WO2005009104A2 - Derives d'acide benzoique et phenylacetique utilises en tant que modulateurs des recepteurs du facteur hnf-4$g(a) - Google Patents

Derives d'acide benzoique et phenylacetique utilises en tant que modulateurs des recepteurs du facteur hnf-4$g(a) Download PDF

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WO2005009104A2
WO2005009104A2 PCT/US2004/023788 US2004023788W WO2005009104A2 WO 2005009104 A2 WO2005009104 A2 WO 2005009104A2 US 2004023788 W US2004023788 W US 2004023788W WO 2005009104 A2 WO2005009104 A2 WO 2005009104A2
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compound
optionally substituted
patient
halogens
pharmaceutical agent
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WO2005009104A3 (fr
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Christopher Mapes
Donald Karanewsky
Anthony Thompson
Pierrre Michellys
Daniel Ruppar
Jyun-Hung Chen
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Ligand Pharmacueticals Incorporated
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    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • This invention relates to compounds that bind to and/or modulate hepatocyte nuclear factor 4 ⁇ receptors and to methods for making and using such compounds.
  • Hepatocyte nuclear factor 4 ⁇ (HNF-4 ⁇ ) has been described as a member of the steroid thyroid superfamily of transcription factors that is expressed in liver, kidney, intestine and pancreas. Sladek, et al. (1990) Genes Dev. 4:, 2353-2365; Miquerol, et al. (1994) J. Biol. Chem. 269: 8944-8951. No ligand has been identified at present and therefore HNF-4 ⁇ is referred to as an orphan member of the intracellular receptor family (3-5). Tsai, O'Malley, (1994) Annu. Rev. Biochem. 63: 451-486; Mangelsdorf, Evans, .
  • HNF-4 ⁇ has been described as being capable of activating transcription in tissue culture cells under certain conditions. Kou et al, (1992) Nature 355:457-461;
  • HNF-4 ⁇ plays a role in one or more metabolic pathways, including glucose and lipid homeostasis. Ladias, et al, (1992) J. Biol. Chem. 267:15849-15860; Montgomery-Snyder etal, (1992) Mol. Cell. Biol. 12:1708-1718; Metzger et al, (1993) J. Biol. Chem. 268:16831-16838; Yamagata et al, (1996) Nature 384: 458-460; Stoffel & Duncan (1997) Proc. Natl.
  • HNF-4 ⁇ Certain mutations of HNF-4 ⁇ result in defective function of the endocrine pancreas and maturity-onset diabetes of the young (MODYl), suggesting that HNF-4 ⁇ plays a role in metabolic gene regulation. Yamagata et al, K (1996) Nature 384:458- 460. Liver-specific knockouts demonstrate that HNF-4 plays a role in liver development and function. Li et al, (2000) Genes & Dev. 14:464-474; Hayhurst et al, (2001) Mol. Cell. Biol. 21:1393-1403; Fraser et al, (1998) Nuc. Acids Res. 26:2702-2707.
  • the present invention provides a compound of formula I:
  • R 1 is selected from H, a halogen, a C]-C 4 alkyl optionally substituted with one or more halogens, a C 2 -C 4 alkenyl optionally substituted with one or more halogens, and C 2 -C 4 alkynyl optionally substituted with one or more halogens;
  • R 2 and R 4 are each independently selected from H, a halogen, a -C4 alkyl optionally substituted with one or more halogens, a C 2 -C 4 alkenyl optionally substituted with one or more halogens, C 2 -C alkynyl optionally substituted with one or more halogens, a -C 3 alkoxy optionally substituted with one or more halogens, a carbocyclic or heterocyclic ring optionally substituted with one or more halogens, a nitro, and a NR ,3 R 14 ; or
  • R 1 and R 2 taken together form a five to eight-membered carbocyclic or heterocyclic ring optionally substituted with one or more R 15 ;
  • R 3 is selected from H, a halogen, an acyl, a methyl optionally substituted with one or more halogens, and a methoxy optionally substituted with one or more halogens; or
  • R 2 and R 3 taken together form a five to eight-membered carbocyclic or heterocyclic ring optionally substituted with one or more R 15 ;
  • R 3 and R taken together form a five to eight-membered carbocyclic or heterocyclic ring optionally substituted with one or more R 15 ;
  • R 5 is selected from H, a halogen, a C C 6 optionally substituted with one or more halogens, a C 2 -C 6 alkenyl optionally substituted with one or more halogens, a C 2 -C 6 alkynyl optionally substituted with one or more halogens, C 1 -C 5 alkoxy optionally substituted with one or more halogens, C 1 -C5 thioalkyl optionally substituted with one or more halogens, a C 2 -C 5 alkenyl optionally substituted with one or more halogens, C 2 -C 5 alkynyl optionally substituted with one or more halogens a carbocyclic or heterocyclic ring optionally substituted with one or more R 15 , an acyl, a nitro, and a NR 16 R 17 ; or
