US Patent No. 4,668,232).
  • controlled release formulations may be found, for example, in US Patent Nos. 4,572,833; 4,587,1 1 7; 4,606,909; 4,610,870; 4,684,516; 4,777,049; 4,994,276: 4.996,058; 5, 128, 143 ; 5,202, 128; 5,376,384; 5,384,133 ; 5,445,829; 5,510, 1 19: 5,618,560; 5,643,604: 5,891 ,474; 5,958.456; 6,039,980; 6,143,353 ; 6,126,969; 6, 156,342; 6,197,347; 6,387,394; 6,399,096; 6,437,000; 6,447,796; 6,475,493; 6,491 ,950; 6,524,615: 6,838,094; 6,905,709; 6.923,984; 6,923,988; and 6,93 1 ,217; each of which is
  • a compound provided herein may be conveniently added to food or drinking water (e g , for administration to non-human animals including companion animals (such as dogs and cats) and livestock).
  • Animal feed and drinking water compositions may be formulated so that the animal takes in an appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to feed or drinking water.
  • Compound(s) provided herein are generally administered in a therapeutically effective amount.
  • Preferred systemic doses are no higher than 50 mg per kilogram of body weight per day (e.g., ranging from about 0.001 mg to about 50 mg per kilogram of body weight per day), with oral doses generally being about 5-20 fold higher than intravenous doses (e.g., ranging from 0.01 to 40 mg per kilogram of body weight per day).
  • Dosage units wi ⁇ l generally contain from about 10 ⁇ g to about 500 mg of an active ingredient.
  • the dosage unit contains an amount of the compound that is sufficient to effect a decrease in the patient's caloric intake (i.e., an appetite-suppressing amount) following single dose administration or repeated administration according to a predetermined regimen.
  • Optimal dosages may be established using routine testing, and procedures that are well known in the art.
  • compositions may be used for treating a condition responsive to CB 1 modulation.
  • Such conditions include, for example: appetite disorders (e.g., binge eating disorder, bulimia, anorexia); obesity and complications associated therewith, including left ventricular hypertrophy; weight loss or control (e.g., reducing calorie or food intake and/or appetite suppression); and dependency disorders such as: alcohol dependency (e.g., alcoho!
  • abuse, addiction and/or dependency including treatment for abstinence, craving reduction and relapse prevention of alcohol intake
  • nicotine dependency e.g., smoking addiction, cessation and/or dependency including treatment for craving reduction and relapse prevention of tobacco smoking
  • drug dependency e.g., chronic treatment with or abuse of drugs such as opioids, barbiturates, cannabis, ***e, amphetamines, phencyclide, hallucinogens, and/or benzodiazepines
  • metabolic disorders e.g., type 2 diabetes, dyslipidemia and metabolic syndrome
  • bone loss e.g., resulting from estrogen deficiency
  • CNS disorders e.g., anxiety, depression, panic disorder, bipolar disorder, psychosis, schizophrenia, behavioral addiction, dementia (including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive disorder), attention deficit disorder (ADD/ADHD), stress, amnesia, cognitive disorders, memory disorders, neurodegeneration, cerebellar and spinocerebellar disorder, cranial trauma, cerebral vascular accidents, obsessive- compulsive disorder, senile dementia, impulsivity), thymic disorders, septic shock, Tourette's syndrome. Huntington's chorea.
  • CNS disorders e.g., anxiety, depression, panic disorder, bipolar disorder, psychosis, schizophrenia, behavioral addiction, dementia (including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive disorder), attention deficit disorder (ADD/ADHD), stress, amnesia, cognitive disorders, memory disorders, neurode
  • the condition responsive to CB 1 modulation is an appetite disorder, obesity, a dependency disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension or drug-induced hypotension.
  • Certain pharmaceutical compositions provided herein comprise a first agent that is a compound as provided herein in combination with a second agent that differs in structure from the first agent and is suitable for treating the condition of interest.
  • the second agent is not a CB l antagonist as provided herein.
  • the second agent is suitable for treating an appetite disorder, obesity, a dependency disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone ioss, portal hypertension, fibrosis of internal organs, orthostatic hypotension and/or drug-induced hypotension.
  • Representative second agents for use within such pharmaceutical compositions include anti-obesity agents such as MCH receptor antagonists, apo-B/MTP inhibitors, l l ⁇ -hydroxy steroid dehydrogenase-!
  • inhibitors include, for example, phentermine, orlist
  • Representative second agents suitable for treating a dependency disorder include, for example, Methadone.
  • LAAM flavo-alpha-acetyl-methadol
  • naltrexone ondansetron, sertraline, fluoxetine, diazepam, chlordiazepoxide, varenicline and buproprion.
  • Other representative second agents for use within the pharmaceutical compositions provided herein include nicotine receptor partial agonists, opioid antagonists and/or dopaminergic agents.
  • compositions may be packaged for treating conditions responsive to CB l modulation (e.g., treatment of appetite disorder, obesity and/or dependency disorder, or other disorder indicated above).
  • Packaged pharmaceutical preparations generally comprise a container holding a pharmaceutical composition as described above and instructions (e g , labeling) indicating that the composition is to be used for treating a condition responsive to CB I modulation in a patient, ⁇ n certain embodiments, a packaged pharmaceutical preparation comprises one or more compounds provided herein and one or more additional agents in the same package, either in separate containers within the package or in the same container (i.e., as a mixture).
  • Preferred mixtures are formulated for oral administration (e.g., as pills, capsules, tablets or the like).
  • the package comprises a label bearing indicia indicating that the components are to be taken together for the treatment of an appetite disorder, obesity, a dependency disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension and/or drug-induced hypotension.
  • the present invention provides methods for treating a condition responsive to CBl modulation in a patient and/or for appetite suppression.
  • the patient may be afflicted with such a condition, or may be free of symptoms but considered at risk for developing such a condition.
  • a condition is "responsive to CB l modulation" if the condition or symptom(s) thereof arc alleviated, attenuated, delayed or otherwise improved by modulation of CB l activity.
  • Such conditions include, for example, appetite disorders, obesity, dependency disorders, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, memory disorders, cognitive disorders, movement disorders, metabolic disorders, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension and drug-induced hypotension, as well as other disorders indicated above.
  • methods comprise administering to the patient a therapeutically effective amount of at least one compound as provided herein.
  • compounds provided herein may be administered alone or in combination with one or more additional agents that are suitable for treating the disorder of interest.
  • additional agent(s) may be present in the same pharmaceutical composition, or may be administered separately in either order.
  • Representative additional agents for use in such methods include the second agents described above.
  • Suitable dosages for compounds provided herein are generally as described above. Dosages and methods of administration of any additional agent(s) can be found, for example, in the manufacturer's instructions or in the Physician's Desk Reference. In certain embodiments, combination administration results in a reduction of the dosage of the additional agent required to produce a therapeutic effect (i. e., a decrease in the minimum therapeutically etieciivc amount). Thus, preferably, the dosage of additional agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the manufacturer for administration of the agent without combination with a compound of Formula I.
  • this dose is less than VA, even more preferably less than Vz, and highly preferably less than VA of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the agent(s) when administered without combination administration as described herein. It will be apparent that the dose of compound as provided herein needed to achieve the desired effect may similarly be affected by the dose and potency of the additional agent.
  • Administration to the patient can be by way of any means discussed above, including oral, topical, nasal or transdermal administration, or intravenous, intramuscular, subcutaneous, intrathecal, epidural, intracerebroventrilcular or like injection. Oral administration is preferred in certain embodiments (e.g , formulated as pills, capsules, tablets or the like).
  • Treatment regimens may vary depending on the compound used and the particular condition to be treated. In general, a dosage regimen of 4 times daily or less is preferred, with 1 or 2 times daily particularly preferred. It will be understood, however, that the specific dose level and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Dosages are generally as described above; in general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented.
  • the present invention provides a variety of non-pharmaceutical in vitro and in vivo uses for the compounds provided herein.
  • such compounds may be labeled and used as probes for the detection and localization of CB l (in samples such as cell preparations or tissue sections, preparations or fractions thereof).
  • compounds provided herein that comprise a suitable reactive group such as an aryl carbonyl, nitro or azide group may be used in photoaffinity labeling studies of receptor binding sites.
  • compounds provided herein may be used as positive controls in assays for receptor activity, as standards for determining the ability of a candidate agent to bind to CB l , or as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
  • PET positron emission tomography
  • SPECT single photon emission computerized tomography
  • Such methods can be used to characterize CB l receptors in living subjects.
  • a compound may be labeled using any of a variety of well known techniques (e g , radiolabeled with a radionuclide such as tritium, as described herein), and incubated with a sample for a suitable incubation time (e g , determined by first assaying a time course of binding).
  • unbound compound is removed (e g , by washing), and bound compound detected using any method suitable for the label employed (e g , autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods may be used to detect luminescent groups and fluorescent groups).
  • any method suitable for the label employed e g , autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods may be used to detect luminescent groups and fluorescent groups.
  • a matched sample containing labeled compound and a greater (e.g , 10-fold greater) amount of unlabeled compound may be processed in the same manner. A greater amount of detectable label remaining in the test sample than in the control indicates the presence of CB l in the sample.
  • Detection assays including receptor autoradiography (receptor mapping) of CB 1 in cultured cells or tissue samples may be performed as described by Kuhar in sections 8.1 .1 to 8.1 ,9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York.
  • Compounds provided herein may further be used within assays for the identification of other non-competitive antagonists of CBl .
  • assays are standard competition binding assays, in which a labeled compound as provided herein is displaced by a test compound.
  • such assays are performed by: (a) contacting CB I with a labeled (e.g., radiolabeled) compound and a test compound, under conditions that permit binding to CB l (b) removing unbound labeled compound and unbound test compound; (c) detecting a signal that corresponds to the amount of bound, labeled compound: and (d) comparing the signal to a reference signal that corresponds to the amount of bound labeled compound in a similar assay performed in the absence of test compound.
  • the reference signal and the signal described in step (c) are generally obtained simultaneously (e.g., the assays are performed in different wells of the same plate); in addition, multiple concentrations of test compound are generally assayed. Non-competitive antagonist activity can be confirmed for test compounds that decrease the amount of bound, labeled compound using procedures described herein.
  • Mass spectroscopy data in the following Examples is Electrospray MS, obtained in positive ion mode using a Micromass Time-of-Flight LCT (Micromass, Beverly MA), equipped with a Waters 600 pump (Waters Corp.; Milford, MA), Waters 996 photodiode array detector, and a Gilson 21 5 autosampler (Gilson, Inc.; Middleton, WI). MassLynx (Advanced Chemistry Development, Inc; Toronto, Canada) version 4.0 software with OpenLynx Global ServerTM, OpenLynxTM and AutoLynxTM processing is used for data collection and analysis.
  • Sample volume of 1 microliter is injected onto a 50x4.6mm Chromoliih SpeedPvOD PvP-I Se column (Merck KGaA, Darmstadt, Germany), and eluted using a 2-phase linear gradient at a flow rate of 6 ml/min. Sample is detected using total absorbance count over the 220-340nm UV range.
  • the elution conditions are: Mobile Phase A - 95% water, 5% MeOH with 0.05% TFA; Mobile Phase B - 5% water, 95% MeOH with 0.025% TFA.
  • the following gradient is used: 0-0.5 min I 0-l O0%B, hold at 100%B to 1.2 min, return to 10%B at 1 .21 min. Inject to inject cycle is 2.15 min.
  • EXAMPLE 1 ⁇ l -[2-(2-CHLORO-PHENYL)-6-OXO-l -(4-TR)FLUOROMETHYL-PHENYL)- 1 ,6-DIH YDRO- PYRIMIDIN-4-YL]-PIPERIDIN-4-YL ⁇ -CARBAMIC ACID 7EKf-BUTYL ESTER (COMPOUND 1 )
  • DIHYDRO-1 ,3, 5-TRIAZIN-2-YL ⁇ PIPERIDIN-4- YL)PROPANAMIDE (COMPOUND 4)
  • reaction mixture is cooled to 0 0 C, and a solution of propionyi chloride (4.6 mg, 0.05 mmol) in DCM is added slowly. After stirring for 10 rnin at 0 0 C, the mixture is purified by PTLC (5% MeOH in DCM) to give the title compound as an off-white solid.
  • Step 1 jV-[(2-Chloro ⁇ phenyl)-(4-trifluoromethyl-phenylimino)-methyl]-thiomo ⁇ holine-4- carboximidothioic acid methyl ester
  • the title compound is synthesized essentially as described in Example 1 , using thiomorphoiine instead of 4- ⁇ 7 -Boc-aminopiperidine. The reaction yields the title compound as a yellow viscous oil.
  • This Example illustrates the preparation of recombinant bacuiovirus for use in generating CB 1 -expressing insect cells.
  • Human CB l sequence has GenBank Accession Number HSU73304 (see Hoehe et al. (1991 ) New Biol. J(Pj:88O-85).
  • Human CB l fhCB 1 cDNA is amplified from a human brain cDNA library (Gibco BRL, Gaithersburg, MD) using PCR, in which the 5' primer includes the optimal Kozak sequence CCACC.
  • the resulting PCR product is cloned into pcDNA3.1/V5-His-TOPO (Invitrogen Corp, Carlsbad, CA) using the multiple cloning site, and then subcloned into pBACPAK 8 (BD Biosciences, Palo Alto, CA) at the Bam/Xho site to yield a hCB l baculoviral expression vector.
  • the hCB l baculoviral expression vector is co-trans fected along with B ACULOGOLD DNA
  • the S ⁇ cell culture supernatant is harvested three days post-transfection.
  • the recombinant virus-containing supernatant is serially diluted in Hink's TNM-FH insect medium (JRH Biosciences, Kansas City, MO) supplemented with Grace's salts and with 4.I mM L-GIn, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10% heat-inactivated fetal bovine serum (hereinafter 'Insect medium”) and plaque assayed for recombinant plaques. After four days, recombinant piaques are selected and harvested into 1 ml of insect medium for amplification.
  • Each 1 ml volume of recombinant bacuiovirus (at passage 0) is used to infect a separate T25 flask containing 2 x 10 6 S/9 cells in 5 ml of insect medium. After five days of incubation at 27 0 C, supernatant medium is harvested from each of the T25 infections for use as passage 1 inoculum. Two of seven recombinant baculoviral clones are then chosen for a second round of amplification, using 1 ml of passage 1 stock to infect I x 10 s cells in 100 ml of insect medium divided into 2 Tl 75 flasks.
  • passage 2 medium from each 100 ml preparation is harvested and plaque assayed for titer.
  • the ceil pellets from the second round of amplification are assayed by affinity binding as described below to verify recombinant receptor expression.
  • a third round of amplification is then initiated using a multiplicity of infection of 0.1 to infect a liter of S/9 cells. Seventy-two hours post-infection the supernatant medium is harvested to yield passage 3 baculoviral stock.
  • Radioligand is 25pM-5.0nM f H]CP55,940 for saturation binding and 0.5nM for competition binding (New England Nuclear Corp., Boston, MA); the hCB 1 -expressing baculoviral cells are used; the assay buffer contains 50 mM Tris pH 7.4, 120 mM NaCI, 5 inM MgCl 2 , 0.5% BSA and 0.2 rng/ml bacitracin; filtration is carried out using GF/C WHATMAN filters (presoaked in 0.3% non-fat dry milk (H 2 O) for 2 hours prior to use); and the filters are washed twice with 5 mL cold 50 mM Tris pH.7.4.
  • Titer of the passage 3 baculoviral stock is determined by piaque assay and a multiplicity of infection, incubation time course, binding assay experiment is carried out to determine conditions for optimal receptor expression.
  • Log-phase S/9 cells (Invitrogen Corp., Carlsbad, CA), are infected with one or more stocks of recombinant baculovirus followed by culturing in insect medium at 27 0 C. Infections are carried out either oniy with virus directing the expression of hCB l or with this virus in combination with three G- protein subun it-express ion virus stocks: 1 ) rat Ga 12 G-protein-encoding virus stock, 2) bovine ⁇ l G- protein-encoding virus stock, and 3) human ⁇ 2 G-protein-encoding virus stock, all of which are obtained from Biosignal Inc., Montreal, Canada.
  • Typical hCB l infections are conducted using Sf9 cells that are cultured in insect medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) as discussed above.
  • FBS heat-inactivated fetal bovine serum
  • Higher receptor and G-protein (Ga, G ⁇ , G ⁇ ) expression can be obtained if the Sf9 cells are cultured in insect medium with 5% FBS and 5% Gibco serum-free medium (Invitrogen Corp.; Carlsbad, CA). Maximal CB I expression and functional activity is achieved if the Sf9 cells are cultured in insect medium without FBS and with 10% Gibco serum-free medium.
  • the infections are carried out at a multiplicity of infection of 0.1 : 1.0:0.5 :0.5.
  • a sample of cell suspension is analyzed for viability by trypan blue dye exclusion, and the remaining S/9 cells are harvested via centrifugation (3000 rpm/ I 0 min/ 4°C).
  • S/9 cell pellets are resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 ⁇ g/mi leupeptin, 2 ⁇ g/ml Aprotinin, 200 ⁇ M PMSF, and 2.5 mM EDTA. pH 7.4) and homogenized using a POLYTRON homogenizer (setting 5 for 30 seconds).
  • the homogenate is centrif ⁇ ged (536 x g/ 10 min/ 4°C) to pellet the nuclei.
  • the supernatant containing isolated membranes is decanted to a clean centrifuge tube, centrifuged (48,000 X g/ 30 min, 4 0 C) and the resulting pellet resuspended in 30 ml homogenization buffer.
  • P2 membranes are resuspended by Dounce homogenization (tight pestle) in binding buffer (50 mM Tris pH. 7.4, 12OmM NaCL 5 mM MgCl 2 , 0.5% BSA and 0.2 mg/ml bacitracin).
  • membranes (10 ⁇ g) are added to polypropylene tubes containing 25pM-0.5nM [ 3 H]CP55,940 (New England Nuclear Corp., Boston, MA).
  • Nonspecific binding is determined in the presence of lO ⁇ M CP55,940 (Tocris Cookson Inc., Ellisville, MO) and accounts for less than 10% of total binding-
  • GTP ⁇ S is added to duplicate tubes at the final concentration of 50 ⁇ M.
  • membranes (10 ⁇ g) are added to polypropylene tubes containing 0.5nM [ 3 H]CP55,940.
  • Non-radiolabeled displacers are added to separate assays at concentrations ranging from 10 "10 M to 10 "5 M to yield a final volume of 0.250 mL.
  • Nonspecific binding is determined in the presence of l O ⁇ M CP55,940 and accounted for less than 10% of total binding.
  • This Example illustrates the use of agonist-stimulated GTP ⁇ 35 S binding ("GTP binding") activity to identify CB 1 agonists and antagonists, and to differentiate neutral antagonists from those that possess inverse agonist activity.
  • This assay can also be used to detect partial agonism mediated by antagonist compounds.
  • a compound being analyzed in this assay is referred to herein as a "test compound.”
  • Agonist-stimulated GTP binding activity is measured as follows: Four independent baculoviral stocks (one directing the expression of hCB ! and three directing the expression of each of the three subunits of a heterotrimeric G-protein) are used to infect a culture of Sfi cells as described in Example 1 1.
  • Agonist-stimulated GTP binding on purified membranes is initially assessed using the cannabinoid agonist CP55,940 to ascertain that the receptor/G- protein-alpha-beta-gamma combination(s) yield a functional response as measured by GTP binding.
  • P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 mM Tris pH 7.4, 120 mM NaCI, 5 mM MgCi 2 , 2 mM EGTA, 0.1 % BSA, 0.1 mM bacitracin, I QOKILVmL aprotinin, 5 ⁇ M GDP) and added to reaction tubes at a concentration of 10 ⁇ g protein/reaction tube. After adding increasing doses of the agonist CP55,940 at concentrations ranging from 10 " ' 2 M to 10 "6 M, reactions are initiated by the addition of 100 pM GTPy 35 S. In competition experiments, non-radiolabeied test compounds are added to separate assays at concentrations ranging from I 0 "10 M to 3 O "5 M along with 1 nM CP55,940 to yield a final volume of 0.25 ml.
  • GTP binding assay buffer 50 mM Tris pH 7.4, 120
  • the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1 % BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 32OmM NaCI),
  • the amount of receptor-bound (and thereby membrane-bound) GTPy 35 S is determined by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filters.
  • Non-specific binding is determined using 10 mM GTPy 35 S and typically represents less than 5 percent of tota! binding. Data is expressed as percent above basal (baseline).
  • the results of these GTP binding experiments are analyzed using SIGMAPLOT software and IC 50 determined. The IC 50 may then be used to generate K 1 as described by Cheng and Prusoff (1973) Biochem Pharmacol. 22(23):3099-l 0%.
  • the data is analyzed as follows. First, the average bound radioactivity from negative control wells (no agonist) is subtracted from the bound radioactivity detected for each of the other experimental wells. Second, average bound radioactivity is calculated for the positive control wells (agonist wells). Percent inhibition for each compound tested is calculated using the equation:
  • the % inhibition data is plotted as a function of test compound concentration and test compound IC 50 is determined using a linear regression in which x is ln(concentration of test compound) and y is ln(percent inhibition/ ⁇ 100 - percent inhibition). Data with a percent inhibition that is greater than 90% or less than 15% are rejected and are not used in the regression.
  • the IC 30 is e ( - mter " pl/slope) , and K 1 is generated as described above.
  • Neutral antagonists are those test compounds that reduce the CP55,940-stimulated GTP binding activity towards, but not below, baseline (the level of GTP bound by membranes in this assay in the absence of added CP55,940 or other agonist and in the further absence of any test compound). In contrast, in the absence of added CP55,940. CB l inverse agonists reduce the GTP binding activity of the receptor-containing membranes below baseline. If a test compound that displays antagonist activity does not reduce the GTP binding activity below baseline in the absence of the CB l agonist, it is characterized as a neutral antagonist.
  • An antagonist test compound that elevates GTP binding activity above baseline in the absence of added CP55,940 in this GTP binding assay is characterized as having partial agonist activity.
  • Preferred CB 1 antagonists do not elevate GTP binding activity under such conditions more than 10%, more preferably less than 5% and most preferably less than 2% of the maximal response elicited by the agonist, CP55,940.
  • the GTP binding assay can also be used to determine antagonist selectivity towards CB l over CB2.
  • Agonist-stimulated GTP binding activity at CB2 is measured as described above for CB l except that the S ⁇ cells are infected with one baculoviral stock directing the expression of hCB2 and three directing the expression of each of the three subunits of a heterotrimeric G-protein.
  • the IC 50 and K 1 are generated as described above for CB 1.
  • EXAMPLE 13 SURMOUNTABIL ⁇ TY ASSAYS Certain CB l antagonists are insurmountable with regard to the agonist induced GTPy 15 S binding effect.
  • P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 mM Tris pH 7.4, 120 mM NaCl, 5 mM MgCl 2 , 2 mM EGTA, l O ⁇ g/ml saponin, 0.1 % BSA, 0.1 mM bacitracin, 100KIU/mL aprotinin, 5 ⁇ M GDP) and added to reaction tubes at a concentration of 10 ⁇ g protein/reaction tube.
  • GTP binding assay buffer 50 mM Tris pH 7.4, 120 mM NaCl, 5 mM MgCl 2 , 2 mM EGTA, l O ⁇ g/ml saponin, 0.1 % BSA, 0.1 mM baci
  • Agonist dose- response curves (typically CP55,940) at concentrations ranging from 10 "12 M to 10 "5 M, are run either in the absence or in the presence of a test compound at one of several doses up to I OOX the IC 50 of the test compound as measured in the competition GTPy 35 S binding.
  • the reactions are initiated by the addition of 100 pM GTPy 35 S to yield a final volume of 0.25 mL. Following a 90-minute incubation at room temperature, the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1 % BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 120 mM NaCl).
  • the amount of receptor-bound (and thereby membrane-bound) GTPy 15 S is determined by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filters. Non-specific binding is determined using 10 ⁇ M GTPyS and typically represents less than 5 percent of total binding. Data is expressed as percent above basal (baseline). The results of these GTP binding experiments may be conveniently analyzed using SIGMAPLOT software.
  • a surmountable test compound is one which shifts the EC 50 of the agonist to the right (weaker) without affecting the maximum functional response of the agonist. Insurmountable antagonist test compounds have no significant effect on the hCB I agonist ECj 0 at concentrations roughly I OOX the IC 50 , but significantly reduce or eliminate the agonist stimulated GTPy 35 S binding response of the receptor.
