WO2007146761A2 - Diaryl pyrimidinones et composés associés - Google Patents

Diaryl pyrimidinones et composés associés Download PDF

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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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WO2007146761A3 (fr
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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, cocaine, 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.

Abstract

La présente invention concerne des composés répondant à la Formule (I), les variables étant telles que décrites dans ce document. De tels composés peuvent être utilisés pour moduler l'activité du CB 1 in vivo ou in vitro, et ils se révèlent particulièrement utiles pour le traitement de pathologies sensibles à la modulation du CB 1 chez les êtres humains, les animaux de compagnie et les animaux d'élevage, y compris les troubles de l'appétit, l'obésité et les troubles de dépendance. L'invention concerne également des compositions pharmaceutiques et des procédés permettant de les utiliser en vue de traiter lesdits troubles, de même que des procédés destinés à utiliser de tels ligands pour des études de localisation des récepteurs et des essais variés in vitro.
PCT/US2007/070676 2006-06-12 2007-06-08 Diaryl pyrimidinones et composés associés WO2007146761A2 (fr)

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010101246A1 (fr) * 2009-03-05 2010-09-10 塩野義製薬株式会社 Dérivés de la pipéridine et de la pyrrolidine dotés d'un antagonisme pour les récepteurs npy y5
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012011592A1 (fr) * 2010-07-23 2012-01-26 武田薬品工業株式会社 Composé hétérocyclique et application de celui-ci
JP2012508785A (ja) * 2008-11-14 2012-04-12 サノフイ アルキル−複素環のカルバメート誘導体、これらの調製およびこれらの使用
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
WO2016031987A1 (fr) * 2014-08-29 2016-03-03 国立大学法人東京大学 Dérivé de pyrimidone ayant une activité inhibitrice de l'autotaxine
US10183949B2 (en) 2014-08-29 2019-01-22 The University Of Tokyo Pyrimidinone derivative having autotaxin-inhibitory activity
US10828302B2 (en) 2016-03-10 2020-11-10 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US11059828B2 (en) 2009-10-23 2021-07-13 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators

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WO2007118149A2 (fr) * 2006-04-07 2007-10-18 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical Lollege Thiazole et thiophene analogues et leur utilisation pour traiter des maladies auto-immunes et des cancers

Patent Citations (1)

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WO2007118149A2 (fr) * 2006-04-07 2007-10-18 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical Lollege Thiazole et thiophene analogues et leur utilisation pour traiter des maladies auto-immunes et des cancers

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
JP2012508785A (ja) * 2008-11-14 2012-04-12 サノフイ アルキル−複素環のカルバメート誘導体、これらの調製およびこれらの使用
WO2010101246A1 (fr) * 2009-03-05 2010-09-10 塩野義製薬株式会社 Dérivés de la pipéridine et de la pyrrolidine dotés d'un antagonisme pour les récepteurs npy y5
JP5642661B2 (ja) * 2009-03-05 2014-12-17 塩野義製薬株式会社 Ｎｐｙｙ５受容体拮抗作用を有するピペリジンおよびピロリジン誘導体
US8889674B2 (en) 2009-03-05 2014-11-18 Shionogi & Co., Ltd. Piperidine and pyrrolidine derivatives having NPY Y5 receptor antagonism
JPWO2010101246A1 (ja) * 2009-03-05 2012-09-10 塩野義製薬株式会社 Ｎｐｙｙ５受容体拮抗作用を有するピペリジンおよびピロリジン誘導体
US11059828B2 (en) 2009-10-23 2021-07-13 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators
USRE48841E1 (en) 2009-10-23 2021-12-07 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
US11667644B2 (en) 2009-10-23 2023-06-06 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012011592A1 (fr) * 2010-07-23 2012-01-26 武田薬品工業株式会社 Composé hétérocyclique et application de celui-ci
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US10183949B2 (en) 2014-08-29 2019-01-22 The University Of Tokyo Pyrimidinone derivative having autotaxin-inhibitory activity
EP3187492A4 (fr) * 2014-08-29 2018-05-09 The University of Tokyo Dérivé de pyrimidone ayant une activité inhibitrice de l'autotaxine
JPWO2016031987A1 (ja) * 2014-08-29 2017-07-13 国立大学法人 東京大学 オートタキシン阻害活性を有するピリミジノン誘導体
WO2016031987A1 (fr) * 2014-08-29 2016-03-03 国立大学法人東京大学 Dérivé de pyrimidone ayant une activité inhibitrice de l'autotaxine
US10828302B2 (en) 2016-03-10 2020-11-10 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US11241432B2 (en) 2016-03-10 2022-02-08 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists

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