  • R 4 and R 5 taken together form a five to eight-membered carbocyclic or heterocyclic ring optionally substituted with one or more R 5 ;
  • R 6 is selected from H, a halogen, a methyl optionally substituted with one or more fluorines and a methoxy;
  • R 7 is selected from a CH 2 OH, CHO, a carboxylic acid or a (C(R 9 )(R 10 )) n CO 2 H or a (C(R 9 )(R 10 )) n CO 2 (CH 2 ) m CH 3 , wherein n is 0, 1, or 2; and m is 0, 1, or 2;
  • R 9 and R 10 are each independently selected from H, F, and OH; or R 9 and R 10 taken together form an oxygen;
  • R 13 and R 14 are each independently selected from H, a C ⁇ -C 5 alkyl optionally substituted with one or more halogens, a C 2 -C 5 alkenyl optionally substituted with one or more halogens, a C 2 -C 5 alkynyl optionally substituted with one or more halogens, and a carbocyclic ring optionally substituted with one or more halogens; or R 13 and R 14 taken together with the nitrogen to which they are each bound to form a five to eight- membered heterocyclic ring;
  • R 15 is selected from H, a halogen, NO 2 , a cyano, an acyl, a C.-C 3 alkyl optionally substituted with one or more halogens, a C 2 -C 3 alkenyl optionally substituted with one or more halogens, a C 2 -C 3 alkynyl optionally substituted with one or more halogens a C !
  • R 16 and R 17 are each independently selected from H, a d-C 5 alkyl optionally substituted with one or more halogens, a C 2 -C 5 alkenyl optionally substituted with one or more halogens, a C 2 -C 5 alkynyl optionally substituted with one or more halogens, and a carbocyclic ring optionally substituted with one or more R 15 ; and
  • X and Y are each independently selected from a methylene optionally substituted with one or more halogens, a C]-C 2 alkyl optionally substituted with one or more halogens, a C 2 alkenyl optionally substituted with one or more halogens, C 2 alkynyl optionally substituted with one or more halogens, O, S, a NR 18 , and benzyl optionally substituted with one or more fluorines, wherem if X is methylene, then Y is selected from NR 18 , O and S; if Y is methylene, then X is selected from NR 18 , O and S; and
  • R is selected from H a -C 5 alkyl, a C 2 -C 6 alkenyl, and aC 2 -C 6 alkynyl.
  • the invention provides a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a compound of Formula I.
  • the invention provides a method of treating a patient comprising administering to said patient a pharmaceutical agent comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Formula I.
  • the invention provides a selective HNF-4 ⁇ modulator of Formula I.
  • Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen” and “H” are understood to have identical meaning.
  • Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA methodology, oligonucleotide synthesis, tissue culture and transformation (e.g., electroporation, lipofection).
  • Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications, as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general or more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. (1989)), which is incorporated herein by reference for any purpose.
  • selective binding compound refers to a compound that selectively binds to any portion of one or more target receptors.
  • selective HNF-4 ⁇ receptor binding compound refers to a compound that selectively binds to any portion of an HNF-4 ⁇ receptor.
  • selectively binds refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor.
  • selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non-target.
  • target receptor refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound.
  • a target receptor is an HNF-4 ⁇ receptor.
  • modulator refers to a compound that alters or elicits an activity of a molecule. For example, a modulator may cause an increase or decrease in the magnitude of a certain activity of a molecule compared to the magnitude of the activity in the absence of the modulator.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities of a molecule. In certain embodiments, an inhibitor completely prevents one or more activities of a molecule. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity of a molecule. In certain embodiments the presence of a modulator results in an activity that does not occur in the absence of the modulator. [019] The term “selective modulator” refers to a compound that selectively modulates a target activity. [020] The term “selective HNF-4 ⁇ receptor modulator” refers to a compound that selectively modulates at least one activity associated with an HNF-4a receptor.