  • This Example illustrates the evaluation of compound toxicity using a Madin Darby canine kidney (MDCK) cell cytotoxicity assay.
  • test compound 1 ⁇ L is added to each well of a clear bottom 96-well plate (Packard, Meriden, CT) to give final concentration of compound in the assay of 10 ⁇ M, 100 ⁇ M or 200 ⁇ M. Solvent without test compound is added to control wells.
  • MDCK cells ATCC no. CCL-34 (American Type Culture Collection, Manassas, VA), are maintained in sterile conditions following the instructions in the ATCC production information sheet.
  • Confluent MDCK ceils are trypsinized, harvested, and diluted to a concentration of 0.1 x 10 6 cells/mL with warm (37°C) medium (VITACELL Minimum Essential Medium Eagle, ATCC catalog # 30- 2003). 100 ⁇ L of diluted cells is added to each well, except for five standard curve control wells that contain 100 ⁇ L of warm medium without cells. The plate is then incubated at 37 0 C under 95% O 2 , 5% CO 2 for 2 hours with constant shaking.
  • mammalian DC ATP-LITE-M Luminescent ATP detection kit 50 ⁇ L of mammalian DC lysis solution (from the Packard (Meriden, CT) ATP-LITE-M Luminescent ATP detection kit) is added per well, the wells are covered with PACKARD TOPSEAL stickers, and plates are shaken at approximately 700 rpm on a suitable shaker for 2 min. Compounds causing toxicity will decrease ATP production, relative to untreated cells.
  • mammalian DC lysis solution from the Packard (Meriden, CT) ATP-LITE-M Luminescent ATP detection kit
  • ATP-LlTE-M Luminescent ATP detection kit is generally used according to the manufacturer's instructions to measure ATP production in treated and untreated MDCK cells.
  • PACKARD ATP LITE-M reagents are allowed to equilibrate to room temperature. Once equilibrated, the lyophilized substrate solution is reconstituted in 5.5 ml of substrate buffer solution (from kit). Lyophilized ATP standard solution is reconstituted in deionized water to give a 10 mM stock.
  • 10 ⁇ L of serially diluted PACKARD standard is added to each of the standard curve control wells to yield a final concentration in each subsequent well of 200 nM, 100 nM, 50 nM, 25 nM, and 12.5 nM.
  • PACKARD substrate solution 50 ⁇ L is added to all wells, which are then covered, and the plates are shaken at approximately 700 rpm on a suitable shaker for 2 min.
  • a white PACKARD sticker is attached to the bottom of each plate and samples are dark adapted by wrapping plates in foil and placing in the dark for 10 min.
  • Luminescence is then measured at 22°C using a luminescence counter (e.g., PACKARD TOPCOUNT Microplate Scintillation and Luminescence Counter or TECAN SPECTRAFLUOR PLUS), and ATP levels calculated from the standard curve. ATP levels in cells treated with test com ⁇ ound(s) are compared to the levels determined for untreated cells.
  • a luminescence counter e.g., PACKARD TOPCOUNT Microplate Scintillation and Luminescence Counter or TECAN SPECTRAFLUOR PLUS
  • Cells treated with 10 ⁇ M of a preferred test compound exhibit ATP levels that are at least 80%, preferably at least 90%, of the untreated cells.
  • ATP levels that are at least 50%, preferably at least 80%, of the ATP levels detected in untreated cells.

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Abstract

Compounds of Formula (I) are provided. In which the variables are as described herein. Such compounds may be used to modulate CB 1 activity in vivo or in vitro, and are particularly useful in the treatment of conditions responsive to CB 1 modulation in humans, domesticated companion animals and livestock animals, including appetite disorders, obesity and dependency disorders. Pharmaceutical compositions and methods for using them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies and various in vitro assays.

Description

DIARYL PYRIMIDINGNES AND RELATED COMPOUNDS
FIELD OF THE INVENTION
This invention relates generally to diaryl pyrimidinones and related compounds, and to the use of such compounds to treat conditions responsive to cannabinoid receptor-1 (CB l ) modulation. The invention further relates to the use of such compounds as reagents for the identification of other agents that bind to CB l , and as probes for the detection and localization of CB l .
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application 60/804,451 , filed June 12, 2006, which provisional application is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
Obesity is the most common nutritional problem in developed countries. This condition is often both harmful and costly, as it increases the likelihood of developing serious health conditions (such as cardiovascular diseases, stroke and diabetes) and complicates numerous chronic conditions such as respiratory diseases, osteoarthritis, osteoporosis, gall bladder disease and dyslipidemias. Fortunately, however, many of the conditions caused or exacerbated by obesity can be resolved or dramatically improved by weight loss.
Once considered merely a behavioral problem (i.e., the result of voluntary hyperphagia), obesity is now recognized as a complex multifactorial disease involving defective regulation of food intake, food-induced energy expenditure and the balance between lipid and lean body anabolism. Both environmental and genetic factors play a role in the development of obesity. As a result, treatment programs that focus entirely on behavior modification have limited efficacy and are associated with recidivism rates exceeding 95%. Pharmacotherapy is now seen as a critical component of weight loss and subsequent weight management.
Currently available prescription drugs for managing obesity generally reduce weight by inducing satiety or decreasing dietary fat absorption. Such drugs, however, often have unacceptable side effects. Several, such as the older weight-loss drugs (e.g., amphetamine, methamphetamine, and phenmetrazine. are no longer recommended because of the risk of their abuse. Fenfluramine and dexfenfluramine, both serotonergic agents used to regulate appetite, are also no longer available for use.
Thus, there exists a need for more effective agents for promoting weight loss and for reducing or preventing weight-gain. In addition, there exists an unmet need for more effective agents for the treatment of alcohol and tobacco dependence. The present invention fulfills this need, and provides further related advantages. SUMMARY OF THE INVENTION
The present invention provides diaryi pyrimidinones and related compounds that satisfy Formula 1:
Formula I
Figure imgf000003_0001
or are a pharmaceutically acceptable salt, solvate (e.g , hydrate) or ester of such a compound. Within Formula I:
Ar, and Ar2 are independently chosen from phenyl, naphthyl and 5- to IO-membered heteroary], each of which is optionally substituted, and each of which is preferably substituted with from 0 to 6 substituents independently chosen from RA; R1 is:
(i) hydrogen, halogen, hydroxy, cyano, amino, nitro, aminocarbonyi, aminosulfonyl or -COOH;
(ii) C,-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C8cycloalkyl)Co-C4alkyl, CrC6alkyS ether, C,-
Qalkoxy, d-C6alkylthio, C3-C6alkanone, CrC6alkoxycarbonyl, mono- or di-(Cr
C6alkyI)aminoCo-C4alkyl, mono- or di-(C|-C6alkyl)aminocarbonylCo-C4alkyl, (C1-
Figure imgf000003_0002
mono- or di-(Ci-C6alkyl)aminosulfonylC0-C4alkyl, (Ci-
CfialkyIsuIfonyl)C0-C4alkyl, (Ci-C3alkyl)sulfonylaminoCo-C<,alkyl or (4- to 8-membered heterocycle)C0-Cjalkyl; each of which is optionally substituted, and each of which is preferably substituted with from O to 6 substituents independently chosen from RB; or
(iii) taken together with R2 to form a fused 5- to 8-membered carbocycle or heterocycle that is optionally substituted and is preferably substituted with from 0 to 4 substituents independently chosen from R8; R2 is a non-hydrogen substituent; preferably R2 is:
(i) CrC6alkyl, C2-C6a!kenyl, C2-C6alkynyl, (C3-Cgcycloalkyl)Co-C4alkyϊ, C2-C6alkyi ether, Cr C6alkoxy, CrC6a]koxycarbonyl, mono- or di-(CrCήalkyl)aminoC0-C4alky[, mono- or di-(Cr Cβalky])aminocarbonylC0-C4alkyl,
Figure imgf000003_0003
mono- or di-(Cr
C6alkyi)aminosuifonyICo-C4alkyI, (Cj-C6alky])suSfony]C0-C4alky[, mono- or di-(Cr C6atkyl)suJfonyIaminoCo-C4alkyl, (C3-Ciocarbocycle)C0-Cjalkyl or (4- to 10-membered heterocycie)C0-C4alkyl: each of which is substituted with from 0 to 6 substituents independently chosen from RB; (ii) a group of the formula:
Figure imgf000003_0004
is O. C(=O). S,
SO, SO2, N(R3) or C(R4J(R41,); °r (iii) taken together with R1 to form a fused 5- to 8-membered, optionally substituted carbocycle or hetero cycle; R3 Is:
(i) hydrogen; or (ii) CrC6alkyl, C2-C6a]kenyl, C2-C6alkynyl, CrCsalkylsulfonyl, (C3-C8carbocycle)Co-C4alkyl or
(4- to 8-membered heterocycle)Co-C4alkyl, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 6 substituents independently chosen from
RB;
R4;, and R4I, are independently: (i) hydrogen, halogen, cyano, -COOH or CrC6aIkyI;
(ii) -Z-N(R5)(R6) or wherein Z is absent,
Figure imgf000004_0001
N(RW)C(=O) (i.e
Figure imgf000004_0002
or SO2 (i.e. ; wherein Rw is hydrogen or CrC6alkyI;
Figure imgf000004_0003
wherein Rw is hydrogen or CrCβalkyl;
(iii) phenyl, naphthyl or 5- to 10-membered heteroaryl, each of which is optionally substituted and each of which is preferably substituted with from O to 6 substituents independently chosen from RA; or
(iv) taken together to form a 4- to 7-membered cycloalkyl or heterocycloalkyl that is optionally substituted, and is preferably substituted with from O to 4 substituents independently chosen from RB; R5 and R6 are independently (i) hydrogen; or
(ii) C]-C3alkyl, C2-C6alkenyl, C2-Cήalkynyl, C,-C6alkanoyl, Ci-C6alkoxycarbonyl, Cr
Qalkylsulfonyl, (C3-C8cycloalkyl)C0-C4alkyl, (4- to 8-membered heterocycloaIky!)C0-
C4alkyl, mono- or di-(CrC6alkyl)aminocarbonyI, or mono- or di-(Cj-C6aIkyl)aminosulfony], each of which is optionally substituted, and is preferably substituted with from O to 6 substituents independently chosen from RB; or R5 and R6 are taken together to form a 4- to 7-membered heterocycle that is optionally substituted, and is preferably substituted with from O to 4 substituents independently chosen from RB; R7 is hydrogen, CrC6a[kyl, C2-C3alkenyl, C2-Cθalkynyl, (C3-C3cycIoalkyl)C(rC4alkyI or (4- to 8- membered heterocycloalky[)Co-C4alkyI, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 6 substituents independently chosen from R3; Each RA is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, amino sulfonyl and -COOH; and (ii) CrC6afkyI, C2-C6alkenyl, C2-C6alkynyl, (C3-CacycloaIkyl)C0-C4alkyl, CrC6haloaIkyl, C1-
C6alkoxy, CrC6alkylthio, C,-C6alkylsulfinyl. CrC6alkoxycarbonyl, C|-C6alkylsulfonylC0-
C4alkyl, mono- or di-(Ci-C6alkyl}aminoCo-C4alky], mono- or di-(Cr
Cύalky])aminosulfonylC0-C4alkyl, mono- or di-(CrC6a]kyl)aminαcarbonylCo-C4aSky!, phenylCo-C4aIkyl, (4- to 8-membered heterocycle)Co-C4aIkyϊ and (4- to 8-membered heterocycle)C1-C4alkoxy; each of which is optionally substituted, and each of which is preferably substituted with from O to 4 substituents independently chosen from RB; and
Each RB is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, -COOH, Ci-C6alkyl, d-Cβafkenyl, CrC6alkynyI, Ci-Qhaloalkyl, C ,-C6alkoxy, CrC6haloalkoxy, Cj-C6alkylthio. CrC6aIkanoyi, Ci-C6alkoxycarbonyl, C]-C6alkanoyloxy, C3-
Cealkanone, mono- or di-(C|-C6aIkyI)amino, C|-C6alkanoylamino, CpCβalkylsulfonyl, mono- or di-(C]-C6alkyl)aminosu!fonyl, mono- or di-(CrC6alkyl)aminocarbonyl, (C3-C(ocarbocycle)C0-
Qalkyi, and (4- to 10-raembered heterocycle)C0-C4alkyL
Within certain aspects, diaryl pyrimidinones and related compounds of Formula 1, and other Formulas provided herein, exhibit a K, of no greater than 2 micromolar, 1 micromolar, 500 nanomolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in a CB l ligand binding assay and/or have an IC50 value of no greater than 2 micromolar, 1 micromolar, 500 nanomolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in an assay for determination of CB l antagonist activity,
In certain embodiments, diaryl pyrimidinones and related compounds provided herein exhibit no detectable agonist activity.
Within certain aspects, diaryl pyrimidinones and related compounds provided herein are labeled with a detectable marker (e.g., radiolabeled or fluorescein conjugated).
The present invention further provides, within other aspects, pharmaceutical compositions comprising at least one diaryl pyrimidinone or related compound as described herein in combination with a physiologically acceptable carrier or excipient.
The present invention further provides methods for treating a condition responsive to CB l modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one diaryl pyrimidinone or related compound as described herein. Such conditions include, for example, appetite disorders, obesity, dependency disorders such as alcohol dependency and nicotine dependency, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, memory disorders, cognitive disorders, movement disorders, metabolic disorders, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension and drug- induced hypotension.
In further aspects, methods are provided for suppressing appetite in a patient, comprising administering to the patient an appetite reducing amount of at least one diaryi pyrimidinone or related compound as described herein. The present invention further provides pharmaceutical compositions, comprising (a) a first agent that is a diaryl pyrimidinone or related compound as described herein, (b) a second agent that is suitable for treating an appetite disorder, obesity, a dependency disorder such as alcohol dependency and nicotine dependency, asthma, liver cirrhosis, sepsis, irritable bowe! disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension or drug- induced hypotension; and (c) a physiologically acceptable carrier or excipient.
The present invention also provides packaged pharmaceutical preparations, comprising: (a) a composition comprising a diaryl pyrimidinone or related compound as described herein in a container; and (b) instructions for using the composition to treat one or more conditions responsive to CB l modulation.
Within further aspects, the present invention provides methods for determining the presence or absence of CB l in a sample, comprising: (a) contacting a sample with a diaryl pyrimidinone or related compound as described herein under conditions that permit binding of the compound to CB l ; and (b) detecting a signal indicative of a level of the diaryl pyrimidinone or related compound bound to CB l .
In yet another aspect, the invention provides methods of preparing the compounds disclosed herein, including the intermediates.
These and other aspects of the present invention will become apparent upon reference to the following detailed description.
DETAILED DESCRIPTION
As noted above, the present invention provides diaryl pyrimidinones and related compounds. Such compounds may be used in vitro or in vivo in a variety of contexts as described herein.
TERMINOLOGY Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. If a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass ail tautomeric forms. Certain compounds are described herein using a general formula that includes variables {e.g., X, A, Ar1). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. The term "diaryl pyrimidinones and related compounds" encompasses all compounds of
Formula I, and includes pharmaceutically acceptable salts, solvates {e.g., hydrates) and esters of such compounds. It will be apparent that, unless otherwise specified herein, such formulas encompass compounds in which one or both of Ari and Ar2 is a heterocycle, as well as compounds in which neither Ar1 nor Ar2 is a heterocycle. Such formulas further encompass compounds in which A is optionally substituted carbon (pyrimidinones) and compounds in which A is N (triazinones). A "pharmaceutically acceptable salt" of a compound recited herein is an acid or base salt that is suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as wei) as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutically acceptable anions for use in salt formation include, but are not limited to, acetate, 2-acetoxybenzoate, ascorbate, benzoate, bicarbonate, bromide, calcium edetate, carbonate, chloride, citrate, dihydrochioride, diphosphate, ditartrate, edetate, estolate (ethylsuccinate), formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylars anil ate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, hydroxymaleate, hydroxynaphthoate, iodide, isethionate, lactate, Iactobionate, malate, maleate, mandelate, methylbromide, methylnitrate, methylsυlfate, mucate, napsylate, nitrate, pamoate, pantothenate, phenyl acetate, phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfamate, sulfanilate, sulfate, sulfonates including besylate (benzenesulfonate), camsylate (camphorsulfonate), edisylate (ethane-l ,2-disulfonate), esyiate (ethanesulfonate) 2- hydroxy ethy [sulfonate, mesylate (methanesulfonate), triflate (trifiuoromethanesulfonate) and tosylate (p-toluenesulfonate), tannate, tartrate, teoclate and triethiodide. Similarly, pharmaceutically acceptable cations for use in salt formation include, but are not limited to ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethyl en ediamine, meglumine, procaine, and metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile, is preferred.
It will be apparent that each compound provided herein may, but need not, be formulated as a solvate {e.g., a hydrate) or non-covalent complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention. Also provided herein are prodrugs of the compounds provided herein. A "prodrug" is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, amine or sulfhydryi groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, amino, or sulfhydryi group, respecliveϊy. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon. Alkyl groups include groups having from 1 to 8 carbon atoms (Cj-Cgalkyl), from 1 to 6 carbon atoms (CrQalkyl) and from 1 to 4 carbon atoms (CrC4alky[), such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, rerf-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexy!, 2-hexyl, 3-hexyl or 3-methylpentyl. "Co-C4alkyr refers to a single covalent bond (C0) or an alkyiene group having 1 ,
2, 3 or 4 carbon atoms; "C0-C6aikyl" refers to a single covalent bond or a d-C6alkyIene group; "C0-
C8alkyl" refers to a single covalent bond or a CrCsalkylene group. In certain instances, a substituent of an alkyl group is indicated, as in the term "CrC4hydroxyalkyl," which refers to a C]-C4alkyl group that is substituted with one or more hydroxy groups, and "CrC4aminoaIkyl," which refers to a C1-
C4aikyl group that is substituted with one or more -NH2 groups.
"Alkyiene" refers to a divalent aSkyl group, as defined above. CrC4alkyfene is an alkyiene group having 1 , 2, 3 or 4 carbon atoms.
"Alkenyl" refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C2-C3alkenyl, C2-C6afkenyl and C2-
C4alkenyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, such as ethenyl, ally! or isopropenyl. "Alkynyl" refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyi groups include
C2-C3alkynyl, C2-C6alkynyl and CrC4alkynyI groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
A "cycloalkyl" is a saturated or partially saturated cyclic group in which all ring members are carbon, such as cyclopropyl, cyclobutyi, cyclopentyl and cyclohexyl, as well as partially saturated variants thereof. Certain cycloalkyl groups are C-,-C3cycloalkyl, in which the ring contains from 3 to
8 ring members, all of which are carbon. A "(C3-C8cycloalkyl)Co-C.jalkyl" is a C3-C8cycloalkyl group linked via a single covalent bond or a CrC4alkylene group.
By "alkoxy,1' as used herein, is meant an alkyl group attached via an oxygen bridge. Alkoxy groups include C3-C6alkoxy and Cj-Qalkoxy groups, which have from 1 to 6 or 1 to 4 carbon atoms, respectively. Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, /ert-butoxy, n-pentoxy,
2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy are representative alkoxy groups.
"Alkylthio" refers to an alkyl group as described above attached via a sulfur bridge. "Alkylsulfinyl" refers to groups of the formula -(SO)-alkyl, in which the sulfur atom is the point of attachment. Alkylsulfinyl groups include CrC6alkylsulfinyl and CrC4alkyIsuIfmyl groups, which have from I to 6 or I to 4 carbon atoms, respectively.
"Alkylsulfonyl" refers to groups of the formula -(SO2)-aIkyl, in which the sulfur atom is the point of attachment. Alkylsulfonyl groups include CrQalkylsu!fonyi and CrC4alkylsulfonyI groups, which have from 1 to 6 or 1 to 4 carbon atoms, respectively. "(C1-C6alkyl)sulfonyIC0-C4alkyl" is a C i-Cealkylsulfony! group linked via a single covalent bond or a C|-C4alkylene group.
The term "oxo" is used herein to refer to an oxygen substituent of a carbon atom that results in the formation of a carbonyl group (C=O). An oxo group that is a substituent of a nonaromatic carbon atom results in a conversion of -CH2- to -C(=O)-. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH- to -C{=0)- and may result in a loss of aromaticity.
The term "alkanoy!11 refers to an acyl group (e.g., -(C=O)-alkyl), where attachment is through the carbon of the keto group. Alkanoyl groups include C2-C8 alkanoy 1, C2-C6alkanoyl and C2-
C4alkanoyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively. "Cialkanoyl" refers to -(C=O)H, which (along with C2-C3alkanoyl) is encompassed by the term "Cj-Cgalkanoy!.11
Ethanoyi is C2alkanoyl.
An "alkanone" is a ketone group in which carbon atoms are in a linear or branched alkyl arrangement. "C3-C8alkanone," "C3-Cβalkanone" and "C3-C4alkanone" refer to an aϋkanone having from 3 to 8, 6 or 4 carbon atoms, respectively. A C3 alkanone has the structure -CH3-(C=O)-CH3. Similarly, "alkyl ether" refers to a linear or branched ether substituent. Alkyl ether groups include C2-C8alkyl ether, C2-C6alkyl ether and C2-QaIkVl ether groups, which have 2 to 8, 6 or 4 carbon atoms, respectively. A C2 alkyl ether has the structure -CH2-O-CH3.
The term "alkoxycarbonyl" refers to an alkoxy group linked via a carbonyl (i.e. , a group having the general structure -C(=O)-O-alkyl). Alkoxycarbonyl groups include C)-C8, Cj-Ce and C,- Qalkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the alkyl portion of the group. "Cjalkoxycarbonyl" refers to -Cf=O)-O-CH3.
"Alkanoyloxy," as used herein, refers to an alkanoyl group linked via an oxygen bridge (i.e., a group having the general structure -O-C(=O)-alkyl). Alkanoyloxy groups include C2-C8, C2-C6 and C2-C4alkanoyloxy groups, which have from 2 to 8, 6 or 4 carbon atoms, respectively. !lC2aIkanoyloxy" refers to -O-C(=0)-CH3.
"Alkylamino" refers to a secondary or tertiary amine that has the general structure -NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl is selected independently from alkyl, cycloalkyl and
(cycloalkyl)alkyl groups. Such groups include, for example, mono- and di-(CrCsalkyl)amino groups, in which each Ci-C8alkyl may be the same or different, as well as mono- and ds-(Ci-C6alkyl)amino groups and mono- and di-(CrC4alkyl)amino groups.
"Alkylaminoalkyl" refers to an alkylamino group linked via an alkylene group (i.e., a group having the general structure -alkylene-NH-alkyl or -alkylene-N(alkyl)(alkyl)) in which each alkyl is selected independently from alkyl, cycSoalkyl and (cycloalkyl)alkyl groups. Alkyiaminoalkyl groups include, for example, mono- and di-(CrC8alkyI)aminoCi-C8alkyl, mono- and di-(C5- C6alkyl)aminoCi-Cfialkyl and mono- and di-(Ci-C3alkyI)aminoCi -C4 alkyl. "Mono- or di-(C,- C6alkyl)aminoCo-C4alkyl" refers to a mono- or
Figure imgf000010_0001
group linked via a single covalent bond or a CrC4aIkylene group. The following are representative alkylaminoalkyi groups:
Figure imgf000010_0002
It will be apparent that the definition of "alkyl" as used in the terms "alkyiamino" and "alkyiaminoalkyl" differs from the definition of "alkyl" used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cyc[oaikyl)alkyl groups (e.g., (C3-C8cycloa[kyl)Co-C4alkyl). The term "Ci-Cealkanoylammo" refers to a mono- or di-(CrC6aIkyl)amino group in which at least one C|-C6alkyl is substituted with oxo at the carbon atom adjacent to the amino group (e.g., H
VV O ). "(Ci-C6alkanoy])aminoCιrC4alkyi" refers to a mono- or di-(Ci-Qalkyl)aminoCo-C4a]kyI moiety in which at least one C|-C6alkyl is substituted with oxo at the carbon atom adjacent to the amino group. The following are representative (CrC6alkanoyl)ammoC0-C4alkyl groups:
Figure imgf000010_0003
The term "aminocarbony!" refers to an amide group (i. e., -C(=O)NH2). "Mono- or di-(Ci- C6alkyI)aminocarbonyIC0-C4aIkyr refers to an aminocarbonyl group in which one or both hydrogens are replaced with an independently selected CrC6alkyl group, and which is linked via a single covalent bond or a Cj-C4alkylene group. The term "aminosulfonyl" refers to a sulfonamide group (i.e., -SO2NH2). "Mono- or di-(Cr
C6alkyl)aminosulfonylCo-C4alkyl" refers to an aminosulfonyl group in which one or both hydrogens are replaced with an independently selected C]-C6alkyl group, and which is linked via a single covalent bond or a CrC4aikylene group.
Similarly, "mono- or di-(C|-CflalkyI)sulfony[aminoC0-C4alkyl" refers to a group of the formula -(Co-C4alkyl)-N(Rχ)Sθ2(Rγ), in which Rx is hydrogen or CrC6aIkyi and Ry is an independently selected CrC6alkyl group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
A ::haloalkyϊ:: is an alkyl group that is substituted with I or more independently chosen halogens (e.g., "Cj~Cshaioalkyl" groups have from 1 to 8 carbon atoms; "CrC6haloalkyl" groups have from 1 to 6 carbon atoms). Examples of haloalkyl groups include, but are not limited to, mono-, di- or tri-fϊuoromethyl; mono-, di- or tri-chbromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; and 1 ,2,2,2-tetrafluoro-l -trifluoromethyl-ethyl. Typical haloalkyl groups are trifluoromethyl and difluoromethyl. The term "haloalkoxy" refers to a hatoalky! group as defined above attached via an oxygen bridge. "Ci-C8haloalkoxy" groups have 1 to S carbon atoms.
A dash ("-") that is not between two letters or numbers is used to indicate a point of attachment for a substitυent. For example, -CX=O)NH2 is attached through the carbon atom. 5 A "carbocycle" has from 1 to 3 fused, pendant or spiro rings, each of which has oniy carbon ring members. Typically, a carbocycle that has a single ring contains from 3 to S ring members (i.e., C3-Cgcarbocycles); rings having from 4 or 5 to 7 ring members (i.e., CrCvcarbocycles or C5- C7carbocycles) are recited in certain embodiments. Carbocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Carbocycles may be optionally substituted with a I O variety of substituents, as indicated. Unless otherwise specified, a carbocycle may be a cycloalkyl group (i. e., each ring is saturated or partially saturated as described above) or an aryl group (i.e., at least one ring within the group is aromatic). Representative aromatic carbocycles are phenyl, naphthyl and biphenyl. In certain embodiments preferred carbocycles have a single ring, such as phenyl and C3-C3cycloa!kyl groups. 5 A "heterocycle" (also referred to herein as a "heterocyclic group") has from 1 to 3 fused, pendant or spiro rings, at least one of which is a heterocyclic ring (i.e , one or more ring atoms is a heteroatom independently chosen from oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon). Typically, a heterocyclic ring comprises 1 , 2, 3 or 4 heteroatoms; within certain embodiments each heterocyclic ring has 1 or 2 heteroatoms per ring. Each heterocyclic ring generally 0 contains from 3 to 8 ring members (rings having from 4 or 5 to 7 ring members are recited in certain embodiments) and heterocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Certain heterocycles comprise a suifυr atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SO2. Heterocycles may be optionally substituted with a variety of substituents, as indicated. Certain heterocycles are 4- to 10-membered or 5- to 30- 5 membered, which comprise one or two rings - in certain embodiments, such heterocycles are monocyclic (e.g., 4- to 8-membered, 5- to 8-membered, 5- to 7-membered, or 5- or 6-membered); in other embodiments, such heterocycles are 9- or 10-membered bicyclic heterocycles.
Certain heterocycles are heteroaryl groups (i.e., at least one heterocyclic ring within the group is aromatic), such as a 5- to 10-membered heteroaryl (which may be monocyclic or bicyclic) or a 6- 0 membered heteroaryl (e.g., pyridyl or pyrimidyl). Other heterocycles are heterocycloalkyl groups.
Certain heterocycles may be linked by a single covalent bond or via an alkylene group, as indicated, for example, by the term "(4- to 8-membered heterocycloaikyl)Co-C4alkyl."
A "substituent," as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a 5 halogen, alkyl group, haloaikyl group or other group discussed herein that is covalently bonded to an atom (such as a carbon or nitrogen atom) that is a ring member. The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent as described above, such that the valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.
Groups that are "optionally substituted" are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically 1 , 2, 3, 4 or 5 positions, by one or more suitable groups (which may be the same or different). Optional substitution is also indicated by the phrase
"substituted with from 0 to X substituents," where X is the maximum number of possible substituents.
Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substitutents).
"CB l ," as used herein, refers to the human cannabinoid receptor reported by Hoeche et al. (1991 ) New Biol. J(9j:88G-85, as well as allelic variants thereof and homologues thereof found in other species.
A "CB l antagonist" is a compound that detectably inhibits signal transduction mediated by CB 1. Such inhibition may be determined using the representative agonist-induced GTP binding assay provided in Example 12. Preferred CB I antagonists have an IC50 Of 2 μM or less in this assay, more preferably 1 μM or less, and still more preferably 500 nM or less or 100 nJvl or less. In certain embodiments, the CB l antagonist is specific for CB I {i.e., the IC50 value in a similar assay performed using the predominantly peripheral cannabinoid receptor CB2 is greater than 2 μM and/or the 1CJO ratio (CB2/CB I ) is at least 10, preferably 100, and more preferably at least 1000). CB l antagonists preferably have minimal agonist activity (i.e., induce an increase in the basal activity of CB l that is less than 5% of the increase that would be induced by one EC50 of the agonist CP55.940, and more preferably have no detectable agonist activity within the assay described in Example 12). CBl antagonists for use as described herein are generally non-toxic. CB l antagonists include neutral antagonists and inverse agonists.
A "neutral antagonist" of CBl is a compound that inhibits the activity of CBl agonist (e.g., endocannabinoids) at CB l , but does not significantly change the basal activity of the receptor (i.e., within a GTP binding assay as described in Example 12 performed in the absence of agonist, CB l activity is reduced by no more than 10%, more preferably by no more than 5%, and even more preferably by no more than 2%; most preferably, there is no detectable reduction in activity). Neutral antagonists may, but need not, also inhibit the binding of agonist to CB 3 ,
An "inverse agonist" of CB l is a compound that reduces the activity of CB I below its basal activity level in the absence of activating concentrations of agonist. Inverse agonists may also inhibit the activity of agonist at CB l , and/or may inhibit binding of CB l agonist to CB l . The ability of a compound to inhibit the binding of CB l agonists to the CB I receptor may be measured by a binding assay, such as the radioligand binding assay given in Example 1 1 . The reduction in basal activity of CBl produced by an inverse agonist may be determined from a GTP binding assay, such as the assay of Example 12.
A "non-competitive CB l antagonist" is a CB l antagonist that (1 ) does not detectably inhibit binding of CB l agonist (e.g., CP55,940) to CBl at antagonist concentrations up to 10 μM and (2) reduces the maxima! functional response elicited by agonist. Compounds that satisfy these two conditions may be identified using the assays provided herein. Such compounds generally do not display detectable activity in the competition binding assay described in Example 1 1. In functional assays, a non-competitive antagonist concentration-dependently reduces the maxima! functional response elicited by agonist without altering agonist EC50. The suppression of functional activity by a non-competitive antagonist cannot be overcome by increasing agonist concentrations (i. e., the antagonist activity is insurmountable).
A "therapeutically effective amount" (or dose) is an amount that, upon administration to a patient, results in a discernible patient benefit (e.g., provides detectable relief from a condition being treated). Such relief may be detected using any appropriate criteria, including the alleviation of one or more symptoms of dependency or an appetite disorder, or the promotion of weight loss. In the case of appetite suppression, a therapeutically effective amount is sufficient to decrease patient appetite, as assessed using patient reporting or actual food intake. Such an amount is referred to herein as an "appetite reducing amount." A therapeutically effective amount or dose generally results in a concentration of compound in a body fluid (such as blood, plasma, serum, CSF, synovial fluid, lymph, cellular interstitial fluid, tears or urine) that is sufficient to result in detectable alteration in CB l - mediated signal transduction (using an assay provided herein). The discernible patient benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a predetermined regimen, depending upon the indication for which the compound is administered. A "patient" is any individual treated with a compound as provided herein. Patients include humans, as well as other animals such as companion animals (e.g , dogs and cats) and livestock. Patients may be experiencing one or more symptoms of a condition responsive to CB l modulation or may be free of such symptom(s) (i.e., treatment may be prophylactic in a patient considered to be at risk for the development of such symptoms). DlΛRYL PYRIMIDJNONES AND RELATED COMPOUNDS
As noted above, the present invention provides diary! pyrimidinones and related compounds that may be used in a variety of contexts, including in the treatment of appetite disorders, obesity and dependency disorders (addictive disorders). Such compounds may also be used within ui
Figure imgf000013_0001
assays
(e.g., assays for CB l activity), as probes for detection and localization of CB l and within assays to identify other CB l antagonists, including non-competitive CB l antagonists.
Diary! pyrimidinones and related compounds provided herein generally satisfy Formula I: Formula I
Figure imgf000014_0001
or are a pharmaceutical Jy acceptable salt, solvate or ester of such a compound, in which variables are a described above.
Within certain aspects, referred to herein as Formula IA, the variables within Formula I carry the following definitions: A is CR, or N;
Ar, and Ar2 are independently chosen from phenyl, naphthyl and 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from RA;
(i) hydrogen, hydroxy, amino or nitro; or (ii) CrQalkyl, C2-C6alkynyl, (C3-C8cycloalkyl)Co-C4alkyI, C2-C6alkyl ether, C3-C6alkanone, C1-
Qafkoxycarbonyl, mono- or di-(CrC6alky])aminoCo-C4alkyl, mono- or di-(C,- C6alkyl)aminocarbonylCo-C4alkyl, (C|-C6alkanoyl)aminoC0-C4aikyl, mono- or di-(C|- C6alkyl)aminosulfonylC0-C4aikyl, (Ci-C6alkyl)sulfonylC0-C4alkyl, or mono- or di-(Ci- C6alkyl)suIfonylaminoC0-C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from Rn; or
R2 is:
(i) C2-C6alkenyl, C2-C6alkynyi, (C3-C8cycIoalky[)Co-C4aIky!, CrC6aIkanoyI, C3-Cfiaikanone, C2- C6alkyl ether, CrC6alkoxy, Ci-C6alkoxycarbonyl, mono- or di-(CrC6alkyl)aminoCrC4alkyi, mono- or di-(CrC6alkyl)aminocarbonylC(rC4alkyI, (Ci-C6alkanoyl)aminoCo-C4alkyl, mono- or di-(Ci-C6alkyI)aminosulfonylCo-C4alkyI, (CrC6alkyl)sulfonylC0-C4alkyl or mono- or di-
(C1-C6alkyl)sulfonylaminoC0-C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB;
(ii) mono- or di-(Ci-C6a]kyl)amino that is substituted with hydroxy, amino, aminocarbonyl, aminosulfonyl, mono- or di-(Ci-C6alkyI)amino, mono- or di-(CrCfialkyl)aminocarbonyl, mono- or di-(C1-C6alkyl)aminosulfonyl, (CrC[;aikanoyl)airιino, mono- or di-(C,-
C6alky[)sulfonylamϊno or 4- to 8-membered heterocycle; each of which is further substituted with from 0 to 4 substituents independently chosen from R3; or (iii) a group of the formula: (/^x
O , wherein q is 0 or 1 ; each n is independently 0, I or 2; and X is C(=O), S, SO, SO2, N(R3) or C(R48)(R4I1): such that R] is not a halogen, cyano, CpCealkyl or C2-Cfialkenyl if R2 is CrC6alkyl; R3 is: (i) hydrogen; or
(ii) C,-C6alkyl, C2-C6 alkenyl, C2~C6alkyny!, Ci-C6a!kylsulfony!, (C3-C8carbocyde)Co-Qalkyf or (4- to 8-membered heterocycle)C0-C4alkyl, each of which is substituted with from 0 to 6 substituenls independently chosen from RB; R4a and R4h are independently:
(i) hydrogen, halogen, cyano, -COOH or Q-Qalkyl;
(ii) -Z-N(R5)(R6) or -Z-O(R7), wherein Z is absent, C(O), OC(O), N(RΛ)C(=0) or SO2: wherein Rw is hydrogen or Ci -C6 alky 1;
(iii) phenyl, naphthyi or 5- to 10-membered heteroaryl, each of which is substituted with from O to 6 substituents independently chosen from RA; or
(Iv) taken together to form a 4- to 7-membered cycloaikyl or heterocycloalkyl that is substituted with from O to 4 substituents independently chosen from RB; such that at least one of R41 and R4I, is not hydrogen; R5 and R6 are independently: (i) hydrogen; or
(ii) Cj-Qalkyl, C2-C<jalkenyl, C2-C6alkynyl, Ci-C6alkanoyl, CrC6alkoxycarbonyl, Cr
Cealkylsulfoπyl, (C^Cacycloalkyi)CB-C4alkyl, (4- to 8-membered heterocycloalkyl)C0-
C4alkyl, mono- or di-fCrCβalkyOaminocarbonyl, or mono- or di-(CrC6alkyI)aminosulfonyI, each of which is substituted with from O to 6 substituents independently chosen from Rg; or R5 and R6 are taken together to form a 4- to 7-membered heterocycle that is substituted with from O to 4 substituents independently chosen from RB;
R7 is hydrogen, CrCsaIkyl, C2-C6alkenyl, C2-C6alkynyl, (C,-C3cycloalkyl)Co-C4alkyl or (4- to 8- membered heterocycloalkyl)Co-C4alkyl, each of which is substituted with from O to 6 substituents independently chosen from RB; Each RA is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl and -COOH; and (ii) Cj-Qalkyl. C2-C6alkenyl, C2-C6alkynyl, (C3-C8cycloalkyI)C0-C4alkyl, CrC6haloalkyl, C1- C6alkoxy3 CrC6alkylthio, C-Calkylsulfinyl, C]-C6alkoxycarbonyl. CrC6aIkylsulfonylC0- C4alkyl, mono- or di-(Ci-C6alkyl)aminoCo-C4alkyl, mono- or di-(Cr C6alkyl)aminosulfonylCo-C4alkyI, mono- or di-(CrC6alkyl)aminocarbonylC0~C4alkyl, ρhenylC0-C4alkyl, (4- to 8-membered heterocycle)C0-C4alkyl and (4- to 8-membered heterocycle)C|-C4alkoxy; each of which is substituted with from O to 4 substituents independently chosen from RB; and
Each RB is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro. aminocarbonyl, aminosulfonyl, -COOH, Cϊ-C6alkyl, CrC6a!kenyl, C,-C6alkynyl, (C3-C3cycloalkyl)Co-C4alky],
CrCfihaloalkyl. Ci-C6alkoxy, C,-C6haloalkoxy. CrC6alkylthio. CrC6alkanoyϊ, C1-
C6alkoxycarbonyl, CrC6alkanoyloxy, C3-C6alkanone, mono- or di-(CrC6alkyl)amino, Cr Qalkanoylamino, Cj-Cβalkylsulfonyl, mono- or di-(C!-C6alkyl)sulfonylaiτiino, mono- or di-(Cr C6alkyl)aminosulfonyl, mono- or di-(C]-C6alky[)aminocarbonyl and (4- to 8-membered heierocycle)Co-C4alky!.
Within other aspects, referred to herein as Formula IB, the variables within Formula I carry the following definitions:
Arj and Ar2 are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 1 to 5 substituents independently chosen from RA; such that Ar2 is substituted para to the point of attachment {i.e., if Ar2 is phenyl, then the phenyl ring is substituted at the 4-position, and may (but need not) be additionally substituted at from 1 to 4 other ring carbon atoms); R1 is:
(i) hydrogen, halogen, hydroxy, cyano, amino or nitro: or
(ii) CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C8cycloa]kyl)Co-C4alkyl. C2-C6aikyl ether, C1- C6alkoxy, C3-C6a!kanone, CrC6alkoxycarbonyl, mono- or di-(CrC6alkyl)aminoCo-C4alkyl, mono- or di-(CrC6alkyl)aminocarbonylCo-C4alkyl, (CrC6alkanoyl)aminoC0-C^alkyl, mono- or di-(CrC6alkyl)aminosulfonylC0-C4alkyl,
Figure imgf000016_0001
mono- or di-(C(- C6alkyl)sulfonyIaminoC0-C,jalkyl or (4- to 8-membered heterocycle)Co-C4alkyl: each of which is substituted with from O to 6 substituents independently chosen from RB; R2 is:
(i) Ci-Cf,alkyl, C2-C6alkenyi, C2-C6alkynyl, C2-C6alkyl ether, CrC6aikoxy, Q-Qalkoxycarbonyl, mono- or di-fCi-Cealky^aminocarbonylCo-Qalkyl, mono- or di-(CrC6a!kyl)aminoC0-
C4alkyl, (CrC6aIkanoyl)aminoCo-C4a]kyl. mono- or di-(Ci-C6alkyl)aminosulfonylC0~C4aikyl,
(C|-C6alkyl)suIfonylC{rC4alkyl, mono- or di-(CrC6alkyl)suIfonylaminoC0-C4a]ky[, (C3- C|ocarbocycle)Co-C4alkyl or (4- to IO-membered heterocycle)C0-C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or (ii) a group of the formula:
Figure imgf000016_0002
is O, C(=O), S,
SO. SO2, N(R3) or C(R43)(R^); such that Rj is not CrC6afkyl if R2 is CrC6alkyl; R3 is:
(i) hydrogen; or
(ii) C,-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, CrC6alkylsu!fonyl, (C3-C3carbocycle)C0-C4a!kyl or (4- to 8-membered heterocycle)C0-C4alkyl. each of which is substituted with from 0 to 6 substituents independently chosen from RB; R411 and R41, are independently:
(i) hydrogen, halogen, cyano, -COOH or C,-C6alkyl;
(ii) -Z-N(R5)(Re) or -Z-O(R7), wherein Z is absent, C(=O), 0C(=0), N(RW)C(=O) or SO2; wherein Rw is hydrogen or Ci-Qalkyl; (iii) phenyl, naphthyl or 5- to 10-mernbered heteroaryl, each of which is optionally substituted and each of which is preferably substituted with from O to 6 substituents independently chosen from RA; or
(iv) taken together to form a 4- to 7-membered cycloalkyl or heterocycioalkyl that is optionally substituted, and is preferably substituted with from O to 4 substituents independently chosen from RB ;
R.5 and R6 are independently: (i) hydrogen; or
(ii) Cj-Qalkyl, Ci-Cealkenyl, C2-C6alkynyl, C|-C6alkanoyl, Ci-Cealkoxycarbonyl, Cr
Cβalkylsulfonyl, (C3-CsCycloalkyl)Co-C4alkyl, (4- to 8-membered heterocycloalkyl)C0- Cjalkyl, mono- or di-(CrC6a]kyl)aminocarbony], or mono- or di-(CrC6aIkyl)aminosuIfonyl, each of which is substituted with from O to 6 substituents independently chosen from RB; or R5 and R6 are taken together to form a 4- to 7-membered heterocycie that is substituted with from O to 4 substituents independently chosen from RB;
R7 is hydrogen, CrC6alkyI, C2-C6alkenyls C2-C6alkynyl, (C3-C8cycloalkyl)Co-C4alkyl or (4- to 8- membcred heterocycloalky!)C0-C4alkyl, each of which is substituted with from O to 6 substituents independently chosen from RB; Each RA is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfony! and -COOH; and (ii) C,-C6alkyl, C2-C6alkenyl, C2-C6aikynyl, (C3-C8cycloalkyl)C0-C4aIkyl, C,-C6haloalkyi, C1- Qalkoxy, CrC6aIkyIthio, CrC6alkylsulfmyI, CrC6a[koxycarbonyϊ, (CrC6alkyl)sulfonylC0-
C4alkyl, mono- or di-(CrC6alkyl)aminoCo-C4alkyl, mono- or di-(C,- C6alkyl)aminosulfonylCo-C4alkyl, mono- or di-tCrQalky^aminocarbonylCo^alkyl, phenyl C0-C4alkyl, (4- to 8-membered heterocycle)C0-C.(alkyl and (4- to 8-membered heterocycle)Ci-C4alkoxy: each of which is substituted with from O to 4 substituents independently chosen from RB; and
Each RB is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl. aminosulfonyl, -COOH, CrC6alkyl, C,-C6alkenyl, CrC6alkynyl, (C3-C3cycloalkyI)C0-C,alkyl. CrC6haloafkyL Ci-Calkoxy, C,-C6haloalkoxy, C,-Cr,alkylthio, C,-C6alkanoyL C1- Cfialkoxycarbonyl. CrC6alkanoyloxy, C3-C6alkanone, mono- or di~(C|~C6alkyl)amino. C1- C6aikanoylamino, CrC6alkylsulfonyl, mono- or di-(CrCsalkyl)aminosulfonyl, mono- or di-(Cr
C6alkyl)aminocarbonyl and (4- to 8-membered heterocycle)C0-C4alkyϊ. Within certain diary! pyrimidinones and related compounds of Formulas I and IA, Ar, and Ar2 are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from RΛ. Substituents chosen from RΛ may be located at any ring carbon atom; however, in certain compounds of Formulas I and IA, Ar2 is substituted at the para position, with additional substituents optionally present at other ring carbon atom(s). In certain compounds of Formulas I, IA and IB, Ax \ is substituted ortho and/or para to the point of attachment (e g., Arj contains one substituent located ortho or para to the point of attachment, or Arj is di-substituted with one substituent ortho and one substituent para to the point of attachment). In certain embodiments of Formulas I, IA and IB, each RA is independently chosen from halogen, cyano, C3-C6alkyi, CVQalkenyl, C2-C6alkynyl, C,-C6haloalkyl, (C3-C8cycloalkyl)C0-C4alkyl and C1- C6alkoxy.
As noted above, the variable "A" in Formulas ϊ, IA and IB is N or CR1. Within certain compounds of Formulas I, IA and IB, and subfoπnulas thereof, A is CRj and R1 is hydrogen or Ci- Cfialkyl, Within other such compounds, R1 is C3-C6alkanone, CrC6aIkoxycarbonyl, mono- or di-(Cj- Cfialkyl)aminoCo-C4alkyl, mono- or di-(CrC6alkyi)aminocarbonylC0-C4alkyi, (C1- Cύalkanoyl)aminoCo-C,talkyl, mono- or di-(Ci-C6alkyl)aminosulfony!Co-C4aIkyl, (Ci- C6a!kyl)suIfonylCo-C4aIkyl, mono- or di-(Ci-C6alkyl)sulfonylaminoC0-C4alkyI, or (4- to 8-membered heterocycle)Co-C4alkyl, each of which is substituted with from 0 to 6 substituents independently chosen from RB. R2 of Formulas I and IA is, within certain embodiments:
(i) mono- or di-(Cj-C6alkyI)aminocarbonylCo-C2alkyl, (Ci-CβalkanoylJaminoCo-Cialkyl, mono- or di- (Cj-C6alky])aminosulfonylCo-C2aIkyl, (Ci-C6alkyl)suIfonylCo-C2alkyl or mono- or di-(Cr C6alkyl)sulfony!aminoCo-C2aIkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or
X
%,N^ / — v
-ξ-N X (ii) a group of the formula O (e.g., ' \ — / }, wherein X is C(=O), S, SO, SO2, N(R3) or
CH(R4,).
For example, R2 moieties include groups of the
Figure imgf000018_0001
. wherein R5 is Cr
Cβalkanoyl, CrC6alkoxycarbonyl or mono-or di-(CrC6alkyl)aminocarbonyl. Other R2 moieties
•|-N N-R3 include groups of the formula ^' — ' ; in certain such groups R3 is C3-C3cycloaikyl, Cp C6alkanoyl,
Figure imgf000018_0002
or mono- or di-(C]-C6alkyl)aminocarbonyi.