  • target activity refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, changes in binding affinity, signal transduction, enzymatic activity, transcription of one or more genes, tumor growth, changes in blood glucose concentration, and inflammation or inflammation-related processes.
  • receptor-mediated activity refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor.
  • agonist refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor.
  • partial agonist refers to a compound the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude.
  • antagonist refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor.
  • alkyl refers to an optionally substituted straight-chain or branched-chain alkyl radical having from 1 to about 12 carbon atoms.
  • the term also includes substituted straight-chain or branched-chain alkyl radicals having from 1 to about 6 carbon atoms as well as those having from 1 to about 4 carbon atoms.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.
  • alkenyl refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 18 carbon atoms.
  • the term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon double bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms.
  • alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like.
  • alkynyl refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 12 carbon atoms.
  • the term also includes substituted straight-chain or branched-chain alkyl radicals having one or more carbon-carbon tyriple bonds and having from 2 to about 6 carbon atoms as well as those having from 2 to about 4 carbon atoms.
  • alkynyl radicals include ethynyl, propynyl, butynyl and the Hke.
  • an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term “alkyl” also includes instances where no numerical range of carbon atoms is designated). [029] The term “lower alkyl” refers to an alkyl comprising 1 to 6 carbon atoms.
  • intermediate alkyl refers to an alkyl comprising 7 to 12 carbon atoms.
  • An alkyl may be designated as “C 1 -C 4 alkyl” or similar designations.
  • "d-C 4 alkyl”, "Q-C 4 alkenyl” and"C 1 -C 4 alkynyl” indicate a radical having one, two, three, or four carbon atoms (e.g., methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl).
  • haloalkyl refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as each other. In certain of such embodiments, the halogen atoms are not all the same as each other.
  • heteroalkyl refers to a group comprising an alkyl and one or more heteroatoms. Certain heteroalkyls are acylalkyls, in which the one or more heteroatoms are outside an alkyl chain.
  • thioalkyl refers to a heteroalkyl comprising at least one sulfur atom.
  • heterohaloalkyl refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom.
  • the term "carbocycle” refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom. Carbocylic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles may be optionally substituted. [036]
  • the term "heterocycle” refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms.
  • heterocyclic rings may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms.
  • those two or more heteroatoms may be the same as or different from each other.
  • Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. For example, binding for benzo-fused derivatives, may be via a carbon of the benzenoid ring.
  • heterocycles include, but are not limited to the following:
  • D, E, F, and G each independently represent a heteroatom.
  • D, E, F, and G may be the same as or different from each other.
  • heteroatom refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same, or some or all of the two or more heteroatoms may each be different from the others.
  • aromatic refers to a group comprising a covalently closed ring having a delocalized ⁇ -electron system. Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics may be optionally substituted.
  • aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.
  • aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Q.
  • an aromatic group is substituted at one or more of the para, meta, and/or ortho positions.
  • aromatic groups comprising substitutions include, but are not limited to, phenyl, 3- halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl- 4- aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4- morpholin-4-ylphenyl, 4-pyrrolidin-l-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and4-(2-oxopyrrolidin-l-yl)phenyl.
  • aryl refers to an aromatic group wherem each of the atoms forming the ring is a carbon atom.
  • Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms.
  • Aryl groups may be optionally substituted.
  • heteroaryl refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C 3 .
  • heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C ⁇ -C 6 alkoxy, C ⁇ -C 6 alkyl, C ⁇ -C 6 hydroxyalkyl, C C 6 aminoalkyl, C ⁇ -C 6 alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, and trifluoromethyl.
  • heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazin
  • the substituents are halo, hydroxy, cyano, O-Q-6 alkyl, C]-C 6 alkyl, hydroxy-d-Ce alkyl, or amino-C ⁇ -C 6 alkyl.
  • non-aromatic ring refers to a group comprising a covalently closed ring that does not have a delocalized ⁇ -electron system.
  • cycloalkyl alone or in combination, refers to a monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety has from 3 to about 8 carbon atoms.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Cycloalkyl rings may be fo ⁇ ned by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may be optionally substituted.
  • non-aromatic heterocycle refers to a group comprising a non- aromatic ring wherein one or more atoms forming the ring is a heteroatom.
  • Non- aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms.
  • Non-aromatic heterocycles may be optionally substituted.
  • non-aromatic heterocycles comprise one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
  • non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tefrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,
  • arylalkyl refers to a group comprising an aryl group bound to an alkyl group.