Within other embodiments of Formulas I and IA, R2 is Ci-Cealkanovϊamino, mono- or di-(Cr C5alkyl)sulfonylamino, CrC6a]koxycarbonyl, mono- or di-(CrC6alkyl)aminocarbonyl. or a group of the formula O , wherein n is O or 1 and q is O or 1 ; each of which is substituted with from
0 to 4 substituents independently chosen from RB. Within other embodiments of Formulas I and IA, R2 is C2-C6alkenyl, C2-C6alkynyl, (C3-C8cyc[oalkyI)Co-C4alkyI, CrC6aIkanoyI, C3-C6alkanone, or C2- Cealkyl ether, each of which is substituted with from 0 to 6 substituents independently chosen from RB. Within such compounds, Rj is preferably C3-C6alkanone, Ci-C6alkoxycarbonyl, mono- or CU-(C1- C6alkyl)aminoC<rC4aikyl, mono- or di-(CrC6alkyI)aminocarbonylCo-C4alkyl, (C1- C6aϊkanoyl)aminoCo-C4alkyl, mono- or di~(Ci-C6alkyl)aminosulfonylCo-C4alky[, (Cp C6alkyl)sulfonylCo-C4alkyl, or mono- or di-(Ci~C6alkyl)su!fonylaminoCo-C4alkyl, each of which is substituted with from O to 6 substituents independently chosen from RB. R2 of Formulas I and IB is, within certain embodiments:
(i) mono- or di-(CrC6alkyl)aminocarbonylCo-C2alkyl, (Ci-C6alkanoyl)aminoC0-C2alkyI, mono- or di- (Ci-CealkylJaminoCo-Cialkyl, mono- or di-(C1-C6alkyl)aminosulfonylC0-C2alkyI, (Ci- C6alkyl)sulfony!C0-C2alkyI or mono- or dHCi-QalkyOsuIfonylaminoCo-Cialkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or
X
(ii) a group of the formula O (e.g., s — / ), wherein X is O, C(O), S, SO, SO2, N(R3) or CH(R43). Representative R2 moieties in which X is CH(R4J include, for example, groups of the
Figure imgf000019_0001
, wherein R5 is CrC6alkanoyl, Ci-Cealkoxycarbonyl or mono-or di-(Cr
C6alky3)aminocarbonyl. R1 is preferabiy hydrogen or CpCealkyl within such compounds. Within other embodiments of Formulas I and IB, R2 is Ci-C6alkyl, C2-C6alkenyl, C2-
C6alkynyl, (C3-C8cycloalkyl)Co-C4alkyl. C2-C6alkyl ether or mono- or di-(Ci-C6alkyl)amino (e.g., mono- or di-(C3-C6alkyI)amino), each of which is substituted with from O to 6 substituents independently chosen from RB. Within such compounds, R, is preferably C3-Cs;alkanone, Cr C6alkoxycarbonyl, mono- or di-(Ci-Cbalkyi)aminoCo-C2alkyl, mono- or di-(Cr C6alkyl)aminocarbonylC0-C2alkyl. (Cj-Cβalkanoyl)aminoCo-C2alkyl, mono- or di-(Cr C6alkyl)aminosulfonylCo-C3alkyi, (Ci-C6aIkyl)sulfonylCo-C2alkyl, mono- or di-(Cr C6alkyI)sulfonylaminoCo-C2alky]. or (4- to 8-membered heterocycle)C0-C2alkyI, each of which is substituted with ironi O to 6 substituents independently chosen from Rg.
Further representative R2 moieties for Formulas I, IA and IB include mono- or di-(Cr C6 alky 1) amino, CrC6alkanoy!amino, mono- or di-(CrC6alkyl)sulfonylamino, CrC6alkoxycarbonyl, mono- or (Ji-(Q -C6alkyl)aminocarbonyl, and groups of the formula O 5 wherein n is O or
S ; q is 0 or I and X is as described above; each of which is substituted with from 0 to 4 substituents independently chosen from RB.
In other embodiments, R2 groups for Formulas ϊ, IA and IB include bicyclic, N-linked
Figure imgf000020_0001
Certain diaryl pyrimidinones and related compounds of Formula I, IA or IB further satisfy any one of Formulas H-V:
Figure imgf000020_0002
Formula II Formula ΪII
Figure imgf000020_0003
Formula IV Formula V wherein: B and D are independently CRn or N; R1 is hydrogen or CrC(,alkyl; R2 for compounds of Formulas I and IA is:
(i) mono- or di-(CrC6alkyl)aminocarbonylC<rC2aikyl, (CrC6alkanoyl)aminoCo-C2alkyl, mono- or di-(CrC6alkyl)aminosulfonylC0-C2aiky], (Ci-C6aIky!)sulfonylCo-C2alkyl or mono- or di- (C|-C6alkyl)sulfonylaminoCu-C2a]kyl; each of which is substituted with from 0 to 6 substituents independently chosen from R8: or X
/ \
%N^ ■ξ-N X (il) a group of the formula O (e g , N — / ), wherein X is C(=0), S, SO, SO2,
N(R1) or CH(R43); or R2 for compounds of Formulas I and IB is:
(i) mono- or di-(Ci-C6alkyl)aminoC0-C2alkyl, mono- or di-(CrC6alkyl)amiπocarbonylCo-C2alkyl, (Cj-C6a]kanoyl)aminoCo-C2aikyl, mono- or di-(Cj-C6alkyl)aminosu[fonylCo-C2alkyl, (C1-
C6alkyl)suIfonylCo-C2a]kyl, or mono- or di-(Ci-C6alkyl)sulfonylaminoC0-C2alkyl; each of which is substituted with from O to 6 substituents independently chosen from RB; or
(ii) a group of the
Figure imgf000021_0001
S, SO, SO2,
N(R3) Or CH(R4,); R8 is halogen, cyano, CrC6alkyl. C2-C6alkenyl, C2-C6alkynyl, C,-C6haloalkyl, (C3-C8cycIoalkyl)C0-
C4alkyl or Ci-C6alkoxy; and
R5, Rio and Rn are independently hydrogen, halogen, cyano, CrC6alkyl, C2-C6alkenyl, Ca-Cealkynyl, Ci-CehaloalkyS, (C3-C8cycloalkyl)Co-C4alkyl or CrC6alkoxy; in certain such compounds, at least one ofR9 and R10 (where present) is not hydrogen, Certain diary] pyrimidinones and related compounds of Formula I, IA or IB further satisfy
Formula Vl:
Formula VI
Figure imgf000021_0002
wherein: at least one ofR9 and R)0 is other than hydrogen; X is N(R1) or CH(R4a); R3 is C3-C8cycloalkyl, Ci-Qalkanoyl, Ci-C6alko\ycarbonyl, or mono- or di-(Cr Cήalky!)aminocarbonyl; and
— — — INfH
R(d is a group of the formula ' , wherein R5 is Ci-C6alkanoyl, C rC6alkoxycarbonyl or mono-or di-(C i -C6alky f)aminocarbonyi .
Representative compounds provided herein include, but are not limited to. those specifically described in the Examples below. It wiϊl be apparent that the specific compounds recited herein are representative only, and are not intended to limit the scope of the present invention. Further, as noted above, all compounds of the present invention may be present as a free acid or base or as a pharmaceutically acceptable salt. As noted above, diaryl pyrimidinones and related compounds provided herein are generally CB l antagonists. Certain such compounds are non-competitive CB l antagonists. In addition, or alternative ϊy, certain compounds provided herein display CB l specificity. CB l antagonist activity may be confirmed using an agonist-induced GTP binding assay, such as the assay described in Example 12, herein. Such assays employ a CB 1 -containing cell membrane preparation (e.g., a preparation of membranes of insect cells that recombinantly express CB l ) to determine the effect of a test compound on CB l agonist-induced GTP binding to CB l . Briefly, a first cell membrane preparation comprising CB l is contacted with: (i) labeled GTP; (ii) a CB l agonist; and (iii) a test compound to yield a test membrane preparation. Simultaneously, or in either order, a second cell membrane preparation comprising CB l is contacted with: (i) labeled GTP; and (ii) a CB l agonist to yield a control membrane preparation. The iabeled GTP is preferably GTPy35S; a representative CBl agonist is CP55,940. Such contact is performed under conditions that are suitable for GTP binding to CBl , such as the conditions described in Example 12. The concentrations of labeled GTP and CBl agonist used are generally concentrations that are sufficient to result in a detectable increase in the amount of labeled GTP bound to the membrane preparation in the presence of CB l agonist. Such concentrations may be determined by routine experimentation; representative suitable concentrations are provided in Example 12. Generally, a range of test compound concentrations is used (e.g., ranging from 10"i0 m to 10"5M).
After sufficient contact (e.g., incubation) to allow GTP binding to the membrane preparations, a signal that corresponds to (represents) the amount of bound, labeled GTP is detected (typically, unbound labeled GTP is first removed via a washing step). In other words, simultaneously or in either order: (i) a test signal that represents an amount of bound, labeled GTP in the test membrane preparation is detected; and (ii) a control signal that represents an amount of bound, labeled GTP in the control membrane preparation is detected. The nature of the signal detected is determined by the type of label used. For example, if the GTP is radioactively labeled, the signal detected is radioactive decay (e.g., via liquid scintillation spectrometry). The CB l antagonist activity of the test compound is then determined by comparing the test signal with the control signal. A test signal that is lower than the control signal indicates that the test compound is a CB 1 antagonist.
In certain embodiments, preferred compounds are cannabinoid receptor-specific. This means that they only bind to, activate, or inhibit the activity of certain receptors other than cannabinoid receptors (preferably other than CB l) with affinity constants of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 4 micromolar. Alternatively, or in addition, such compounds exhibit 200-foid greater affinity for CB l than for other cellular receptors.
Such other non-cannabinoid cellular receptors include histamine receptors, bioactive peptide receptors (including NPY receptors such as NPY Y5), and hormone receptors (e.g., melanin-concentrating hormone receptors). Assays for evaluating binding to such receptors are well known, and include those disclosed in US patent 6,566,367, which is incorporated herein by reference for its disclosure of NPY receptor binding assays in Example 676 columns 82-83; and in PCT International Application Publication No. WO 02/094799 which is incorporated herein by reference for its disclosure of an MCH receptor binding assay in Example 2, pages 108-109.
Utility of the compounds provided herein for the various diseases and disorders may be demonstrated in animai disease models that are known in the art, such as:
Colombo et al. (1998) Life Sciences 55:1 13-17 and Vickers and Kennett (2005) Curr. Drug.
Targets 6:2) 5-23 - food intake and weight loss (rats)
Simiand et al. (1998) Behavioral Pharm. 9: 379-181 - sweet food intake (marmosets) Rowland et al. (2001 ) Psychopharm. 159: \ \ l -\ 6 ~ food intake (rats) Arnone et al. (1997) Psychopharm. 732:104-106 - sucrose and ethaπol intake (mice)
Colombo et al. (2004) Eur. J. Pharmacol 498:1 19-23 - alcohol motivational properties (rats) Serra et al. (2002) Eur. J. Pharmacol. 443:95-97 - alcohol deprivation effect (rats) Rubino et al. (2000) Life Sciences 22:2213-29 - opiate withdrawal syndrome (rats) Chaperon et al. (1998) Psychopharm. /35:324-32 - motor activity, place conditioning (rats) Abraham et al. (1993J J. Clin Invest 93:116 and Milne and Piper (1995) Eur. J. Pharmacol.
282:243 - bronchial hyperresponsiveness (sheep and guinea pigs) Kadoi et al. (2005) British Journal of Anaesthesia 94(5):563-6$ — septic shock (rats) Batkai et al. (2001 ) Nature Medicine 7(7):&27-32 - vasodilation in iiver cirrhosis (rats) Tsusumi et al. (2000) Biol. Pharm. Bull. (Japan) 23(5):657-S9 - constipation (monkeys) Kapur (2001 ) J. Pathology 194(3):271-%% - chronic intestinal pseudo-obstruction (rodents)
Teixeira-Clerc et. al. (2006) Nature Medicine CBl antagonism prevents liver fibrosis (rats)
If desired, compounds provided herein may be evaluated for certain pharmacological properties including, but not limited to, oral bioavailability (preferred compounds are orally bioavailable to an extent allowing for therapeutically effective doses of less than 140 mg/kg, preferably less than 50 mg/kg, more preferably less than 30 mg/kg, even more preferably less than 10 mg/kg, still more preferably less than 1 mg/kg and most preferably less than 0.1 mg/kg), toxicity (a preferred compound is nontoxic when a therapeutically effective amount is administered to a subject), side effects (a preferred compound produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject), serum protein binding and in vitro and in vivo half-life (a preferred compound exhibits an in vivo half-life allowing for Q. LD, dosing, preferably T.LD. dosing, more preferably B. I. D. dosing, and most preferably once-a- day dosing). In addition, differentia! penetration of the blood brain barrier may be desirable. Routine assays that are well known in the art may be used to assess these properties, and identify superior compounds for a particular use. For example, assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound (e.g., intravenously). Serum protein binding may be predicted from albumin binding assays. Compound half-life is inversely proportional to the frequency of dosage of a compound, In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described herein.
As noted above, preferred compounds provided herein are nontoxic. In general, the term "nontoxic" as used herein shaϋ be understood in a relative sense and is intended to refer to any substance that has been approved by the United States Food and Drug Administration ("FDA") for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans). In addition, a highly preferred nontoxic compound generally satisfies one or more of the following criteria: (1 ) does not substantially inhibit cellular ATP production; (2) does not significantly prolong heart QT intervals; (3) does not cause substantial liver enlargement, or (4) does not cause substantial release of liver enzymes.
As used herein, a compound that does not substantially inhibit cellular ATP production is a compound that satisfies the criteria set forth in Example 14, herein. In other words, cells treated as described in Example 14 with 100 μM of such a compound exhibit ATP levels that are at least 50% of the ATP levels detected in untreated cells. In more highly preferred embodiments, such cells exhibit
ATP levels that are at least 80% of the ATP levels detected in untreated cells.
A compound that does not significantly prolong heart QT intervals is a compound that does not result in a statistically significant prolongation of heart QT intervals (as determined by electrocardiography) in guinea pigs, minipigs or dogs upon administration of a dose that yields a serum concentration equal to the ECS0 or IC50 for the compound. In certain preferred embodiments, a dose of 0.01 , 0.05, 0.1 , 0.5, 1 , 5, 10, 40 or 50 mg/kg administered parenterally or orally does not result in a statistically significant prolongation of heart QT intervals. By "'statistically significant" is meant results varying from control at the p<0.1 level or more preferably at the p<0.05 level of significance as measured using a standard parametric assay of statistical significance such as a student's T test.
A compound does not cause substantial liver enlargement if daily treatment of laboratory rodents (e.g., mice or rats) for 5-10 days with a dose that yields a serum concentration equal to the EC50 or IC50 for the compound results in an increase in liver to body weight ratio that is no more than 100% over matched controls. In more highly preferred embodiments, such doses do not cause liver enlargement of more than 75% or 50% over matched controls. If non-rodent mammals (e g., dogs) are used, such doses should not result in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated controls. Preferred doses within such assays include 0.01 , 0.05. 0.1 , 0.5, 1 , 5, 10, 40 or 50 mg/kg administered parenterally or orally. Similarly, a compound does not promote substantial release of liver enzymes if administration of twice the minimum dose that yields a serum concentration equal to the EC50 or IC50 for the compound does not elevate serum levels of ALT, LDH or AST in laboratory rodents by more than 100% over matched mock-treated controls. In more highly preferred embodiments, such doses do not elevate such serum levels by more than 75% or 50% over matched controls. Alternatively, a compound does not promote substantial release of liver enzymes if, in an in vitro hepatocyte assay, concentrations (in culture media or other such solutions that are contacted and incubated with hepatocytes in vitro) that are equal to the EC50 or IC50 for the compound do not cause detectable release of any of such liver enzymes into culture medium above baseline levels seen in media from matched mock-treated control cells. In more highly preferred embodiments, there is no detectable release of any of such liver enzymes into culture medium above baseϊine levels when such compound concentrations are five-foϊd, and preferably ten-fold the EC50 or ICj0 for the compound. In other embodiments, certain preferred compounds do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to the EC50 or IC50 for the compound.
Certain preferred compounds are not clastogenic {e.g., as determined using a mouse erythrocyte precursor cell micronucleus assay, an Ames micronucleus assay, a spiral micronucieus assay or the like) at a concentration equal the EC50 or IC50 for the compound. In other embodiments, certain preferred compounds do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells) at such concentrations.
For detection purposes, as discussed in more detail below, compounds provided herein may be isotopically-labeled or radiolabeled. For example, such compounds may have one or more atoms replaced by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in the compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, ! IC, 13C, MC, 15N, 18O, !7O, 31P, 32P, 35S, 18F and 36Cl. In addition, substitution with heavy isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-fife or reduced dosage requirements and, hence, may be preferred in some circumstances.
PREPARATION OF DIARYL PYRIMIDINONES AND RELATED COMPOUNDS
Compounds provided herein may generally be prepared using standard synthetic methods. In general, starting materials are commerciaily available from suppliers such as Sigma-Aldrich Corp. (St. Louis, MO), or may be synthesized from commercially available precursors using established protocols. By way of example, a synthetic route similar to that shown in any of the following Schemes may be used, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon appreciated by those skilled in the art. It will be apparent that the reagents and synthetic transformations in the following Schemes can be readily modified to produce additional diaryl pyrimidinones and related compounds. Each variable in the following Schemes refers to any group consistent with the description of the compounds provided herein. When a protecting group is required, an optional deprotection step may be employed. Suitable protecting groups and methodology for protection and deprotection, such as those described in Protecting Groups in Organic Synthesis by T. Greene, are well known. Compounds and intermediates requiring protection/deprotection will be readily apparent. Certain abbreviations used in the following Schemes and in the Examples include:
BOC t-butoxycarbonyl
BOP (Benzotriazolyl-n-oxy-tris(dimethylamino)phosphonium hexafluorophosphate)
DCE 1 ,2-dichloroethane
DCM dichloromethane Et ethyl
EtOAc ethyl acetate h hour(s)
1H NMR proton nuclear magnetic resonance
Hz hertz m-CPBA m-chϊoroperoxybeπzoic acid
MeOH methanol min minute(s)
MS mass spectrometry δ chemical shift PTLC preparative thin layer chromatography rt room temperature
TEA triethylamine
TFA trifluoroacetic acid
TMS trimethyisilyl Scheme I illustrates a method for preparing diaryl pyrimidinones of Formula (I) in which R2 is a nitrogen-linked moiety (amine). Amide 1 is prepared by any of a variety of methods known in the art. such as by converting an acid to its acid chloride with, for example, thionyl chloride, followed by addition of the aniline in the presence of a base; or by using a coupling agent such as BOP in an inert solvent such as methylene chloride. Corresponding carboximidoyl chloride 2 is prepared using standard procedures, such as by heating compound 1 in thionyl chloride (SOCl2) or phosphorus oxychloride (POCl3). Intermediate 5 is generated in a single pot from 2. For example, reaction of carboximidoyl chloride 2 with potassium thiocyanate in an inert solvent such as acetone at O 0C produces the carbυximidoyl isothiocyanate 3, which reacts further w ith the desired amine under the same temperature to give the intermediate 4. Compound 4 is further methylated using a reagent such as iodomethane or dimethyl sulfate to afford 5.
Compound 6 (e g , compounds of Formula I where A is C-H) is prepared by reacting 5 with (trimethyisilyl)ketene or Reformatsky reagent (essentially as described by Mazumdar et al. (1990) Tetrahedron Letters, 31(29):A2\ 5-\ %) at an elevated temperature in an inert solvent such as DCE. Compound 7 {e.g., compounds of Formula I where A is N) is prepared by reacting 5 with (trimethylsilyl)isocyanate at an elevated temperature in an inert solvent such as DCE. Compound 8 (e.g., compounds of Formula I where A is C-Rj) is prepared by reacting 5 with the appropriately substituted acetic acid or acetyl chloride in the presence of a base such as TEA in an inert solvent such as chloroform (essentially as described by Mazumdar et al. (1991 ) Tetrahedron 47(8): \473-84 and Mazumdar et al. (1994) Tetrahedron 50(25):1579-S8), or with the appropriately substituted (trimethylsilyl)ketene at an elevated temperature in an inert solvent such as DCE.
Scheme I
Figure imgf000027_0001
Scheme II illustrates an approach for preparing diaryl pyrimidinones of Foπnula I in which R2 linked via a -C(=0)N moiety (carboxamides). Benzarnidine 9 is prepared by reacting intermediate with ammonia in a solvent such as DMF at room or elevated temperature, or is prepared from the corresponding benzonitrile and aniline essentially as described by Ramsden et al, (1997) J. Chem. Soc. Perkin Trans. ](J6):23 [9-232&. Acid I I is prepared by reacting benzamidine 9 with acetyienedicarboxylate or the appropriately substituted oxaloacetate in a solvent such as DMF at elevated temperature, followed by hydrolysis of the ester 10. Amide 12 is prepared by any of the various methods known in the art, such as by converting the acid to its acid chloride with, for example, thionyl chloride, followed by reacting with amine in the presence of a base, or by reacting with the amine in the presence of a coupling agent such as BOP in an inert solvent such as methylene chloride.
Scheme II
Figure imgf000028_0001
Amine
Figure imgf000028_0003
Figure imgf000028_0002
Scheme III illustrates a method for preparing diaryl pyrimidinones of Formula I in which R2 is other than an amine or carboxamide. Compound 13 is prepared by reacting benzamidine 9 with the appropriately substituted ketoester in a solvent such as DMF at elevated temperature.
Scheme III
Figure imgf000028_0004
9 13
In certain embodiments, a compound provided herein may contain one or more asymmetric carbon atoms, so that the compound can exist in different stereoisomeric forms. Such forms can be, for example, racemates or optically active forms. As noted above, all stereoisomers are encompassed by the present invention. Nonetheless, it may be desirable to obtain single enantiomers (i.e., optically active forms). Standard methods for preparing single enantiomers include asymmetric synthesis and resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography using, for example a chiral HPLC column.
Compounds may be radiolabeled by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. Each radioisotope is preferably carbon (e.g., 14C), hydrogen (e.g., Η), sulfur (e.g., 35S) or iodine (e.g., 125I). Tritium labeled compounds may also be prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas using the compound as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas. tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate. Preparation of radiolabeled compounds may be conveniently performed by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
PHARMACEUTICAL COMPOSITIONS
The present invention also provides pharmaceutical compositions comprising one or more compounds provided herein, together with at least one physiologically acceptable carrier or excipient Pharmaceutical compositions may comprise, for example, one or more of water, buffers (e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethylsuifoxide, carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives. In addition, other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein.
Pharmaceutical compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral (including, but not limited to, sublingual), nasal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions suitable for oral use are preferred. Such compositions include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, compositions of the present invention may be formulated as a lyophilizate. Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such exdpienls include, for example, inert diϊuents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or talc). The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be empioyed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).
Aqueous suspensions contain the active material(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (e g., sodium carboxymethy!ce!lulose, methylcellulose, hydropropyimethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitoi such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitoi anhydrides such as polyethylene sorbitan monooleate). Aqueous suspensions may also comprise one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil
(e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide paiatabJe oral preparations. Such suspensions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions may also be foπnulated as oil-in-water emulsions. The oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums (e.g , gum acacia or gum tragacanth). naturally-occurring phosphatides (e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitoi), anhydrides (e.g., sorbitan monoleate) and condensation products of partial esters derived from fatty acids and hexitoi with ethylene oxide (e.g., polyoxyethylene sorbitan monoleate). An emulsion may also comprise one or more sweetening and/or flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components. Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery. Topical vehicles include water; organic solvents such as alcohols (e.g., ethanoi or isopropyl alcohol) or glycerin; glycols (e g , butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices. A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale— The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsuies.
A topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions. Typical modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush: spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing. Controlled release vehicles can also be used. A pharmaceutical composition may be prepared as a sterile injectible aqueous or oleaginous suspension. The compound(s) provided herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Such a composition may be formulated according to the known art using suitable dispersing, wetting and-Or suspending agents such as those mentioned above. Among the acceptable vehicles and solvents that may be employed are water, 1 ,3-butanediol, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectible compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.
Compounds may also be formulated as suppositories (e.g., for rectal administration). Such compositions can be prepared by mixing the drug with a suitable non-irritating cxcipient that is soϊid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Compositions for inhalation typically can be provided in the form of a solution, suspension or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofluoromethane). Pharmaceutical compositions may be formulated for release at a pre-determined rate.
Instantaneous release may be achieved, for example, via sublingual administration (i.e., administration by mouth in such a way that the active ingredient(s) are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract). Controlled release formulations (/ e., formulations such as a capsule, tablet or coated tablet that slows and/or delays release of active ingredient(s) following administration) may be administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at a target site. In general, a controlled release formulation comprises a matrix and/or coating that delays disintegration and absorption in the gastrointestinal tract (or implantation site) and thereby provides a delayed action or a sustained action over a longer period. One type of controlled-release formulation is a sustained-release formulation, in which at least one active ingredient is continuously released over a period of time at a constant rate.