  • carbocyclic cycloalkyl ring refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted.
  • ring refers to any covalently closed structure.
  • Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system. [047] The term “ring system” refers to two or more rings, wherein two or more of the rings are fused. The term “fused" refers to structures in which two or more rings share one or more bonds.
  • R refers to a substituent selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).
  • null refers to a group being absent from a structure. For R' R" example, in the structure ⁇ - ⁇ , if X is C, then both R' and R" exist, but if X is N, then one of those R groups is null, meaning that only three groups are bound to the N.
  • cyano refers to a group of formula -CN.
  • isocyanato refers to a group of formula -NCO.
  • thiocyanato refers to a group of formula -CNS.
  • isothiocyanato refers to a group of formula -NCS.
  • esteer refers to a chemical moiety with formula -(R) n -COOR', where R and R' are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl (bonded through a ring carbon) and non- aromatic heterocycle (bonded through a ring carbon), where n is 0 or 1.
  • amide refers to a chemical moiety with formula -(R)n-C(O)NHR or -(R)n-NHC(O)R, where R and R' are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1.
  • an amide may be an amino acid or a peptide.
  • alkoxy refers to an alkyl ether radical.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy and the like.
  • formyl includes aldehydes attached to a compound via an alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl group (e.g., -alkyl-CHO, -aryl-CHO, • arylalkyl-CHO or -heteroarylalkyl-CHO, etc.).
  • oxime refers to a group of formula:
  • hydrazone refers to a group of formula:
  • hydroxylamine refers to a group of formula:
  • sulfonamide refers to a group of formula:
  • halogen includes F, Cl, Br and I
  • amine includes F, Cl, Br and I
  • hydroxy includes F, Cl, Br and I
  • carboxyl include such groups that have been esterified or amidified. Procedures and specific groups used to achieve esterification and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is inco ⁇ orated by reference herein in its entirety.
  • the term “optionally substituted,” refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, heterohaloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, alkenylthio, alkynylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O- carbamyl, N
  • protective derivatives and protecting groups that may form such protective derivatives
  • the substituent groups may together form a ring.
  • carrier refers to a compound that facilitates the incorporation of another compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • pharmaceutical agent refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient.
  • a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect.
  • a pharmaceutical agent comprises a prodrug.
  • a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.
  • therapeutically effective amount refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect.
  • prodrug refers to a pharmaceutical agent that is converted from a less active form into a corresponding more active form in vivo.
  • pharmaceutically acceptable refers to a formulation of a compound that does not significantly abrogate biological activity, a pharmacological activity and or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient.
  • co-administer refers to administering more than one pharmaceutical agent to a patient. In certain embodiments, co-administered pharmaceutical agents are administered together in a single dosage unit. In certain embodiments, co-administered pharmaceutical agents are administered separately. In certain embodiments, co-administered pharmaceutical agents are administered at the same time. In certain embodiments, co-administered pharmaceutical agents are administered at different times.
  • the term "patient” includes human and animal subjects.
  • substantially pure means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition).
  • a substantially purified pure composition is a composition wherem the object species comprises at least about 50 percent (on a molar basis) of all species present.
  • a substantially pure composition is a composition wherein the object species comprises more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition.
  • tissue-selective refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue.
  • the biological activities modulated in the different tissues may be the same or they may be different.
  • the biological activities modulated in the different tissues may be mediated by the same type of target receptor.
  • a tissue-selective compound may modulate an HNF-4 ⁇ receptor-mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, an HNF-4 ⁇ receptor-mediated biological activity in another tissue type.
  • monitoring refers to observing an effect or absence of any effect.
  • cells are monitored after contacting those cells with a compound of the present invention. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, an HNF-4 receptor activity, or the interaction between an HNF-4 ⁇ receptor and a natural binding partner.
  • the term "cell phenotype” refers to physical or biological characteristics.
  • cell proliferation refers to the rate at which cells divide.
  • the number of cells growing in a vessel can be quantified by a person skilled in the art (e.g., by counting cells in a defined area using a light microscope, or by using laboratory apparatus that measure the density of cells in an appropriate medium).
  • One skilled in that art can calculate cell proliferation by determining the number of cells in a sample at two or more times.
  • contacting refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Certain compounds
  • Certain compounds that bind to HNF-4 receptors and/or certain compounds that modulate an activity of such receptors play a role in health (e.g., normal growth, development, and/or absence of disease).