Preferably, the therapeutic agent is released at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic levels, over a period of time that is at least 4 hours, preferably at least 8 hours, and more preferably at least 12 hours. Such formulations may generally be prepared using weli known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented. Controlled release may be achieved by combining the active ingredient(s) with a matrix material that itself alters release rate and/or through the use of a controlled-reiease coating. The release rate can be varied using methods well known in the art, including (a) varying the thickness or composition of coating, fb) altering the amount or manner of addition of plasticizer in a coating, (c) including additional ingredients, such as release-modifying agents, (d) altering the composition, particle size or particle shape of the matrix, and (e) providing one or more passageways through the coating. The amount of modulator contained within a sustained release formulation depends upon, for example, the method of administration (e.g., the site of implantation), the rate and expected duration of release and the nature of the condition to be treated or prevented.
The matrix material, which itself may or may not serve a controlled-release function, is generally any material that supports the active ingredient(s). For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed. Active ingredient(s) may be combined with matrix material prior to formation of the dosage form (e g., a tablet). Alternatively, or in addition, active ingredient(s) may be coated on the surface of a particle, granule, sphere, microsphere, bead or pellet that comprises the matrix material. Such coating may be achieved by conventional means, such as by dissolving the active ingredient(s) in water or other suitable solvent and spraying. Optionally, additional ingredients are added prior to coating (e.g., to assist binding of the active ingredient(s) to the matrix material or to color the solution). The matrix may then be coated with a barrier agent prior to application of contra lled-release coating. Multiple coated matrix units may, if desired, be encapsulated to generate the final dosage foπn.
In certain embodiments, a controlled release is achieved through the use of a controlled release coating (i.e., a coating that permits release of active ingredient(s) at a controlled rate in aqueous medium). The controlled release coating should be a strong, continuous film that is smooth, capable of supporting pigments and other additives, non-toxic, inert and tack-free. Coatings that regulate release of the modulator include pH -independent coatings, pH-dependent coatings (which may be used to release modulator in the stomach) and enteric coatings (which allow the formulation to pass intact through the stomach and into the small intestine, where the coating dissolves and the contents are absorbed by the body). It will be apparent that multiple coatings may be employed (e.g., to allow release of a portion of the dose in the stomach and a portion further along the gastrointestinal tract). For example, a portion of active ingredient(s) may be coated over an enteric coating, and thereby released in the stomach, while the remainder of active ingredient(s) in the matrix core is protected by the enteric coating and released further down the GI tract. pH dependent coatings include, for example, shellac, cellulose acetate phthalate, polyvinyl acetate phthaiate, hydroxypropylmethylcellulose phthalate, methacrylic acid ester copolymers and zein. in certain embodiments, the coating is a hydrophobic material, preferably used in an amount effective to slow the hydration of the gelling agent following administration. Suitable hydrophobic materials include alkyl celluloses (e.g., ethylcellulose or carboxymethylcellulose), cellulose ethers, cellulose esters, acrylic polymers (e.g., poly(acrylic acid), poly(methacrylic acid), acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxy ethyl methacrylates, cyanoethyl methacrylate, methacrylic acid alkamide copolymer, polyfmethyl methacrylate), polyacrylamide, ammonio methacrylate copolymers, aminoalky! methacrylate copolymer, poly(methacrylic acid anhydride) and glycidyl methacrylate copolymers) and mixtures of the foregoing. Representative aqueous dispersions of ethylcellulose include, for example,
AQUACOAT® (FMC Corp., Philadelphia, PA) and SURELEASE® (Colorcon, Inc., West Point, PA), both of which can be applied to the substrate according to the manufacturer's instructions. Representative acrylic polymers include, for example, the various EUDRAGIT® (Rohm America, Piscataway, NJ) polymers, which may be used singly or in combination depending on the desired release profile, according to the manufacturer's instructions. The physical properties of coatings that comprise an aqueous dispersion of a hydrophobic material may be improved by the addition or one or more plasticizers. Suitable plasticizers for alkyl celluloses include, for example, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin. Suitable plasticizers for acrylic polymers include, for example, citric acid esters such as triethyl citrate and tributyl citrate, dibutyl phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin.
Controlled-reiease coatings are generally applied using conventional techniques, such as by spraying in the form of an aqueous dispersion. If desired, the coating may comprise pores or channels or to facilitate release of active ingredient. Pores and channels may be generated by well known methods, including the addition of organic or inorganic materia! that is dissolved, extracted or leached from the coating in the environment of use. Certain such pore-forming materials include hydrophilic polymers, such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose), cellulose ethers, synthetic water-soluble polymers (e.g., polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone and polyethylene oxide), water-soluble polydextrose, saccharides and polysaccharides and alkali metal salts. Alternatively, or in addition, a controlled release coating may include one or more orifices, which may be formed my methods such as those described in US Patent Nos. 3,845,770; 4,034,758; 4,077,407; 4,088,864; 4,783,337 and 5,071 ,607. Controlled-release may also be achieved through the use of transdermal patches, using conventional technology (see, e.g., US Patent No. 4,668,232).
Further examples of controlled release formulations, and components thereof, may be found, for example, in US Patent Nos. 4,572,833; 4,587,1 1 7; 4,606,909; 4,610,870; 4,684,516; 4,777,049; 4,994,276: 4.996,058; 5, 128, 143 ; 5,202, 128; 5,376,384; 5,384,133 ; 5,445,829; 5,510, 1 19: 5,618,560; 5,643,604: 5,891 ,474; 5,958.456; 6,039,980; 6,143,353 ; 6,126,969; 6, 156,342; 6,197,347; 6,387,394; 6,399,096; 6,437,000; 6,447,796; 6,475,493; 6,491 ,950; 6,524,615: 6,838,094; 6,905,709; 6.923,984; 6,923,988; and 6,93 1 ,217; each of which is hereby incorporated by reference for its teaching of the preparation of controlled release dosage forms. In addition to or together with the above modes of administration, a compound provided herein may be conveniently added to food or drinking water (e g , for administration to non-human animals including companion animals (such as dogs and cats) and livestock). Animal feed and drinking water compositions may be formulated so that the animal takes in an appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to feed or drinking water.
Compound(s) provided herein are generally administered in a therapeutically effective amount. Preferred systemic doses are no higher than 50 mg per kilogram of body weight per day (e.g., ranging from about 0.001 mg to about 50 mg per kilogram of body weight per day), with oral doses generally being about 5-20 fold higher than intravenous doses (e.g., ranging from 0.01 to 40 mg per kilogram of body weight per day).
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage unit will vary depending, for example, upon the patient being treated and the particular mode of administration. Dosage units wiϊl generally contain from about 10 μg to about 500 mg of an active ingredient. In certain embodiments, the dosage unit contains an amount of the compound that is sufficient to effect a decrease in the patient's caloric intake (i.e., an appetite-suppressing amount) following single dose administration or repeated administration according to a predetermined regimen. Optimal dosages may be established using routine testing, and procedures that are well known in the art.
Pharmaceutical compositions may be used for treating a condition responsive to CB 1 modulation. Such conditions include, for example: appetite disorders (e.g., binge eating disorder, bulimia, anorexia); obesity and complications associated therewith, including left ventricular hypertrophy; weight loss or control (e.g., reducing calorie or food intake and/or appetite suppression); and dependency disorders such as: alcohol dependency (e.g., alcoho! abuse, addiction and/or dependency including treatment for abstinence, craving reduction and relapse prevention of alcohol intake); nicotine dependency (e.g., smoking addiction, cessation and/or dependency including treatment for craving reduction and relapse prevention of tobacco smoking); and drug dependency (e.g., chronic treatment with or abuse of drugs such as opioids, barbiturates, cannabis, ***e, amphetamines, phencyclide, hallucinogens, and/or benzodiazepines), metabolic disorders (e.g., type 2 diabetes, dyslipidemia and metabolic syndrome); bone loss (e.g., resulting from estrogen deficiency).
Other conditions responsive to CB l modulation include CNS disorders (e.g., anxiety, depression, panic disorder, bipolar disorder, psychosis, schizophrenia, behavioral addiction, dementia (including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, mild cognitive impairment, age-related cognitive decline, and mild neurocognitive disorder), attention deficit disorder (ADD/ADHD), stress, amnesia, cognitive disorders, memory disorders, neurodegeneration, cerebellar and spinocerebellar disorder, cranial trauma, cerebral vascular accidents, obsessive- compulsive disorder, senile dementia, impulsivity), thymic disorders, septic shock, Tourette's syndrome. Huntington's chorea. Raynaud's syndrome, peripheral neuropathy, diabetes (type II or non insulin dependent), glaucoma, migraine, seizure disorders, epilepsy, locomotor disorders (movement disorders induced by medicaments, dyskinesias or Parkinson's disease), respiratory disorders (such as asthma), gastrointestinal disorders (e.g., dysfunction of gastrointestinal motility or intestinal propulsion, constipation, chronic intestinal pseudo-obstruction, irritable bowel syndrome, Crohn's disease), liver cirrhosis, vomiting, diarrhea, ulcer, multiple sclerosis, cardiovascular disorder, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, a disorder of the endocrine system, urinary or bladder disorders, cancer, infectious disease, inflammation, infection, cancer, neuroinflammation (such as atherosclerosis), Guillain-Barre syndrome, viral encephalitis, crania! trauma, sepsis, hair loss or a reproductive disorder. In certain embodiments, the condition responsive to CB 1 modulation is an appetite disorder, obesity, a dependency disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension or drug-induced hypotension. Certain pharmaceutical compositions provided herein comprise a first agent that is a compound as provided herein in combination with a second agent that differs in structure from the first agent and is suitable for treating the condition of interest. In certain embodiments, the second agent is not a CB l antagonist as provided herein. In certain embodiments, the second agent is suitable for treating an appetite disorder, obesity, a dependency disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone ioss, portal hypertension, fibrosis of internal organs, orthostatic hypotension and/or drug-induced hypotension.. Representative second agents for use within such pharmaceutical compositions include anti-obesity agents such as MCH receptor antagonists, apo-B/MTP inhibitors, l l β-hydroxy steroid dehydrogenase-! inhibitors, peptide YYi-36 or an analog thereof, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, P3 adrenergic receptor agonists, dopamine agonists, melanocyte-stimulating hormone receptor analogues, 5-HT2c receptor agonists, leptin or an analog thereof, Ieptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, neuropeptide-Y receptor antagonists, thyromimetic agents, dehydroepiandrosterone or analog thereof, glucocorticoid receptor antagonists, orexin receptor antagonists, glucagon-Iike peptide- 1 receptor agonists, ciliary neurotrophic factors, human agouti-related protein antagonists, ghrelin receptor antagonists, histamine 3 receptor antagonists, and neuromedin U receptor agonists. Such agents include, for example, phentermine, orlistat and sibutramine (e.g., sibutramine HCl monohydrale).
Representative second agents suitable for treating a dependency disorder include, for example, Methadone. LAAM (fevo-alpha-acetyl-methadol), naltrexone, ondansetron, sertraline, fluoxetine, diazepam, chlordiazepoxide, varenicline and buproprion. Other representative second agents for use within the pharmaceutical compositions provided herein include nicotine receptor partial agonists, opioid antagonists and/or dopaminergic agents.
Pharmaceutical compositions may be packaged for treating conditions responsive to CB l modulation (e.g., treatment of appetite disorder, obesity and/or dependency disorder, or other disorder indicated above). Packaged pharmaceutical preparations generally comprise a container holding a pharmaceutical composition as described above and instructions (e g , labeling) indicating that the composition is to be used for treating a condition responsive to CB I modulation in a patient, ϊn certain embodiments, a packaged pharmaceutical preparation comprises one or more compounds provided herein and one or more additional agents in the same package, either in separate containers within the package or in the same container (i.e., as a mixture). Preferred mixtures are formulated for oral administration (e.g., as pills, capsules, tablets or the like). In certain embodiments, the package comprises a label bearing indicia indicating that the components are to be taken together for the treatment of an appetite disorder, obesity, a dependency disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension and/or drug-induced hypotension..
METHODS OF USE
Within certain aspects, the present invention provides methods for treating a condition responsive to CBl modulation in a patient and/or for appetite suppression. The patient may be afflicted with such a condition, or may be free of symptoms but considered at risk for developing such a condition. A condition is "responsive to CB l modulation" if the condition or symptom(s) thereof arc alleviated, attenuated, delayed or otherwise improved by modulation of CB l activity. Such conditions include, for example, appetite disorders, obesity, dependency disorders, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, memory disorders, cognitive disorders, movement disorders, metabolic disorders, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension and drug-induced hypotension, as well as other disorders indicated above. In general, such methods comprise administering to the patient a therapeutically effective amount of at least one compound as provided herein.
It will be apparent that compounds provided herein may be administered alone or in combination with one or more additional agents that are suitable for treating the disorder of interest. Within combination therapy, the compound(s) and additional agent(s) may be present in the same pharmaceutical composition, or may be administered separately in either order. Representative additional agents for use in such methods include the second agents described above.
Suitable dosages for compounds provided herein (either alone or within such combination therapy) are generally as described above. Dosages and methods of administration of any additional agent(s) can be found, for example, in the manufacturer's instructions or in the Physician's Desk Reference. In certain embodiments, combination administration results in a reduction of the dosage of the additional agent required to produce a therapeutic effect (i. e., a decrease in the minimum therapeutically etieciivc amount). Thus, preferably, the dosage of additional agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the manufacturer for administration of the agent without combination with a compound of Formula I. More preferably this dose is less than VA, even more preferably less than Vz, and highly preferably less than VA of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the agent(s) when administered without combination administration as described herein. It will be apparent that the dose of compound as provided herein needed to achieve the desired effect may similarly be affected by the dose and potency of the additional agent. Administration to the patient can be by way of any means discussed above, including oral, topical, nasal or transdermal administration, or intravenous, intramuscular, subcutaneous, intrathecal, epidural, intracerebroventrilcular or like injection. Oral administration is preferred in certain embodiments (e.g , formulated as pills, capsules, tablets or the like).
Treatment regimens may vary depending on the compound used and the particular condition to be treated. In general, a dosage regimen of 4 times daily or less is preferred, with 1 or 2 times daily particularly preferred. It will be understood, however, that the specific dose level and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Dosages are generally as described above; in general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented. For example, treatment of obesity is considered to be effective if it results in a statistically significant decrease in weight or BMI. Within separate aspects, the present invention provides a variety of non-pharmaceutical in vitro and in vivo uses for the compounds provided herein. For example, such compounds may be labeled and used as probes for the detection and localization of CB l (in samples such as cell preparations or tissue sections, preparations or fractions thereof). In addition, compounds provided herein that comprise a suitable reactive group (such as an aryl carbonyl, nitro or azide group) may be used in photoaffinity labeling studies of receptor binding sites. In addition, compounds provided herein may be used as positive controls in assays for receptor activity, as standards for determining the ability of a candidate agent to bind to CB l , or as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT). Such methods can be used to characterize CB l receptors in living subjects. For example, a compound may be labeled using any of a variety of well known techniques (e g , radiolabeled with a radionuclide such as tritium, as described herein), and incubated with a sample for a suitable incubation time (e g , determined by first assaying a time course of binding). Following incubation, unbound compound is removed (e g , by washing), and bound compound detected using any method suitable for the label employed (e g , autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods may be used to detect luminescent groups and fluorescent groups). As a control, a matched sample containing labeled compound and a greater (e.g , 10-fold greater) amount of unlabeled compound may be processed in the same manner. A greater amount of detectable label remaining in the test sample than in the control indicates the presence of CB l in the sample. Detection assays, including receptor autoradiography (receptor mapping) of CB 1 in cultured cells or tissue samples may be performed as described by Kuhar in sections 8.1 .1 to 8.1 ,9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York. Compounds provided herein may further be used within assays for the identification of other non-competitive antagonists of CBl . In general, such assays are standard competition binding assays, in which a labeled compound as provided herein is displaced by a test compound. Briefly, such assays are performed by: (a) contacting CB I with a labeled (e.g., radiolabeled) compound and a test compound, under conditions that permit binding to CB l (b) removing unbound labeled compound and unbound test compound; (c) detecting a signal that corresponds to the amount of bound, labeled compound: and (d) comparing the signal to a reference signal that corresponds to the amount of bound labeled compound in a similar assay performed in the absence of test compound. In practice, the reference signal and the signal described in step (c) are generally obtained simultaneously (e.g., the assays are performed in different wells of the same plate); in addition, multiple concentrations of test compound are generally assayed. Non-competitive antagonist activity can be confirmed for test compounds that decrease the amount of bound, labeled compound using procedures described herein.
The following Examples are offered by way of illustration and not by way of limitation.
Unless otherwise specified all reagents and solvent are of standard commerciai grade (available, for example, from Sigma-Aldrich, St. Louis. MO)) and are used without further purification. Using routine modifications, the starting materials may be varied and additional steps employed to produce other compounds provided herein.
EXAMPLES
Mass spectroscopy data in the following Examples is Electrospray MS, obtained in positive ion mode using a Micromass Time-of-Flight LCT (Micromass, Beverly MA), equipped with a Waters 600 pump (Waters Corp.; Milford, MA), Waters 996 photodiode array detector, and a Gilson 21 5 autosampler (Gilson, Inc.; Middleton, WI). MassLynx (Advanced Chemistry Development, Inc; Toronto, Canada) version 4.0 software with OpenLynx Global Server™, OpenLynx™ and AutoLynx™ processing is used for data collection and analysis. MS conditions are as follows: capillary voltage = 3.5 kV; cone voltage = 30 V, desolvation and source temperature = 35O0C and 1200C, respectively; mass range = 181 -750 with a scan time of 0.22 seconds and an interscan delay of 0.05 seconds.
Sample volume of 1 microliter is injected onto a 50x4.6mm Chromoliih SpeedPvOD PvP-I Se column (Merck KGaA, Darmstadt, Germany), and eluted using a 2-phase linear gradient at a flow rate of 6 ml/min. Sample is detected using total absorbance count over the 220-340nm UV range. The elution conditions are: Mobile Phase A - 95% water, 5% MeOH with 0.05% TFA; Mobile Phase B - 5% water, 95% MeOH with 0.025% TFA. The following gradient is used: 0-0.5 min I 0-l O0%B, hold at 100%B to 1.2 min, return to 10%B at 1 .21 min. Inject to inject cycle is 2.15 min.
EXAMPLE 1 . { l -[2-(2-CHLORO-PHENYL)-6-OXO-l -(4-TR)FLUOROMETHYL-PHENYL)- 1 ,6-DIH YDRO- PYRIMIDIN-4-YL]-PIPERIDIN-4-YL}-CARBAMIC ACID 7EKf-BUTYL ESTER (COMPOUND 1 )
Step 1. 2-Chloro-N-[4-(trifluoFomethyl)phenyl]benzamide
Figure imgf000040_0001
To a solution of 4-trifiuoromethylaniiine (16.1 g, 100 mmol) and TEA (21 mL, 150 mmol) in
DCM (100 mL) at 0 0C, is added slowly a solution of 2-chiorobenzoyl chloride (17.5 g, 100 mmoi) in DCM (40 mL) over a period of 30 min. After addition, the reaction mixture is stirred for 30 min before it is quenched with saturated aqueous sodium carbonate solution. The white solid is filtered off to give the title compound. The two layer filtrate is separated with separatory funnel. The organic layer is washed with water and brine, dried over sodium sulfate and concentrated to give additional title compound.
Step 2. 4-/ert-Butoxycarbony]amino-iV-[(2-chloro-phenyl)-(4-trifluoromethyl-phenylimino>methyi]» piperidine-1 -carboximidothioic acid methyl ester
Figure imgf000040_0002
A 100 mL round-bottom flask is charged with 2-chloro-Λr-[4-
(trif!uoromethyl)ρhenyl]benzamide (3 g. 10 mmol) and thionyi chloride (10 mL). The reaction mixture is heated under reflux for 1 h. After cooling to rt, the excess thionyi chloride is removed under vacuum. The residue is dissolved in acetone (30 mL), and cooled to -10 0C. A solution of potassium thiocyanate in acetone (15 mL) is added slowly. After addition, the reaction mixture is stirred for 1 h at 0 0C. 4-Ar-Boc-aminopiperidine (2 g, 10 mmol) is added, and the mixture is stirred at rt for 1 h. Iodomethane (1.25 mL, 20 mmol) is added neat. The reaction mixture is stirred at rt overnight. EtOAc and saturated aqueous sodium carbonate are added, and the organic layer is separated. The aqueous layer is back extracted with EtOAc once. The combined organic layers are washed with water and brine, dried with sodium sulfate, and concentrated. The residue is purified with column chromatography (5% MeOH in DCM) to give the title compound as a yellow solid. Step 3. { l -[2-(2-Ch!oro-phenyI)-6-oxo-l-(4-trifluoromethyi-phenyl)-l ,6-dihydro-pyrimidin-4-yl]- piperidin-4-yl}-carbamic acid tert-butyl ester (Compound 1 )
Figure imgf000041_0001
A solution of 4-fert-butoxycarbonyIamino-N-[(2-chioro-phenyl)-(4-trifluoromethyl- ρhenylimino)-methy]]-pipeπdine-l -carboximidothioic acid methyl ester (100 mg, 0,1 8 mmol) and (trimethylsi]yl)ketene (22,6 mg, 0.2 mmol) in DCE (1 niL) is heated at 120 0C for 1 h. After cooling to rt, the mixture is purified by PTLC (5% MeOH in DCM) to give the title compound as an off-white solid.
EXAMPLE 2. TERT-BUTYL ( 1 -{6-(2-CHLOROPHENYL)-4-OXO-5-[4-(TRIFLUOROMETHYL)PHENYL]- 4,5-DIHYDRO-I ^^-TRIAZlN^-YLjPIPERIDIN^-YLjCΛRBΛMAΪE (COMPOUND 2)
Figure imgf000041_0002
A solution of 4-/er/-butoxycarbonylamino-N-[(2-chloro-phenyi)-(44rifluoromethyl- ρhenylimino)-methyl]-piperidine-l~carboximidothioic acid methyl ester (100 mg, 0.18 mmoi) and (trimetbyjsilyl)isocyanate (41.5 mg. 0.36 mmol) in DCE (1 mL) is heated at 120 0C overnight. After cooling to rt, the mixture is purified by PTLC (5% MeOH in DCM) to give the titie compound as a off-white solid. MS = 550.05; retention time = 1 ,3 min.
EXAMPLE 3. N-(I -{2-(2-CHLOROPHENYL)-6-OXO- 1 -[4-(TRIFLUOROMETHYL)PHENYL]- 1 ,6- DIHYDR0PYRIMIDlN-4-YL}PlPERIDIN-4-YL)PR0P10NAMIDE (COMPOUND 3)
Figure imgf000041_0003
To a solution of { l -[2-(2-chloro-phenyl)-6-nχo- l -(4-trifluoromethyl-pheny!)- ! .6-dihydro- pyrimidin-4-yl]-piperidin-4-yl}-carbamic acid fer/-butyl ester (43.3 mg. 0.079 mmol) in DCM ( i mL), is added TFA (1 mL). The reaction mixture is stirred for 20 min at rt. The solvent and excess TFA is removed under vacuum. The residue is re-dissolved in DCM (1 mL) and diisopropylethylamine (0.1 mL) is added. The reaction mixture is cooled to 0 0C. and a solution of propionyi chloride (7.3 mg, 0.079 mmol) in DCM is added slowly. After stirring for 10 min at 0 0C, the mixture is purified by PTLC (5% MeOH in DCM) to give the title compound as a white solid. 1H- NMR (δ, ppm, CDCl3 as internal standard): 7.48 (d, J = 8.1 Hz, 2H), 7.42-7.1 1 (m, 6H), 5.59 (s, I H), 5.46 (ά, J = 8.1 Hz, I H), 4.34-4.22 (m, 2H), 4.12-4.03 (m, I H), 3.04 (tm, J = 12.5 Hz, 2H), 2.18 (q, J = 7.8 Hz, 2H), 2.04-1.98 (m, 2H), 1.46-1.35 (m, 2H), 1.13 (t, J = 7.S Hz, 3H). MS = 505.15; retention time = 1.28 min.
EXAMPLE 4. N-( 1 -{6-(2-CHLOROPHENYL)-4-OXO-5-[4-(TRIFLUOROMETHYL)PHENYL]-4,5-
DIHYDRO-1 ,3, 5-TRIAZIN-2-YL}PIPERIDIN-4- YL)PROPANAMIDE (COMPOUND 4)
Figure imgf000042_0001
To a solution of tø-r-butyl (l -{6-(2-chtorophenyl)-4-oxo-5-[4-(trifiuoromethyI)phenyl]-4,5- dihydro-I ,3,5-triazin-2-yl}piperidin-4-yl)carbamate (28.3 mg, 0.05 mmol) in DCM (1 mL), is added TFA (1 mL). The reaction mixture is stirred for 20 min at rt. The solvent and excess TFA is removed under vacuum. The residue is re-dissolved in DCM (1 mL) and diisopropylethylamine (0.1 mL) is added. The reaction mixture is cooled to 0 0C, and a solution of propionyi chloride (4.6 mg, 0.05 mmol) in DCM is added slowly. After stirring for 10 rnin at 0 0C, the mixture is purified by PTLC (5% MeOH in DCM) to give the title compound as an off-white solid. 1H-NMR (δ, ppm, CDCl3 as internal standard): 7.49 (d, J = 8.7 Hz, 2H), 7.31-7.18 (m, 6H), 5.41 (d, J= 7.8 Hz, I H), 4.94 (dm, J= 14.1 Hz, IH), 4.78 (dm, J = 14.7 Hz, I H), 4.15-4.04 (m, I H), 3.18-3.08 (m, 2H), 2.19 (q, J = 7.8 Hz, 2H), 2.09-2.04 (m. 2H), 1 .54-1.25 (m, 2H), 1 .15 (t, J = 7.8 Hz, 3H). MS = 506.07; retention time = 1 .24 min.
EXAMPLE 5. 2-(2-CHLOROPHENYL )-6-THIOMGRPHOLIN-4-YL-3-[4- (TRIFLUOROMETHYL)PHENYL]PYRIMIDΓN-4(3H)-ONE (COMPOUND 5)
Step 1 . jV-[(2-Chloro~phenyl)-(4-trifluoromethyl-phenylimino)-methyl]-thiomoφholine-4- carboximidothioic acid methyl ester
Figure imgf000042_0002
The title compound is synthesized essentially as described in Example 1 , using thiomorphoiine instead of 4-Λ7-Boc-aminopiperidine. The reaction yields the title compound as a yellow viscous oil.
Step 2. 2-(2-Chloropheny!)-6-thiomoφholin-4-yi-3-[4-(trifiuoromethyI)phenyl]ρyrimidin-4(3H)-one
Figure imgf000043_0001
A solution of 7\f-[(2-chloro-phenyl)-(4-trifluoromethyl-phenyIimino)-methyl]-thiomoφholine- 4-carboximidothioic acid methyl ester (92 mg, 0.2 mmol) and (trimethylsilyl)ketene (34.3 mg, 0.3 mmo!) in DCE (1 mL) is heated at 120 0C for 1 h. After cooling to rt, the mixture is purified by PTLC (5% MeOH in DCM) to give the title compound as light yellow solid. 1H-NMR (δ, ppm, CDCl3 as internal standard): 7.50 (d, / = 8.7 Hz, 2H), 7.42-7.14 (m, 6H), 5.58 (s, I H), 3.98-3.96 (m, 4H), 2.69 (t, J= 5.1 Hz, 4H). MS = 452.10; retention time = 1.28 min.
EXAMPLE 6. 2-(2-CHLOROPHENYL)-6-( 1 , 1-DIOXIDOTHIOMORPHOLIN-4-YL)-3-[4- (TR[FLUOROMETHYL)PHENYL]PYRIMIDIN-4(3H)-ONE (COMPOUND 6)
Figure imgf000043_0002
To a solution of 2-(2-chlorophenyl)-6-thiomorpholin-4-yl-3-[4-(trifiuoromethyl) phenyl]pyrimidin-4(3H)-onc (71 .8 mg, 0.159 mmol) in DCM (2 mL), is added sodium bicarbonate (80 mg, 0.954 mmol), followed by mCPBA (142.5 mg, 77% max, 0.636 mmol). The resulting mixture is stirred for 2 h at rt. PTLC purification (5% MeOH in DCM) affords the title compound. 1H-NMR (δ. ppm, CDCl3 as internal standard): 7.52 (d, J = 8.7 Hz, 2H), 7.42-7.14 (m, 6H), 5.73 (s, I H), 4.18-4.12 (m, 4H), 3.10 (t, J= 5.1 Hz, 4H). MS = 484.09; retention time = 1.19 min.
EXAMPLE 7. ADDITIONAL REPRESENTATIVE DIARYL PYRIMIDINONES AND RELATED COMPOUNDS
Using routine modifications, the starting materials may be varied and additional steps employed to produce other compounds provided herein. Compounds listed in Tables I and II are prepared using such methods. For each compound in Table I, and for Compounds 2-6, above, the K, at CB l , determined as described in Example 12 herein, is I micromolar or less. "Ret." is the retention time in min and mass spectroscopy data generated as described above is presented as in the column headed "MS". All mass spectroscopy data is presented as M+l (mass +1) unless otherwise noted.
Table I
Compound Name Ret MS
I l
Figure imgf000044_0001
Figure imgf000045_0001
Compound Name Ret MS
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Compound Name Ret MS
Figure imgf000049_0001
Compound Name Ret MS
- 1.24 507.14
- 1.27 523.14
,6- 1 2g 50Q 1 g
Figure imgf000050_0001
- - 1.24 522.16 -
Figure imgf000050_0002
3-(4-chloro-2- fluoroρheny[)-2-(2- chloropheny])-6-(4- 1.26 475.07 proρionylpiρerazin-1 - yl)pyrimidin-4(3H)-one
Figure imgf000050_0003
Figure imgf000051_0001
Figure imgf000052_0001
Compound Name Ret MS
Figure imgf000053_0001
Figure imgf000054_0001
Compound Name Ret MS
Figure imgf000055_0001
Compound Name Ret MS
Figure imgf000056_0001
Compound Name Ret MS
- 132 g4g 1g
76
77 1,3 505.15
1 -
78 1.32 535.17
- 9 1.32 521.19
1 - 0 1.34 535.20
Figure imgf000057_0001
Compound Name Ret MS
Figure imgf000058_0001
Compound Name Ret MS
Figure imgf000059_0001
Compound Name Ret MS
ig
18
Figure imgf000060_0001
Compound Name Ret MS
Figure imgf000061_0001
101
102
103
104
105
Figure imgf000062_0001
Compound Name Ret MS
12
7
1
Figure imgf000063_0001
Compound Name Ret MS
1.29 507,16
142 524 u 1] -
Figure imgf000064_0001
Figure imgf000064_0002
Compound Name Ret MS
Figure imgf000065_0001
Table Ii
Compound Name
)-3 -(4- id in-
I H-
-(4-
Figure imgf000066_0001
l -(2-(2,4-dichlorophenyl)-6-oxo-l -(4- (trifluoromelhy!)phenyl)-1 ,6- dihydropyrimidin-4-yl)azetidin-3-yl dimethylcarbamaie
N-(I -(2-(2,4-dichlorophenyl)-6-oxo- 1 - (4-(trifluoromethyl)pheny I)- 1 ,6- dihydropyrimidin-4-yl)ρyrrolidin-3- yl)methanesulfonamide
Figure imgf000066_0002
Compound Name
l -y])piperidin- l)pyrimidin-
Figure imgf000067_0001
EXAMPLE 8. B ACULO VIRAL PREPARATIONS FOR CB l EXPRESSION
This Example illustrates the preparation of recombinant bacuiovirus for use in generating CB 1 -expressing insect cells.
The human CB l sequence has GenBank Accession Number HSU73304 (see Hoehe et al. (1991 ) New Biol. J(Pj:88O-85). Human CB l fhCB 1) cDNA is amplified from a human brain cDNA library (Gibco BRL, Gaithersburg, MD) using PCR, in which the 5' primer includes the optimal Kozak sequence CCACC. The resulting PCR product is cloned into pcDNA3.1/V5-His-TOPO (Invitrogen Corp, Carlsbad, CA) using the multiple cloning site, and then subcloned into pBACPAK8 (BD Biosciences, Palo Alto, CA) at the Bam/Xho site to yield a hCB l baculoviral expression vector. The hCB l baculoviral expression vector is co-trans fected along with B ACULOGOLD DNA
(BD PharMingen, San Diego, CA) into Sβ cells. The Sβ cell culture supernatant is harvested three days post-transfection. The recombinant virus-containing supernatant is serially diluted in Hink's TNM-FH insect medium (JRH Biosciences, Kansas City, MO) supplemented with Grace's salts and with 4.I mM L-GIn, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolate and 10% heat-inactivated fetal bovine serum (hereinafter 'Insect medium") and plaque assayed for recombinant plaques. After four days, recombinant piaques are selected and harvested into 1 ml of insect medium for amplification. Each 1 ml volume of recombinant bacuiovirus (at passage 0) is used to infect a separate T25 flask containing 2 x 106 S/9 cells in 5 ml of insect medium. After five days of incubation at 270C, supernatant medium is harvested from each of the T25 infections for use as passage 1 inoculum. Two of seven recombinant baculoviral clones are then chosen for a second round of amplification, using 1 ml of passage 1 stock to infect I x 10s cells in 100 ml of insect medium divided into 2 Tl 75 flasks. Forty-eight hours post infection, passage 2 medium from each 100 ml preparation is harvested and plaque assayed for titer. The ceil pellets from the second round of amplification are assayed by affinity binding as described below to verify recombinant receptor expression. A third round of amplification is then initiated using a multiplicity of infection of 0.1 to infect a liter of S/9 cells. Seventy-two hours post-infection the supernatant medium is harvested to yield passage 3 baculoviral stock.
The remaining cell pellet is assayed for affinity binding. Radioligand is 25pM-5.0nM f H]CP55,940 for saturation binding and 0.5nM for competition binding (New England Nuclear Corp., Boston, MA); the hCB 1 -expressing baculoviral cells are used; the assay buffer contains 50 mM Tris pH 7.4, 120 mM NaCI, 5 inM MgCl2, 0.5% BSA and 0.2 rng/ml bacitracin; filtration is carried out using GF/C WHATMAN filters (presoaked in 0.3% non-fat dry milk (H2O) for 2 hours prior to use); and the filters are washed twice with 5 mL cold 50 mM Tris pH.7.4.
Titer of the passage 3 baculoviral stock is determined by piaque assay and a multiplicity of infection, incubation time course, binding assay experiment is carried out to determine conditions for optimal receptor expression.
EXAMPLE 9. BACULOVIRAL INFECTIONS
Log-phase S/9 cells (Invitrogen Corp., Carlsbad, CA), are infected with one or more stocks of recombinant baculovirus followed by culturing in insect medium at 270C. Infections are carried out either oniy with virus directing the expression of hCB l or with this virus in combination with three G- protein subun it-express ion virus stocks: 1 ) rat Ga12 G-protein-encoding virus stock, 2) bovine βl G- protein-encoding virus stock, and 3) human γ2 G-protein-encoding virus stock, all of which are obtained from Biosignal Inc., Montreal, Canada.
Typical hCB l infections are conducted using Sf9 cells that are cultured in insect medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) as discussed above. Higher receptor and G-protein (Ga, Gβ, Gγ) expression can be obtained if the Sf9 cells are cultured in insect medium with 5% FBS and 5% Gibco serum-free medium (Invitrogen Corp.; Carlsbad, CA). Maximal CB I expression and functional activity is achieved if the Sf9 cells are cultured in insect medium without FBS and with 10% Gibco serum-free medium. The infections are carried out at a multiplicity of infection of 0.1 : 1.0:0.5 :0.5. At 72 hours post-infection, a sample of cell suspension is analyzed for viability by trypan blue dye exclusion, and the remaining S/9 cells are harvested via centrifugation (3000 rpm/ I 0 min/ 4°C).
EXAMPLE 10. PURIFIED RECOMBINANT INSECT CELL MEMBRANES
S/9 cell pellets are resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 μg/mi leupeptin, 2 μg/ml Aprotinin, 200 μM PMSF, and 2.5 mM EDTA. pH 7.4) and homogenized using a POLYTRON homogenizer (setting 5 for 30 seconds). The homogenate is centrifυged (536 x g/ 10 min/ 4°C) to pellet the nuclei. The supernatant containing isolated membranes is decanted to a clean centrifuge tube, centrifuged (48,000 X g/ 30 min, 40C) and the resulting pellet resuspended in 30 ml homogenization buffer. This centrifugation and resuspension step is repeated twice. The final pellet is resuspended in ice cold Dulbecco's PBS containing 5 mM EDTA and stored in frozen aliquots at -8O0C until needed. The protein concentration of the resulting membrane preparation (hereinafter ''P2 membranes"') is measured using a Bradford protein assay (Bio-Rad Laboratories, Hercules, CA). By this measure, a 1 -liter culture of cells typically yields 100- 150 mg of total membrane protein. EXAMPLE 1 1. RADIOLIGAND BINDING ASSAYS
P2 membranes are resuspended by Dounce homogenization (tight pestle) in binding buffer (50 mM Tris pH. 7.4, 12OmM NaCL 5 mM MgCl2, 0.5% BSA and 0.2 mg/ml bacitracin).
For saturation binding analysis, membranes (10 μg) are added to polypropylene tubes containing 25pM-0.5nM [3H]CP55,940 (New England Nuclear Corp., Boston, MA). Nonspecific binding is determined in the presence of lOμM CP55,940 (Tocris Cookson Inc., Ellisville, MO) and accounts for less than 10% of total binding- For evaluation of guanine nucleotide effects on receptor affinity, GTPγS is added to duplicate tubes at the final concentration of 50 μM.
For competition analysis, membranes (10 μg) are added to polypropylene tubes containing 0.5nM [3H]CP55,940. Non-radiolabeled displacers are added to separate assays at concentrations ranging from 10"10 M to 10"5 M to yield a final volume of 0.250 mL. Nonspecific binding is determined in the presence of l OμM CP55,940 and accounted for less than 10% of total binding.
Following a one-hour incubation at rt, the reaction is terminated by rapid vacuum filtration. Samples are filtered over presoaked (0.3% non-fat dry milk for 2 hours prior to use) GF/C WHATMAN filters and rinsed 2 times with 5 mL cold 50 mM Tris pH 7.4. Remaining bound radioactivity is quantified by gamma counting. K, and Hill coefficient ("nH") are determined by fitting the Hill equation to the measured values with the aid of SIGMAPLOT software (SPSS Inc., Chicago, IL).
EXAMPLE 12. AGONIST-INDUCED GTP BINDING
This Example illustrates the use of agonist-stimulated GTPγ35S binding ("GTP binding") activity to identify CB 1 agonists and antagonists, and to differentiate neutral antagonists from those that possess inverse agonist activity. This assay can also be used to detect partial agonism mediated by antagonist compounds. A compound being analyzed in this assay is referred to herein as a "test compound." Agonist-stimulated GTP binding activity is measured as follows: Four independent baculoviral stocks (one directing the expression of hCB ! and three directing the expression of each of the three subunits of a heterotrimeric G-protein) are used to infect a culture of Sfi cells as described in Example 1 1.
Agonist-stimulated GTP binding on purified membranes (prepared as described in Example 12) is initially assessed using the cannabinoid agonist CP55,940 to ascertain that the receptor/G- protein-alpha-beta-gamma combination(s) yield a functional response as measured by GTP binding. P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 mM Tris pH 7.4, 120 mM NaCI, 5 mM MgCi2, 2 mM EGTA, 0.1 % BSA, 0.1 mM bacitracin, I QOKILVmL aprotinin, 5 μM GDP) and added to reaction tubes at a concentration of 10 μg protein/reaction tube. After adding increasing doses of the agonist CP55,940 at concentrations ranging from 10"'2 M to 10"6 M, reactions are initiated by the addition of 100 pM GTPy35S. In competition experiments, non-radiolabeied test compounds are added to separate assays at concentrations ranging from I 0"10 M to 3 O"5 M along with 1 nM CP55,940 to yield a final volume of 0.25 ml.
Following a 60-minule incubation at room temperature, the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1 % BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 32OmM NaCI), The amount of receptor-bound (and thereby membrane-bound) GTPy35S is determined by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filters. Non-specific binding is determined using 10 mM GTPy35S and typically represents less than 5 percent of tota! binding. Data is expressed as percent above basal (baseline). The results of these GTP binding experiments are analyzed using SIGMAPLOT software and IC50 determined. The IC50 may then be used to generate K1 as described by Cheng and Prusoff (1973) Biochem Pharmacol. 22(23):3099-l 0%.
Alternatively the data is analyzed as follows. First, the average bound radioactivity from negative control wells (no agonist) is subtracted from the bound radioactivity detected for each of the other experimental wells. Second, average bound radioactivity is calculated for the positive control wells (agonist wells). Percent inhibition for each compound tested is calculated using the equation:
Bound radioactivity in Test Wells
Percent Inhibition = 100 - 100 Bound radioactivity in Agonist Weils
The % inhibition data is plotted as a function of test compound concentration and test compound IC50 is determined using a linear regression in which x is ln(concentration of test compound) and y is ln(percent inhibition/^ 100 - percent inhibition). Data with a percent inhibition that is greater than 90% or less than 15% are rejected and are not used in the regression. The IC30 is e(-mter"pl/slope), and K1 is generated as described above.
Neutral antagonists are those test compounds that reduce the CP55,940-stimulated GTP binding activity towards, but not below, baseline (the level of GTP bound by membranes in this assay in the absence of added CP55,940 or other agonist and in the further absence of any test compound). In contrast, in the absence of added CP55,940. CB l inverse agonists reduce the GTP binding activity of the receptor-containing membranes below baseline. If a test compound that displays antagonist activity does not reduce the GTP binding activity below baseline in the absence of the CB l agonist, it is characterized as a neutral antagonist.
An antagonist test compound that elevates GTP binding activity above baseline in the absence of added CP55,940 in this GTP binding assay is characterized as having partial agonist activity. Preferred CB 1 antagonists do not elevate GTP binding activity under such conditions more than 10%, more preferably less than 5% and most preferably less than 2% of the maximal response elicited by the agonist, CP55,940.
The GTP binding assay can also be used to determine antagonist selectivity towards CB l over CB2. Agonist-stimulated GTP binding activity at CB2 is measured as described above for CB l except that the Sβ cells are infected with one baculoviral stock directing the expression of hCB2 and three directing the expression of each of the three subunits of a heterotrimeric G-protein. The IC50 and K1 are generated as described above for CB 1.
EXAMPLE 13. SURMOUNTABILΪTY ASSAYS Certain CB l antagonists are insurmountable with regard to the agonist induced GTPy15S binding effect. To assess surmountability, P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 mM Tris pH 7.4, 120 mM NaCl, 5 mM MgCl2, 2 mM EGTA, l Oμg/ml saponin, 0.1 % BSA, 0.1 mM bacitracin, 100KIU/mL aprotinin, 5 μM GDP) and added to reaction tubes at a concentration of 10 μg protein/reaction tube. Agonist dose- response curves (typically CP55,940) at concentrations ranging from 10"12 M to 10"5 M, are run either in the absence or in the presence of a test compound at one of several doses up to I OOX the IC50 of the test compound as measured in the competition GTPy35S binding. The reactions are initiated by the addition of 100 pM GTPy35S to yield a final volume of 0.25 mL. Following a 90-minute incubation at room temperature, the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1 % BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 120 mM NaCl). The amount of receptor-bound (and thereby membrane-bound) GTPy15S is determined by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filters. Non-specific binding is determined using 10 μM GTPyS and typically represents less than 5 percent of total binding. Data is expressed as percent above basal (baseline). The results of these GTP binding experiments may be conveniently analyzed using SIGMAPLOT software. A surmountable test compound is one which shifts the EC50 of the agonist to the right (weaker) without affecting the maximum functional response of the agonist. Insurmountable antagonist test compounds have no significant effect on the hCB I agonist ECj0 at concentrations roughly I OOX the IC50, but significantly reduce or eliminate the agonist stimulated GTPy35S binding response of the receptor.
EXAMPLE 14. MDCK CYTOTOXICITY ASSAY
This Example illustrates the evaluation of compound toxicity using a Madin Darby canine kidney (MDCK) cell cytotoxicity assay.
1 μL of test compound is added to each well of a clear bottom 96-well plate (Packard, Meriden, CT) to give final concentration of compound in the assay of 10 μM, 100 μM or 200 μM. Solvent without test compound is added to control wells.
MDCK cells, ATCC no. CCL-34 (American Type Culture Collection, Manassas, VA), are maintained in sterile conditions following the instructions in the ATCC production information sheet. Confluent MDCK ceils are trypsinized, harvested, and diluted to a concentration of 0.1 x 106 cells/mL with warm (37°C) medium (VITACELL Minimum Essential Medium Eagle, ATCC catalog # 30- 2003). 100 μL of diluted cells is added to each well, except for five standard curve control wells that contain 100 μL of warm medium without cells. The plate is then incubated at 370C under 95% O2, 5% CO2 for 2 hours with constant shaking. After incubation, 50 μL of mammalian ceii lysis solution (from the Packard (Meriden, CT) ATP-LITE-M Luminescent ATP detection kit) is added per well, the wells are covered with PACKARD TOPSEAL stickers, and plates are shaken at approximately 700 rpm on a suitable shaker for 2 min. Compounds causing toxicity will decrease ATP production, relative to untreated cells. The
ATP-LlTE-M Luminescent ATP detection kit is generally used according to the manufacturer's instructions to measure ATP production in treated and untreated MDCK cells. PACKARD ATP LITE-M reagents are allowed to equilibrate to room temperature. Once equilibrated, the lyophilized substrate solution is reconstituted in 5.5 ml of substrate buffer solution (from kit). Lyophilized ATP standard solution is reconstituted in deionized water to give a 10 mM stock. For the five control wells, 10 μL of serially diluted PACKARD standard is added to each of the standard curve control wells to yield a final concentration in each subsequent well of 200 nM, 100 nM, 50 nM, 25 nM, and 12.5 nM. PACKARD substrate solution (50 μL) is added to all wells, which are then covered, and the plates are shaken at approximately 700 rpm on a suitable shaker for 2 min. A white PACKARD sticker is attached to the bottom of each plate and samples are dark adapted by wrapping plates in foil and placing in the dark for 10 min. Luminescence is then measured at 22°C using a luminescence counter (e.g., PACKARD TOPCOUNT Microplate Scintillation and Luminescence Counter or TECAN SPECTRAFLUOR PLUS), and ATP levels calculated from the standard curve. ATP levels in cells treated with test comρound(s) are compared to the levels determined for untreated cells. Cells treated with 10 μM of a preferred test compound exhibit ATP levels that are at least 80%, preferably at least 90%, of the untreated cells. When a 100 μM concentration of the test compound is used, cells treated with preferred test compounds exhibit ATP levels that are at least 50%, preferably at least 80%, of the ATP levels detected in untreated cells.