  • compounds of the present invention are useful for treating any of a variety of diseases or conditions.
  • Certain compounds have been previously described as receptor modulators. See e.g., U. S. Patent Nos. 6,462,038, 5,693,646; 6,380,207; 6,506,766;
  • cyclothiocarbamate analogues have been described as progesterone receptor modulators (e.g., US 6,436,929 and US 6,509,334). Certain cyclocarbamate analogues have been described as progesterone receptor antagonists (e.g., U.S. Pat. Nos. 6,306,851, 6,380,178, 6,441,019, 6,444,668, 6,509,334, and 6,566,358; Zhang, et al. J. Med. Chem. 45:4379 (2002)). [094] In certain embodiments, the invention provides a compound of formula I:
  • R is selected from H, a halogen, a Q-C ⁇ alkyl optionally substituted with one or more halogens, a C 2 -C 6 alkenyl optionally substituted with one or more halogens, a C 2 -C 6 alkynyl optionally substituted with one or more halogens, an optionally substituted C C 6 heteroalkyl, an optionally substituted C 2 -C 6 heteroalkenyl, an optionally substituted C 2 -C 6 heteroalkynyl, an optionally substituted
  • C ⁇ -C 6 haloalkyl an optionally substituted C 2 -C 6 haloalkenyl, an optionally substituted C 2 -C 6 haloalkynyl, an optionally substituted C C 6 heterohaloalkyl, an optionally substituted C 2 -C 6 heterohaloalkenyl, an optionally substituted C 2 -C 6 heterohaloalkynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, an optionally substituted C 3 -C 8 cycloalkynyl, an optionally substituted C 3 -C 8 heterocycle, an optionally substituted C 3 -C 8 aryl, an optionally substituted C 3 -C 8 heteroaryl, an optionally substituted C ⁇ -C 2 alkoxy, an optionally substituted sulfonamide, an optionally substituted C ⁇ -C 2 thioalkyl, an optionally substituted C
  • R 1 is an optionally substituted C ⁇ -C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 heteroalkyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, or an optionally substituted C 3 - C 8 cycloalkynyl.
  • R 1 is an optionally substituted C C 8 alkyl an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl,, an optionally substituted C 2 -C 8 heteroalkyl an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkyl an optionally substituted C 3 -C 8 cycloalkenyl, or an optionally substituted C 3 -C 8 cycloalkynyl.
  • R is selected from an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 3 heteroalkenyl, an optionally substituted C 2 -C 3 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkenyl, and an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 1 is selected from an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl.
  • R 1 is F or Cl.
  • R 2 and R 4 are each independently selected from H, a halogen, a C 1 -C 3 alkoxy optionally substituted with one or more halogens, a carbocyclic or heterocyclic ring optionally substituted with one or more halogens, a nitro, NR 13 R 14 , a -C ⁇ alkyl substituted with one or more halogens, a C 2 -C 6 alkenyl substituted with one or more halogens, a C 2 -C 6 alkynyl optionally substituted with one or more halogens, an optionally substituted d-C 6 heteroalkyl, an optionally substituted C 2 - C 6 heteroalkenyl, an optionally substituted C 2 -C 6 heteroalkynyl, an optionally substituted d-C 6 haloalkyl, an optionally substituted C 2
  • R and/or R is an optionally substituted d-C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 heteroalkyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, or an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 2 and/or R 4 is an optionally substituted d-C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 heteroalkyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, or an optionally substituted C 3 - C 8 cycloalkynyl.
  • R 2 and/or R 4 is selected from an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 3 heteroalkenyl, an optionally substituted C 2 -C 3 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkenyl, and an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 2 and/or R 4 is selected from an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl.
  • R and/or R is F or Cl.
  • R 1 and R 2 taken together form a five to eight- membered carbocyclic or heterocyclic ring optionally substituted with one or more R
  • the ring formed by R 1 and R 2 in such embodiments would share a bond with the ring to which R 1 and R 9 are both bound.
  • R 3 is selected from H, a halogen, an acyl, a methyl optionally substituted with one or more halogens, and a methoxy optionally substituted with one or more halogens.
  • R 2 and R 3 taken together form a five to eight- membered carbocyclic or heterocyclic ring optionally substituted with one or more R 15 .
  • the ring formed by R 2 and R 3 in such embodiments would share a bond with the ring to which R 2 and R 3 are both bound.