Claims

1 . A compound of the formula:
ATAAR2 or a pharmaceutically acceptable salt or hydrate thereof, wherein:
A is CR1 or N;
Ar1 and Ar2 are independently chosen from phenyl, naphthyl and 5- to 10-membered heteroaryl, each of which is substituted with from 0 to 6 substituents independently chosen from R^; :
(i) hydrogen, hydroxy, amino or nitro; or
(ii) C,-C6alkyl, C2-C6alkynyl, (C3-Cgcycloalkyl)Co-C4a!kyl, C2-C6alkyl ether, C3-C6alkanone, C1- Qalkoxycarbonyl, mono- or di-fCrC6alkyl)aminoC0-C4alky!, mono- or di-(Cr C6alkyl)aminocarbonyIC0-QalkyI, (Ci-C6alkanoyI)aminoCo-C4alkyl, mono- or di-(C|- C6alkyl)aminosulfonylCi)-C4alkyl, (Ci-C6alkyl)su]fonyIC0-C4alkyl, or mono- or di-(Cr C6alkyl)sulfonyIaminoC0-C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or R2 is:
(i) C2-C6alkenyl, C2-C6alkynyl, (C3-C8cycloalkyI)Co-C4alkyl, CrC6alkanoyl, CrC6alkanone: C2- C6a!kyl ether, C)-C6alkoxy, CpCealkoxycarbonyl, mono- or dHCrCealkyOaminoCrQalkyl, mono- or di-(CrC6alkyl)aminocarbonylCo-C4alkyl, (CrQalkanoyOaminoCo-Cialkyl, mono- or di-(Cj-C6alkyl)aminosulfonylCo-C4alkyl, (CrC6alkyl)sulfonylC0-C4alkyl, or mono- or di- (CrC6alkyl)su]fonylaminoC0-C4alkyI; each of which is substituted with from O to 6 substituents independently chosen from RB;
(ii) mono- or di-(C|-C6alkyl)amino that is substituted with hydroxy, amino, aminocarbonyi, aminosulfonyl, mono- or di-(Cj-C6alkyl)amino, mono- or di-(CrC6alkyl)aminocarbonyl, mono- or di-(CrC6alkyl)aminosulfonyl, CrC6alkanoylamino, mono- or di-(Cr C6alkyl)sulfonylamino, or 4- to 8-membered heterocycle; each of which is further substituted with from O to 4 substituents independently chosen from RB; or (iii) a group of the formula:
Figure imgf000073_0001
, wherein: q is O or 1 ; each n is independently O, ϊ or 2; and X is C(=O), S, SO, SO2, N(R3) or C(R48)(R41,); such that Ri is not a halogen, cyano, C]-C<>alkyl or C2-Cfialkenyl if R2 is C]-C6alkyl; R3 is:
(i) hydrogen; or
(ii) Q-C≤alkyl, C2-C6alkenyl, C2-C6a!kynyt, CrC6aϊkyIsuIfony], (C1-C8carbocycle)C0-C4alkyl or (4- to 8-membered heterocyc!e)Co-C4a]kyl, each of which is substituted with from 0 to 6 substituents independently chosen from RE; R43 and R^ are independently:
(i) hydrogen, halogen, cyano, -COOH or CrC6alkyl;
(ii) -Z-N(R5)(R6) or -Z-O(R7), wherein Z is absent, C(O), OC(=O), N(Rw)C{=0) or SO2; wherein Rw is hydrogen or C|-C6aϊkyl; (iii) phenyl, naphthyl or 5- to 10-membered heteroaryl, each of which is substituted with from O to
6 substituents independently chosen from RA; or (iv) taken together to form a 4- to 7-membered cycloalkyl or heterocycloalkyl that is substituted with from O to 4 substituents independently chosen from R0; such that at least one of R4a and R4,, is not hydrogen; Rj and Re are independently: (i) hydrogen; or
(ii) Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C,-C6alkanoyl, C,-C6alkoxycarbonyl, C1-
C6alkylsu1fonyl, (C3-Cscycloalkyl)Co-C4alkyl, (4- to S-membered heterocycloalkyl)C0-
C4alkyl, mono- or di-(Ci-C6alkyI)aminocarbonyl, or mono- or di-(CrC6aikyl)aminosulfonyI, each of which is substituted with from O to 6 substituents independently chosen from RB; or R5 and R6 are taken together to form a 4- to 7-membered heterocycle that is substituted with from O to 4 substituents independently chosen from RB;
R7 is hydrogen, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C3cycloalkyi)Co-C4aikyl or (4- TO 8- membered heterocycloalkyl)C0-Qalkyl, each of which is substituted with from O to 6 substituents independently chosen from RB; Each RA is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro. aminocarbonyl, aminosulfonyl and -COOH; and (ii) CrC6alkyl. C2-C6alkenyl, C2-C6alkynyl, (C3-C8cycloa[kyl)Co-C4alkyl. C rC6haloalkyl, C1- Qalkoxy, CpCealkylthio, Ci-C6alkylsulfinyl. CrC6alkoxycarbonyl, CrC6a]kyisulfonylC0- C4alkyl, mono- or di-(C,-C6alkyl)aminoC0-C4alkyL mono- or di-(Cr C6alkyl)aminosulfonylC0-C4alkyl, mono- or di-(Ci-C6aIkyl)ammocarbonylC0-C4alkyl, phenylCn-Cαalkyl. (4- to 8-membered heterocycle)C0-C4alkyl, and (4- to 8-membered heterocycle)Ci-C4alkoxy; each of which is substituted with from O to 4 substituents independently chosen from RB; and Each RB is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl. aminosulfonyl, -COOH, C,-C6alkyl, C,-C6alkenyl, CrC6alkynyl, (C3-C3cycloalkyl)C0-C,alkyl, Ci-Cβhaloalkyl, CrC6alkoxy; CrC6haloalkoxy. C rC6alkyIthio, CrC6alkanoyl, C1- C6alkoxycarbαnyl, Ci-C6alkanoyloxy, C3-C6alkanone, mono- or di-(Ci-C6alkyl)amino. C1- C6alkanoylamino, CrCβalkylsulfonyl, mono- or di-(Ci-C6alkyl)sυlfonylamino, mono- or di-(Cr Cβalkyl)aminosulfonyl, mono- or di-(CrC<>alkyl)aminocarbonyl, and (4- to 8-membered heterocycle)Co-C4alkyl.
2. A compound or salt or hydrate thereof according to claim 1 , wherein Ar1 and Ar2 are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 0 to 3 substituents independently chosen from RA.
3. A compound or salt or hydrate thereof according to ciaim 2, wherein Ar2 is substituted at the para position.
4. A compound or salt or hydrate thereof according to claim 2 or claim 3, wherein Arj is substituted ortho ox para to the point of attachment.
5. A compound or salt or hydrate thereof according to claim 4, wherein Aη is substituted ortho and para to the point of attachment.
6. A compound or salt or hydrate thereof according to any one of claims 1 -5, wherein each RA is independently chosen from halogen, cyano, Ci-C6alkyi, C2-C6alkenyl, C2-C6alkynyl, Cr C6haloalkyl, (C3~C8cyc]oalkyl)Co-C4a]kyl and CpQalkoxy.
7. A compound or salt or hydrate thereof according to any one of claims 1 -6, wherein A is N.
S. A compound or salt or hydrate thereof according to any one of claims 1 -6, wherein A is CR1.
9. A compound or salt or hydrate thereof according to claim 8, wherein R1 is hydrogen or Ci-C6alkyl.
10. A compound or salt or hydrate thereof according to any one of claims 1 -9, wherein R2 is:
(i) mono- or di-(C|-C6a]kyl)aminocarbonylC0-C2alkyl, (C]-C6alkanoyl)aminoCo-C:>alkyl, mono- or di-(Ci-Csalkyl)aminosulfony]Co-C2alkyl, (Ci-C6alkyi)su!fony]Co-C2a!kyl, or mono- or di- (CrCfjalky^sulfonylaminoCo-Cialkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or (ii) a group of the formula O ; wherein X is C(=O), S, SO, SO2, N(R3) or CH(Rj0).
1 1 . A compound or salt or hydrate thereof according to claim 10, wherein X is CH(R43).
12. A compound or salt or hydrate thereof according to claim 1 1. wherein R2 is a group
of the
Figure imgf000076_0001
wherein R5 is CrC6alkanoyl, CrC6alkoxycarbonyl or mono-or di-
(C i -C6alky l)am inocarbony 1.
13. A compound or salt or hydrate thereof according to claim 10, wherein X is C(=O), S, SO, or SO2.
14. A compound or salt or hydrate thereof according to claim 10, wherein X is N(R3).
1 5. A compound or salt or hydrate thereof according to claim 14, wherein R3 is C3- Cgcycloalkyi, CrC6aikanoyi, C , -Qalkoxycarbonyi, or mono- or di-(CrC6alkyI)aminocarbonyl.
36. A compound or salt or hydrate thereof according to any one of claims 1-9, wherein R2 is Ci-Cβalkanoylamino, mono- or di-(CrC6alkyl)sulfonylamino, CrC6alkoxycarbonyf, mono- or di-
(Ci-Cealkytyaminocarbonyl, or a group of the formula O , wherein n is 0 or I and q is 0 or
1 ; each of which is substituted with from 0 to 4 substituents independently chosen from RB.
17. A compound or salt or hydrate thereof according to claim 8, wherein Rj is C3- C6alkanone, CrC6alkoxycarbonyl, mono- or di-(C]-C6alkyl)aminoCo-C2alkyl, mono- or di-(Cj- C6alkyl)aminocarbonylC0-C2alkyI, (Ci-CβalkanoyOaminoCo-Cialkyl, mono- or di-(Cr C6alkyl)aminosulfonyiCo-C2alkyl, (CrC6alkyl)sulfonylCo-C2alkyl, or mono- or di-(Cj- C6alkyl)sulfonylaminoCo-C2alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB.
18. A compound or salt or hydrate thereof according to claim 17, wherein R2 is C2- Qalkenyl, C2-C6alkynyl, (C3-Cgcycloalkyl)Co-C4a]ky[. Ci-C6alkanoyl, C3-C6alkanone or C2-C6alkyl eiher. each of which is substituted with from 0 to ό substituents independently chosen from RB.
19. A compound or salt or hydrate thereof according to claim 1 , wherein the compound has the formula:
Figure imgf000077_0001
wherein:
B and D are independently CRn or N;
Ri is hydrogen or C|-C6alkyl;
R2 is:
(i) mono- or di-(Cj-C6alkyl)aminocarbonylC0-C2a!kyl, (Ci-C6aIkanoyl)aminoCo-C2aIky!, mono- or di-(CrC6aIkyf)aminosulfony!Co-C2alkyl, (Ci-C6alky])sulfonylCo-C2alkyI or mono- or di- (C1-C6alkyI)sulfonyIaminoCo-C2alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or
(ii) a group of the formula
Figure imgf000077_0002
s wherein X is S, SO, SO2, N(R3) or CH(R43); such that Ri is not Ci-C6alkyl if R2 is CrC6alkyI; R8 is halogen, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, CrC6haloalkyl, (C3-C8cycloalkyl)C0-
C4alkyt or CrC6alkoxy; and Rg, R10 and R1 1 are independently hydrogen, halogen, cyano, Cj-Cealkyi, C2-C,5alkenyl, C2-C6alkynyl,
Ci-Cfihaloalkyl, (C3-C8cycloalkyl)Co-C4alkyl or CrC6alkoxy.
20. A compound or salt or hydrate thereof according to claim 19, wherein the compound has the formula:
Figure imgf000077_0003
wherein: at least one OfR9 and R10 is other than hydrogen; X is N(R3) or CH(R4,);
R3 is C-3-CscycIoalky], C]-C6alkanoyl, Ci-C6alkoxycarbonyl, or mono- or di-(Cr C6alkyi)aminocarbonyl; and _-— J^|_|
R4a is a group of the formula ' , wherein R5 is CrC6alkanoyi, CrC6alkoxycarbonyl or mono-or di-(C ] -C6alky 1 )ami no carbony 1.
21. A compound of the formula:
Figure imgf000078_0001
or a pharmaceutically acceptable sait or hydrate thereof, wherein: A is CR1 or N;
Ar: and Ar2 are independently chosen from phenyl and 6-membered heteroaryl. each of which is substituted with from 1 to 5 substituents independently chosen from RA; such that Ar2 is substituted para to the point of attachment; R1 is:
(i) hydrogen, halogen, hydroxy, cyano, amino or nitro; or
(ii) C,-C6alkyl, C2-C6alkenyl. C2-C6alkynyl, (C3-C3cycloalkyl)C<rC4alkyI, C2-C6alkyl ether, C,- C6alkoxy, C3-Cfialkanone, CrC6alkoxycarbonyl, mono- or di-(Ci-C6alkyi)aminoC0-C4alkyl, mono- or di-(Cj-C6alkyl)aminocarbonylC0-C4alkyl, (CrC6alkanoy[)aminoCo-C4aIkyl, mono- or di-(C|-C6aikyl)aminosulfonylCo-C4alkyl. (Cs-C6aiky])sulfonylC0-C4alkyl, mono- or di-(Cr C6alky[)sulfonylaminoC0-C4alky] or (4- to 8-membered heterocycle)Co-C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; R2 is:
(i) CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6alkyl ether, C!-C6alkoxy, C]-C6alkoxycarbonyl, mono- or di-(C]-C6alkyl)aminocarbonylCo-C4alkyl, mono- or di-(C|-C6alkyl)aminoC0- C4alkyl, (C]-C6alkanoyl)a]ΗinoC0-C4alkyl, mono- or di-(C]-C6alkyl)a:τiinosu]fony!Cϋ-C4alkyI, (CrQafkyOsuIfonylCerQa.lkyl, mono- or di-(C|-C6alkyl)sulfonylaminoCo-C4alkyl, (C3- CiocarbocycIe)C0-C4alky], or (4- to 10-membered hcierocycle)C0-C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or (ii) a group of the formula:
Figure imgf000078_0002
is O. C(=O), S,
SO. SO2. N(R1) or C(R48)(R4LO: such that R1 is not CrC6alkyl if R2 is CrCfialkyl; R-, is:
(i) hydrogen; or (ii) C,-C6alkyl, C2-C6alkenyi, C2-Qalkynyl, CrC6aIkylsuIfonyl, (C3-C3carbocycIe)Co-C4alkyl, or (4- to 8-membered heterocy CIe)C0-C4 alky 1, each of which is substituted with from 0 to 6 substituents independently chosen from RB; R4S and Rib are independently:
(i) hydrogen, halogen, cyano, -COOH or Cj-Cβalkyl;
(ii) -Z-N(R5)(R6) or -Z-O(R7), wherein Z is absent, C(=0), 0C(=0), N(RW)C(=O) or SO2; wherein Rw is hydrogen or Ci-C6alkyl;
(iii) phenyl, naphthyl or 5- to 10-membered heteroaryl, each of which is optionally substituted and each of which is preferably substituted with from O to 6 substituents independently chosen from RA; or
(iv) taken together to form a 4- to 7-membered cycloalkyl or heterocycloalkyl that is optionally substituted, and is preferably substituted with from O to 4 substituents independently chosen from RB;
R5 and R6 are independently: (i) hydrogen; or
(ii) Cj-C6alky!, C2-C6alkenyl. C2-C6aikynyl, CrC6alkanoyl, d-Qalkoxycarbonyi, C1-
C6alky!su!fonyi, (C3-C8cycloalkyl)Co-C4alkyl, (4- to 8-membered heterocyc Io alky I)C0-
C4alkyl, mono- or di-(CrC6alkyl)aminocarbonyl, or mono- or di-(C]-C6alkyl)aminosulfonyi, each of which is substituted with from O to 6 substituents independently chosen from RB; or RJ and R-, are taken together to form a 4- to 7-membered heterocycle that is substituted with from O to 4 substituents independently chosen from RB;
R7 is hydrogen, CrC6aIkyl, CrC6alkenyI, C2-C6alkynyl, (C3-C8cycloalkyl)C0-C4alkyl or (4- to 8- membered heterocycloalkyl)C0-C4alkyl, each of which is substituted with from O to 6 substituents independently chosen from R8; Each RA is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl and -COOH; and (ii) Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C8cycloalkyϊ)C0-C4alkyl, C,-C6haloalkyl, C,- Qalkoxy, CrQalkyϊthio, CrC6alkylsuIfinyl, Ci-C6alkoxycarbonyl, (CrC6alkyl)sulfonylC0- Qalkyl, mono- or di-(CrC6alkyl)aminoCo-C4alkyl, mono- or di-(Cr C6alkyl)aminosulfonylCo-C4alkyl, mono- or di-(CrC6alkyl)aminocarbonylC0-C4alkyl, pbenylC0-C4alkyl, (4- to 8-membered heterocycle)C0-C4alkyl, and (4- to 8-membered heterocycle)Cj-C4alkoxy; each of which is substituted with from O to 4 substituents independently chosen from RB; and
Each RB is independently chosen from oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, -COOH. CrC6alkyl, CrC6aIkenyl, Ci-C6alkynyl. (C3-C8cycloalkyi)C0-C4alkyl, Ci-C6haloalkyl, Ci-C6a!koxy, C,-C6haloaϊkoxy, CrC6alkylthio, CrC6aikanoyI, C1-
C6alkoxycarboπyl, C]-C6alkanoyloxy, C3-C6alkanone, mono- or di-(Ci-C6a!ky!)amino, Cx- Cgalkanoylamino, Q-Cealkylsulfonyl, mono- or di-(C)-C6alkyl)aminosulfonyl, mono- or di-(Cr C6alkyl)aminocarbonyl, and (4- to 8-membered heterocyc]e)C0-C4a]kyl.
22. A compound or salt or hydrate thereof according to claim 21 , wherein Ars is substituted ortho or para to the point of attachment.
23. A compound or salt or hydrate thereof according to claim 22, wherein An is substituted ortho and para to the point of attachment.
24. A compound or salt or hydrate thereof according to any one of claims 21 -23, wherein each R^ is independently chosen from halogen, cyano, CrC6a!kyl, C2-C6alkenyl, C2-Cβalkynyl, C]- C6haloalkyl, (C3-C3cycloalkyi)C0-C4alkyl and Q-Qalkoxy.
25. A compound or salt or hydrate thereof according to any one of claims 21 -24, wherein A is N.
26. A compound or salt or hydrate thereof according to any one of claims 21 -24, wherein A is CR1.
27. A compound or salt or hydrate thereof according to claim 26, wherein Ri is hydrogen or Ci-C6alkyl.
28. A compound or salt or hydrate thereof according to any one of 21 -27. wherein R2 is: (i) mono- or di-(CrCήalkyl)aminocarbonyiCo-C2alkyl, (Cj-C6alkanoyl)aminoCo-C2alkyl, mono- or di-(CrC6alkyl)aminoCo-C2alky], mono- or di-(C]-C6a]kyl)aminosulfonylCo-C2a[kyl, (Ci- C6alkyl)sulfonyIC0-C2alkyl, or mono- or di-(CrC6alkyl)sulfonyIaminoCo-C2alkyi; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or
(ii) a group of the
Figure imgf000080_0001
wherein X is O, C(O)3 S, SO, SO2, N(R3) or CH(R43).
29. A compound or salt or hydrate thereof according to claim 28, wherein X is CH(R4,,).
30. A compound or salt or hydrate thereof according to claim 29, wherein R2 is a group
of the
Figure imgf000080_0002
wherein Rs is Ci-Csalkanoyl. Ci-Qalkoxycarbonyl or mono-or di-
(C i -C6alkyl)aminocarbony I .
31. A compound or salt or hydrate thereof according to claim 28, wherein X is O, S, SO, SO2 or N(R3).
32. A compound or salt or hydrate thereof according to any one of claims 21 -27. wherein R2 is mono- or di-(CrC6alkyl)amino, C]-C6alkanoylamino, mono- or di-(CrC6aikyl)sulfony[amino, Ci-C6alkoxycarbony[, mono- or di-(C|-C6alkyl)aminocarbonyI, or a group of the
Figure imgf000081_0001
wherein n is 0 or 1 ; and q is 0 or I ; each of which is substituted with from 0 to
4 substituents independently chosen from R0.
33. A compound or salt or hydrate thereof according to claim 26, wherein R1 is C3- C6alkanone, Cj-Qalkoxycarbonyl, mono- or di-(CrC6alkyI)aminoCo-C2alkyl, mono- or di-(Cj- C6alkyl)aminocarbonyICo-C2alkyl, (Ci-C6alkanoyl)aminoCo-C2alkyl, mono- or di-fCi- C6alkyl)aminosulfonylCo-C2aIkyl, (C]-C6alkyl)sulfony]Co-C2alkyl, mono- or di-(Cι- C6aIkyl)sulfonylaminoC0-C2alkyl, or (4- to 8-membered heterocycleJCo-Cialkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB.
34. A compound or salt or hydrate thereof according to claim 33, wherein R2 is Cr C6alkyl, C2-C6aikenyi, C2-C6alkynyl, (C3-C8cycloalkyl)Co-C4alkyl, C2-C6alkyl ether or mono- or di- (Ci-C6alkyi)amino, each of which is substituted with from 0 to 6 substituents independently chosen from RB.
35. A compound or salt or hydrate thereof according to claim 21 , wherein the compound has the formula:
Figure imgf000081_0002
wherein:
B and D are independently CRi , or N;
R] is hydrogen or Ci-Qalkyl;
R2 is:
(i) mono- or di-(CrC6alkyl)aminoC0-C2alkyl, mono- or di-(Ci-C6alkyl)aminocarbonylCo-C2alkyl, (C|~C6alkanoy])arninoCo-C2alkyl, mono- or di-(C|-C6alkyl)aminosu[fonylC0-C2alkyi, (Cr CήaIkyI)sulfon>iCo-C2alky], or mono- or di-(CrC6alkyl)sulfonyϊaminoC0-C2alkyi; each of which is substituted with from U to 6 substituents independently chosen from RB; or
(ii) a group of the formula
Figure imgf000081_0003
; wherein X is O, C(=0), S, SO, SO2, N(R3) or CH(R4n); R8 is halogen, cyano, Ci-Qalkyl, C2-C6alk:enyl, C2-C6alkynyf, Ci-C6haloalkyl, (C3-C8cycloalkyl)Co-
C4aikyl or Ci-C6alkoxy; and R9, Rio and Rn are independently hydrogen, halogen, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl,
CrC6haloalkyl, (C1-C3cycloalky[)C0-C4alkyI or Ci-C6alkoxy, such that at least one Of R9 and R10 is not hydrogen.
36. A compound or salt hydrate or ester thereof according to any one of claims 1 -35, wherein the compound exhibits no detectable agonist activity an m vitro assay of CB l agonism.
37. A compound or salt hydrate or ester thereof according to any one of claims 1 -36, wherein the compound is capable of exhibiting an ICJ0 value of 1 micromolar or less in an in vitro assay of CB I antagonism.
38. A pharmaceutical composition, comprising at least one compound or salt or hydrate thereof according to any one of claims 1 -37, in combination with a physiologically acceptable carrier or excipient.
39. A pharmaceutical composition according to claim 38, wherein the composition is formulated as an injectible fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.
40. A pharmaceutical composition, comprising:
(i) a first agent that is a compound or salt or hydrate thereof according to any one of claims 1 -37;
(ii) a second agent that is suitable for treating an appetite disorder, obesity, a dependency disorder, asthma, Hver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension or drug-induced hypotension; and
(iii) a physiologically acceptable carrier or excipient
41. A pharmaceutical composition according to claim 40, wherein the second agent is an anti-obesity agent selected from an MCH receptor antagonist, an apo-B/MTP inhibitor, a 1 l β-hydroxy steroid dehydrogenase- 1 inhibitor, peptide YY3-3ό or an analog thereof, a MCR-4 agonist, a CCK.-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β-j adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, leptin or an analog thereof, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide- 1 receptor agonist, a ciliary neurotrophic factor, a human agouti- related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist, or a neuromedin U receptor agonist.
42. A pharmaceutical composition according to claim 41 , wherein the anti-obesity agent is phentermine, orlistat or sibutramine.
43. A pharmaceutical composition according to claim 40, wherein the second agent is a nicotine receptor partial agonist, an opioid antagonist or a dopaminergic agent.
44. A pharmaceutical composition according to claim 40, wherein the second agent is suitable for treating a dependency disorder, and wherein the agent is selected from methadone, LAAM, naltrexone, ondansetron, sertraline, fluoxetine, diazepam, chlordiazepoxide, varenicline and buproprion.
45. A packaged pharmaceutical preparation, comprising:
(a) a pharmaceutical composition according to claim 38 in a container; and
(b) instructions for using the composition to treat an appetite disorder, obesity, a dependency disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension or drug-induced hypotension.
46. A method for treating a condition responsive to CB l modulation in a patient, in a patient, comprising administering to the patient a therapeutically effective amount of at least one compound or salt or hydrate thereof according to any one of claims 1 -37.
47. A method according to claim 46, wherein the condition is an appetite disorder, obesity, a dependency disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, a metabolic disorder, Crohn's disease, portal hypertension, fibrosis of internal organs, orthostatic hypotension or drug-induced hypotension.
48. A method according to claim 46, wherein the condition is obesity, bulimia, alcohol dependency or nicotine dependency.
49. A method according to claim 48, wherein the condition is obesity.
50. A method according to claim 46, wherein the condition is depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder or bone loss.
51. A method for suppressing appetite in a patient, comprising administering to the patient an appetite reducing amount of at least one compound or sail or hydrate thereof according Io any one of claims 1-37, and thereby suppressing appetite in the patient.
52. A compound or salt according to any one of claims 1 -37, wherein the compound is radiolabeled.
53. Λ method for determining the presence or absence of CBl in a sample, comprising the steps of:
(a) contacting a sample with a compound or salt or hydrate thereof according to any one of claims 1 -37, under conditions that permit binding of the compound to CBl ; and
(b) detecting a signal indicative of a level of the compound bound to CB l , and therefrom determining the presence or absence of CB l in the sample.
54. A method according to claim 53, wherein the compound is radiolabeled, and wherein the step of detection comprises the steps of: fi) separating unbound compound from bound compound; and
(ii) detecting the presence or absence of bound radiolabel in the sample.
55. The use of a compound or salt or hydrate thereof according to any one of claims 1 -37 for the manufacture of a medicament for the treatment of a condition responsive to CB l modulation.
56. A use according to claim 55, wherein the condition is an appetite disorder, obesity, a dependency disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, a metabolic disorder, bone loss, portal hypertension, fibrosis of internal organs, orthostatic hypotension or drug- induced hypotension.
57. A compound or salt or hydrate thereof according to claim 1 or claim 21 , wherein the compound is:
;er/~butyi (l '{6-(2-chlorophenyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1.3,5-triazin-2- yl}piperidin-4-yl)carbamate; jV-(l -{2-(2-ChloiOphenyl)-6-oxo-l -[4-(trifluoromethyl)phenyl]-l ,6-dihydropyrimidin-4-yl}piperidin- 4-yl)propionamide;
N-(l -{6-(2-chlorophenyl)-4-oxo-5-[4-{trifluoromethy])phenyI]-4,5-dihydro-l ,3,5-triazin-2- yl}piperidin-4-yl)propanamide:
2-(2-Chlorophenyl)-6-thiomorpholin-4-yI-3-[4-(trifluoromethyl)phenyl]pyrimidiπ-4(3H)-one;
2-(2-chlorophenyl)-6-(l ,l -dioxidothiomoφholin-4-yl)-3-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)- one;
N-(l-{6-(2-chlorophenyl)-4-oxo-5-[4-(trifluoromethyI)phenyl]-4,5-dihydro-l ,3,5-triazin-2- yl}piperidin-4-yl)-2-methy!propanamide; N-(l-{2-(2-chlorophenyl)-6-oxo-I-[4-(trifluoromethyl)phenyI]-l,6-dihydropyrimidin-4-yI}piperidin-4- yl)-2-methylpropanamide;
N-{ l-[l4-chlorophenyl)-2-dichlorophenyl)-6-oxo- 1,6-diliydropyrimidin4-yl]piperidin4- y]}propanamide;
N-f-{ l-[l-(4-chlorophenyl)-2-(2,4-dichioroρhenyl)-6-oxo-I,6-dihydropyriraidin-4-yl]piperidin-4-yl}-2- methylpropanamide;
N-{ l-[5--chlorophenyl)-6-(-dichlorophenyl4-oxo45-dihydro-l,3,-triazin2-ylpiperidin4- yl}ρropanamide;
N-{ l -[5--chloropheny1)-6-(-dichlorophenyl4-oxo-4-dihydro-l ,3-triazin2-yl]piperidin4- yl}-2-methylpropan amide; tert-butyl {l-[2-(4-chloro-2-methylpheny!)-l -(4-chlorophenyl)-6-oxo-l,6-dihydropyrimidin-4- yl]piperidin-4-yl} carbamate;
2-(2,4-dichlorophenyl)-6-thiomθφholin-4-yl-3-[4-(trifluoromethyl)ρhenyl]pyrimidin-4(3H)-one; tert-butyl (l-{2-(2,4-difluorophenyl)-6-oxo-l -[4-(trifluoromethyl)phenyl]-l,6-dihydropyrimidin-4- yl}piperidin-4-yl)carbamate;
3-(4-chlorophenyl)-2-(2,4-dich]orophenyI)-6-thioinoφho!in-4-ylpyrimidin-4(3H)-one;
2-(2-ch[orophenyl)-6-(l,l-dioxidothiomoφholin-4-yl)-3-[4-(trifluoiOmethyl)phenyI]pyrimidin-4(3H)- one;
6-(2-chlorophenyl)-(1,1-dioxidothiomorpholin4-y^-l -4-(trifluoromethyl)phenyl-l,3,5-triazin- 2(lH)-one;
3-(4-ch]orophenyl)-2-(2,4-dichloroρhenyl)-6-(l ,l-dioxidothiomoφho]in-4-yl)pyπmidin-4(3H)-one; i -(4-ch[orophenyl)-6-(2,4-dichIoropheny!)-4-(] ,l -droxidothiomoφhoIin-4-yl)-L3,5-triazin-2(l H)-one;
N-(I-{2-(2-methylρhenyl)-6-oxo-i-[4-(tπfluoromethyI)phenyI]-l ,6-dihydropyrimidin-4-yl}piperidin- 4-yl)propanamide;
2-methy]-N-(l -{2-(2-methylpheny])-6-oxo-I-[4-(trifluoromethyl)phenyl]-l ,6-dihydropy rimidin-4- yl}piperidin-4-yl)propanamide;
N-(l -{6-(2-methylphenyl)-4-oxo-5-[4-(trifluoromethyl)phenyI]-4,5-dihydro-l ,3,5-triazin-2- yl}piperidin-4-yl)propanamide;
2-methyl-N-(l-{6-(2-methylpheny])-4-oxo-5-[4-(trifluoromethyl)phenyl]-4,5-dihydro-l,3,5-triazin-2- yl}piperidin-4-yl)propanamide;
N-ll-fl4-chlorophenyl)2-(dichlorophenyl^6-oxo-1,-dihydropyrimidin-yl]piperidin4- yl}acetamide; methyl { l-fl^-chlorophenyl)-(-dichlorophenyl)6-oxo-1,-dihydropyrimidin^-ylJpiperidin^- yl} carbamate; ethyl { l-f l^-chlorophenyl)-(2,-dichlorophenylj-6-oxo-1 ,6dihydropyrimidin^-ylJpiperidin^- yl}carbamate;
N-l l -fl^-chlorophenyl^^^-dichlorophenyl-6-oxo-l,6-dihydropyrimidin^-yljpiperidm^-yl}^- methoxyacetamide;
S-f l-fl-^-chlorophenyl)2--dichiorophenyl)6-oxo-l 6-dihydropyrimidin^-ylJpiperidin^-yl}- 1 ,1 -dimethylurea;
N-(l-{2-C2-f1uorophenyl)-6-oxo-l-[4-(trifluoromethyl)ρhenyl]-l,6-dihydropyrimidin-4-yl}piperidin- 4-yl)propanamide;
N-(l-{2-(2-fluorophenyI)-6-oxo-l-[4-(trif!uoromethyl)phenyI]-l,6-dihydropyrimidin-4-yl}piperidin- 4-yl)-2-methylρroρan amide; N-(l-{6-(2-f1uorophenyI)-4-oxo-5-[4-(trifluoiOmethyl)phenyI]-4,5-dihydro-l,3,5-triazEn-2- y!}pipericiin-4-yl)p!Opanamide;
N-(l -{6-(2-fluorophenyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-4,5-dihydro-1 ,3!5-triazin-2- yl}pipeπdin-4-yi)-2-methylpropanamide;
2-(2,4-dichIoroρhenyl)-6-(l,l-dioxidothiomorpholin-4-yl)-3-[4-{trifIuoromethyl)phenyi]pyrimidin- 4(3H)-one;
2-(2,4-dichlorophenyl)-6-(l-oxidothiomoφho]in-4-yl)-3-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)- one;
N-{ l-[2-(4-ch]oro-2-methylphenyl)-l-(4-chlorophenyi)-6-oxo-l,6-dihydropyrimidin-4-yl]piperidin-4- yl}-2-methylpropanamide;
N-{ l-[2-(4-chloro-2-methylphenyl)-l-(4-chlorophenyl}-6-oxo-l,6-dihydropyrimidin-4-yl]piperidin-4- y]}propanamide; ethyl { l-[2-(4-chloro-2-methyIphenyl)-l-(4-chlorophenyl)-6-oxo-I ,6-dihydropyrimidin-4- yl]piperidin-4-yl}carbamate;
N-(l-{2-(2,4-dif!uorophenyl)-6-oxo-] -[4-(trifluoromethyl)phenyl]-I ,6-dihydropyrimidin-4- yl}piperidin-4-yl)-2-methyIpropanamide;
N-(l -{2-(2,4-difluoroρhenyl)-6-oxo-l-[4'(trifluoromethyϊ)phenyl]-l ,6-dihydropyπmidin-4- y[}piperidin-4-yl)propan amide; ethyl (l-{2-(2,4-difluorophenyl)-6-oxo-l-[4-(trifluoromethyl)ρhenyl]-l,6-dihydropyrimidin-4- yl}piperidin-4-yl)carbamate;
3-{ l-[2-(4-ch[oro-2-methy!pheny!)-] -(4-chlorophenyl)-6-oxo-l,6-dihydropyrimidin-4-yl]piperidin-4- yl } - 1 , 1 -dimethylurea;
3 -(I -{2-(2,4-difluorophenyl)-6-oxo-l -[4-(trif!uoromethyl)phenyl]- 1 ,6-dihydropyrimidin-4- yl}piperidin-4-yl)-l ,1 -dimethyiurea;
3-(4-chloro-2-fluoroρhenyi)-2-(2-chIorophenyl)-6-(4-propionylpiperazin-l-yl)pyrimidin-4(3H)-one; methyl 4-[l-(4-chioro-2-fluorophenyl)-2-(2-chloroρhenyl)-6-oxo-l,6-dihydroρyrimidin-4- yljpiperazine- 1 -carboxylate; ethyl 4-[l-(4-ch!oro-2-fluoroρhenyl)-2-(2-chlorophenyl)-6-oxo-l ,6-dihydropyrirr!idin-4-yl]piρerazine- 1 -carboxylate;
3-(4-chloro-2-fluoroρhenyI)-2-(2-ch]orophenyl)-6-(4-isobutyr>'lpiperazin-l-yl)pyrimidin-4(3H)-one
4-[l-(4-chloro-2-fluorophenyl)~2-(2~chloropheny[)-6-oxo-l,6-dihydropyrimidin-4-y]]-N,N- dimethylρiρerazine-1 -carboxamide
3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-6-(4-propionylpiperazin-l-yl)pyrimidin-4(3H)-one: methyl 4-[l -(4-chIoropheny!)-2-(2,4-dichlorophenyl)-6-oxo-1.6-dihydropyrimidin-4-yI]piperazine-l- carboxylate; ethyl 4-[l -(4-chlorophenyl)-2-(2.4-dichlorophenyI)-6-oxo-l ,6-dihydropynmidin-4-yl]piperazine-l- carboxylate;
3-(4-chloiOphenyI)-2-(2,4-dichlorophenyI)-6-(4-isobutyrylpiperazin-l -yl)pyrimidin-4(3H)-one;
4-[l-{4-chloiOphenyl)-2-f2,4-dichlorophenyl)-6-oxo-l ,6-dihydiOpyrimidin-4-yl]-N,N- dimethylpiperazine-1 -carboxamide;
3-(4-chloroρhenyl)-2-(2.4-dichlorophenyl)-6-(4-isobut>'lpiperazin-l-yl)pyrimidin-4(3H)-one; 3-(4-chlorophenyl)-6-(4-cyclobutylpiperazin~l"yl)-2-(2,4-dichloroρhenyi)ρyrimidin-4(3H)-one; N-{l -[l -(4-chloro-2-flυorophenyl)-2-(2-chlorophenyl)-6-oxo-l,6-dihydropyriraidin-4-yl]piperidin-4- yl}-2-methylproρanamide;
3-{ l -[] -(4-chloro-2-fluorophenyl)-2-(2-chlorophenyϊ)-6-oxo-l,6-dihydropyrimidin-4~yl]piperidin-4- yl}-l , 1 -dimethylurea; ethyl { l-[l-(4-chioro-2-fluoropheny!)-2-(2-chlorophenyl)-6-oxo-l ,6-dihydropyrimidin-4-yl]piperidin- 4-yl} carbamate;
N-(l -{2-(4-chlorophenyl)-6-oxo-I-[4-(trifluoromethyl)phenyi]-l,6-dihydropyπmidin-4-y]}piperidin- 4-yl)-2-methy!propanamide;
3-(l-{2-(4-chlorophenyl)-6-oxo-l-[4-(trifluoromethyl)phenyl]-l ,6-dihydropyrimidin-4-yl}piperidm- 4-yl)- 1 , 1 -dimethylurea; ethyl (l-{2-(4-chlorophenyl)-6-oxo-l-[4-(trifIuoromethyl}pheny!]-l56-dihydropyrimidin-4- yl}ρiρeridin-4-yl)carbamate;
N-j l-p^-chloro^-fluorophenylj-l^-chlorophenyO-ό-oxo-l jβ-dihydropyrimidin^-ylJpiperidin^- y 1 } -2 -methy lpropanamide;
3 -{ 1 -[2-{2-chloro-4-fluorophenyl)- 1 -(4-chlorophenyl)-6-oxo- 1 ,6-dihydropyrimidin-4-y I]piperidin-4- y 1 } - 1 , 1 -dimethylurea; ethyl {l-[2-(2-chloro-4-fluorophenyI)-l-(4-chlorophenyl)-6-oxo-l ,6-dihydropyrimidin-4-yl]piperidin- 4-yl} carbamate;
N-(l-{2-(2,4-dimethyIphenyi)-6-oxo-I-[4-(trifluoromethyl)phenyl]-l ,6-dihydropyrimidin-4- yl}piperidin-4-yl)-2-methylpropanamide;
3-(l-{2-(2,4-dimethylphenyl)-6-oxo-l -[4-(trifluoromethyI}phenyl]-l,6-dihydropyrim!din-4- yl}piperidin-4-yl)- 1 , 1 -dimethylurea; ethyl (l-{2-(2,4-dimethylpheny!)-6-oxo-l -[4-(tπfluoromethyI)pheny!]-l ,6-dihydropyπmidin-4- yl}piperidin-4-yl)carbamate;
N-(l-{2-(4-ch[oro-2-methylphenyI)-6-oxo-l-[4-(trifluoromethyl)phenyl]-l,6-dihydropyrimidii>4- yl}piperidin-4-yl)-2-methylpropanamide;
N-(l-{2-(4-chloro-2-methylphenyl)-6-oxo-l-[4-(trif]uoromethyl)phenyl]-l,6-dihydropyriiriidin-4- yl}piperidin-4-yl)ρroρan amide;
2-(2,4-dichlorophenyl}-6-(2,6-dimethylmoφholin-4-yl)-3-[4-(trifϊuoromethyl)phenyl]pyrimidin~ 4(3H)-one;
2-(2,4-dichlorophenyl)-6-(4-isobutyIpiperazin-l -yl)-3-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)- one;
6-(4-cyclobutylpiperazin-l-yl)-2-(2,4-dichloroρheny[)-3-[4-(lrifluoromethyl)ρhenyl]ρyrimidin-4(3H)- one; methyl 4-{2-(2,4-dichloiOphenyl)-6-oxo-l -[4-(trifluoromethyl)ρhenyl]-l ,6-dihydroρyπmidin-4- yl}piρerazine-l -carboxylate;
2-(2,4-dichlorophenyl)-6-(4-isobutyrylpiperazin-l-yl)-3-[4-(trifiuoromethyl)phenyl]pyrimidin-4(3H)- one;
4-{2-(2,4-dichloroρhenyl)-6-oxo-l-[4-(trifluoroiriethyl)phenyl]-l ,6-dihydropyrimidin-4-yl}-N.N- dimethylpiperazine-1-carboxamide;
N-(l-{2-(4-chloro-2-methylphenyl)-6-oxo-l-[4-(trifluoromethyl)phenyl]-l,6-dihydropyrimidin-4- yl}piρeridin-4-yl)-2-hydroxy-2-methyipropanamide;
N-(l_{2-(4-chloro-2-methylρhenyl)-6-oxo-l-[4-(trifluoiOniethyl)phenyl]-1.6-dihydropyrimidin-4- yl}piperidin-4-yl)acetamide; N-{l-{2-(4-chloro-2-methyIpheny])-6-oxo-l-[4-(trifluoromethyl)pheny[]-S,6-dihydropyrimidin-4- y 1 } piperidin-4-y 1 )-2 -methoxy acetamid e ; methyl (I-{2-(4-chIoro-2-methylphenyl)-6-oxo-l-[4-(trifluoromethyl)phenyl]-l,6-dihydropyrimidin- 4 -y 1 } p iperid in-4-y l)carbamate; ethyl ( 1 -{2-(4-chloro-2-methyIpheny])-6-oxo-l -[4-(trifIuoromethyl)phenyl]- 1 ,6-dihydropyrimidin-4- yl}piperidin-4-yl)carbamate;
2-(2,4-dich[orophenyl)-6-(4-hydroxyρiρeridin-l-y])-3-[4-(trifluoromethyl)phenyl]pyrimidin-4(3H)- one;
2-(2,4-dichIorophenyl)-6-(4-fluoroρiρeridin-l-yl)-3-[4-(trifluoromethyl)ρhenyl]pyπmidin-4(3H)-one; 2-(2,4-dich]oroρhenyl)-6-(4-oxopiperidin-l-yl)-3-[4-(trifluoromethy])pheny]]pyrimidin-4{3H)-one; methyl (1 -{6-(2-chtorophenyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-4,5-dihydro-l,3,5-triazin-2- yl}piperidin-4-yl)carbamate; ethyf (1-6-(-chlorophenyl)-4-oxo-5-4-(trifluoromethy)phenyl]-4,-dihydro-l 1^-tπazin^- yl}piperidin-4-y])carbamate;
S-fl -fό^-chlorophenyl^-oxo-S-^-ftrifluoromethyOphenylj^^-dihydro-l ^^-triazin^- yl}ρiperidin-4-y[)-l ,]-dimethyIurea;
2-(2,4-dichlorophenyl)-6-(4,4-difluoropiperidin-l-yl)-3-[4-(trifIuoromethyI)phenyl]pyrimidin-4(3H)- one;
6-(2,4-dich!orophenyl)-4-(4,4-diflυoropiperidin-1 -yl)-l-[4-(trifIuoromethyl)pheny!]-l,3,5-triazin- 2(lH)-one; lert-butyl 4-{6-(4-ch]oro-2-methyIphenyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-4,5-dihydro-l,3,5- triazin-2-y]}piperazine-l-carboxylate; methyl (l-{2-(4-chlorophenyl)-6-oxo-l-[4-(tπfluoromethyl)phenyl]-l ,6-dihydropyπmidin-4- y 1 } p iperidin-4-y l)carbamate ;
2-(4-chloro-2-methylphenyl)-6-(4-isobutyIpiperazin-l-yl)-3-[4-(trifluoromethyI)pheny]]pyrimidin- 4(3H)-one;
N-f l-lό^-chloro^-methylphenyl^-oxo-S-^^trifluoromethy^phenylJ^p-dihydro-i ^^-triazin^- yl}pipeπdin-4-yl)-2-methylpiOpanamide; methyl (l -{6-(4-chloro-2-methylphenyl)-4-oxo-5-[4-(trifluoromethyl)phenyl]-4,5-dihydro- 1 ,3,5- triazin-2-yl}piperidin-4-yl)carbamate; eihyl (l -{6--chloro^-methylphenyl)-oxo-5--trifluoromethylphenyl]-5-dihydro-l^^-triazin- 2-y]}piperidiπ-4-yl)carbamate;
N-(S -{2-(4-chloro-2-fluorophenyl)-6-oxo-1 -[4-(trifluoromethyf)phenyl]-I,6-dihydropyri]Tiidin-4- yI}piperidin-4-yI)propanamide;
N-(l -{2-(4-chIoro-2-fluoiOphenyl)-6-oxo-l-[4-(tnfluoromethyl}phenyl]-l,6-dihydropyrimidin-4- yI}piperidin-4-y!)-2-methylpropanamide; methyl (l -{2-(4-chloro-2-fluorophenyl)-6-oxo-l -[4-(trifluoromethyϊ)phenyl]-l ,6-dihydropyrimidin-4- yI}piperidin-4-yl)carbamate; ethyl (l-{2-(4-chloro-2-fluorophenyl)-6-oxo-l-[4-(trifluoromethy!)phenyl]-l ,6-dihydropyrimidin-4- yi}piperidin-4-yl)carbamate;
N-(l-l64-chlorophenyl)-oxo-5-4-(trifluoromethylphenyl)5-dihydro-l 1,3,5--triazin-2 yl}piperidin-4-yl)propanamide;
N-(I -{6-(4-chlorophenyl)-4-oxo-5-[4-(trifluoromethyl)ρhenyl]-4,5-dihydro- 1 ,3, 5-triazin-2- yl}piperidin-4-yl)-2-methylpropanamide; methyl (I-{6-{4-chloroρhenyl)-4-oxo-5-[4-(trifluoromethy])ρheny]]-4,5-dihydro-l ,3,5-triazin-2- yl }piperidin-4-y l)carbamate; ethyl (l-{6-(4-chlorophenyI)-4-oxo-5-[4-(trifluoromethyl)pheny[]-4,5-dihydro-l,3,5-triazin-2- yl } piperidin-4-yl)carbamate;
2-(4-chloro-2-fluoroρhenyl)-6-(4-ρropiony]ρiperazin-l-y[)-3-[4-(trif]uoromethyϊ)phenyl]pyrimidin- 4{3H)-one;
2-{4-chioro-2-fluoroρhenyl)-6-(4-isobutyrylρiperazin-1 -yl)-3-[4-(trifluoromethyi)phenyl]pyrimidin- 4(3H)-one; methyl 4-{2-(4-chloro-2-fluorophenyI)-6-oxo-3-[4-(trifIuoromethyl)ρhenyl]-l,6-dihydroρyrimidin-4- yi}ρiρerazine-l -carboxylate; ethyl 4-{2-(4-chloro-2-f!uorophenyl)-6-oxo-l -[4-(trifluoromethy!)phenyl]-] ,6-dihydropynmidin-4- yl }piρerazine- 1 -carboxylate;
2-(4-chloro-2-fluorophenyl)-6-(4-isobutylpiperazin-I-yl)-3-[4-(trifluoromethyl)phenyl]pyrimidin- 4(3H)-one;
6-(4-sec-butylpiperazin-l -yi)-2-(4-chloro-2-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]pyrimidin- 4(3H)-one;
6-(4-chloro-2-methyIphenyI)-4-(4-isobυtylpiperazin-l-yl)-l-[4-(trifluoromethyl)phenyl]-l,3,5-triazin- 2(lH)-one;
N-(l -{2-(4-chlorophenyl)-6-oxo-l-[4-(trifluoromethyl)phenyl]-l,6-dihydiOpyrimidin-4-yi}piperidin- 4-yl)methanesulfonamide;
N-(l -{2-(2-methyIphenyl)-6-oxo-l-[4-(trifluoromethy[)ρhenyl]-l ,6-dihydroρyrimidin-4-yi}piperidin- 4-yl)methanesulfonamide; δ^-chloro^-fluorophenyl^^-isobutyrylpiperazin-l -y^-l -^-ttriflυoromethyOphenyπ-l p^- triazin-2(IH)-one; methyl 4-{6-(4-chloro-2-fluorophenyl)-4-xo-5-[4-(trifluoromethyl)ρhenyl]-4,5-dihydro-l ,3,5-triazin- 2-yI }ρiρerazine- 1 -carboxylate; ethyl 4-{6-(4-chloro-2-fluorophenyl)-4-oxo-5-[4-(trifluoromethyl)ρhenyl]-4,5-dihydro-l ,3)5-triazin-2- yl }ρiρerazine-l -carboxylate;
6-(4-chloro-2-fluorophenyl)-4-(4-isobutylpiperazin-1 -yl)-l-[4-(tπfluoromethyl)phenyl]-l,3,5-triazin- 2(lH)-one; methyl (l -{2-(2-methylphenyl)-6-oxo-l-[4-(trifluoromethyl)phenyl]-l ,6-dihydroρyrim]din-4- yl}piperidin-4-yl)carbamate; ethyl ( I -{2-(2-methylphenyl)-6-oxo- 1 -[4-(trifluoromethyl)phenyl]- 1 ,6-dihydropyrimidin-4- yl}piperidin-4-yl)carbamate;
N"(l-{6-(4-ch]oro-2-fluoropheny[)-4-oxo-5-[4-(trifluoiOmethyl)phenyl]-4.5-dihydro-l,3.5-triazin-2- y[}piperidin-4-yl)-2-methylpropanamide; methyl (l -lό^-chloro^-fluorophenyl^-oxo-S-^-CtπfluoromethylJpheny^^^-dihydro-l ^.S- triazin-2-y]}piperidin-4-yl)carbamate; or ethyl (l-{6-(4-chloro-2-fluorophenyl)-4-oxo-5-[4-(trif!uoromethyi)phenyl]-4,5-dihydiO-l ,3,5-triazin- 2-vl}D!Deridin-4-vπcarbamate.
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