  • R 3 and R 4 taken together form a five to eight- membered carbocyclic or heterocyclic ring optionally substituted with one or more R .
  • the ring formed by R 3 and R 4 in such embodiments would share a bond with the ring to which R and R are both bound.
  • R 5 is selected from H, a halogen, a d-C 6 alkyl optionally substituted with one or more halogens, a C 2 -C 6 alkenyl optionally substituted with one or more halogens, C 2 -C 6 alkynyl optionally substituted with one or more halogens, a C 1 -C 5 alkoxy optionally substituted with one or more halogens, a C 1 -C 5 thioalkyl optionally substituted with one or more halogens, a C 2 -C 5 thioalkenyl optionally substituted with one or more halogens, a C 2 -C 5 thioalkynyl optionally substituted with one or more halogens, a carbocyclic or heterocyclic ring optionally substituted with one or more R 15 , an acyl, a nitro, and NR 16 R 17 .
  • R 5 is an optionally substituted d-d alkyl, an optionally substituted C 2 -C 5 alkenyl, an optionally substituted C 2 -C 5 alkynyl,, an optionally substituted d- heteroalkyl, an optionally substituted C 2 -C 5 heteroalkenyl, an optionally substituted C 2 -C 5 heteroalkynyl,, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 - C 8 cycloalkenyl, or optionally substituted C 3 -C 8 cycloalkynyl.
  • R 5 is an optionally substituted d-d alkyl, an optionally substituted C 2 -C 5 alkenyl, an optionally substituted C 2 -C 5 alkynyl, an optionally substituted d-d heteroalkyl an optionally substituted C 2 -C 5 heteroalkenyl, an optionally substituted C 2 -C 5 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 - C 8 cycloalkenyl, or an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 5 is selected from an optionally substituted C 2 -d alkenyl, an optionally substituted C 2 -C 5 alkynyl, an optionally substituted C 2 -C 5 heteroalkenyl, an optionally substituted C 2 -d heteroalkynyl, an optionally substituted C 3 -C 8 heteroalkenyl, and an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 5 is selected from an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl.
  • R 5 is F or Cl.
  • the ring formed by R and R 5 in such embodiments would share a bond with the ring to which R 4 and R 5 are both bound.
  • R 6 is selected from H, a halogen, a methyl optionally substituted with one or more fluorines and a methoxy.
  • R 7 is selected from an optionally CH 2 OH, CHO, a carboxylic acid or a pharmaceutically acceptable salt thereof, C(R 9 )(R 10 )CO 2 H or a pharmaceutically acceptable salt thereof, (C(R 9 )(R 10 )) n CO 2 (CH 2 ) m CH 3 , O(C(R 9 )(R 10 )) n CO 2 H, O(C(R 9 )(R 10 )) n CO 2 (CH 2 ) m CH 3 , an optionally substituted C.-C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C ⁇ -C 6 heteroalkyl, an optionally substituted C 2 -C 6 heteroalkenyl, an optionally substituted C 2 -C 6 heteroalkynyl, an optionally substituted d-C 6 haloalkyl, an optionally substituted C.-C
  • R 7 is an optionally substituted d-C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 heteroalkyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 - C 8 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkyl an optionally substituted d-C 8 cycloalkenyl, or an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 7 is an optionally substituted d-C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 heteroalkyl an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 heteroalkynyl, or an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted d-C 8 cycloalkenyl, an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 7 is selected from an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 3 heteroalkenyl, an optionally substituted C 2 -C 3 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkenyl, and an optionally substituted C 3 -C 8 cycloalkynyl.
  • m and n are each independently selected from 0, 1, 2, and 3.
  • R 9 and R are each independently selected from H, F, and OH. In certain embodiments, R 9 and R 10 taken together form an oxygen.
  • R 13 and R 14 are each independently selected from H, a carbocyclic ring optionally substituted with one or more halogens, C ⁇ -C 6 alkyl substituted with one or more halogens, C 2 -C 6 alkenyl substituted with one or more halogens, C 2 -C 6 alkynyl substituted with one or more halogens, an optionally substituted d-C 6 heteroalkyl an optionally substituted C 2 -C 6 heteroalkenyl, an optionally substituted C 2 -C 6 heteroalkynyl, an optionally substituted d-C 6 haloalkyl, an optionally substituted C 2 -C 6 haloalkenyl, an optionally substituted C 2 -C 6 haloalkynyl, an optionally substituted d-C 6 heterohaloalkyl, an optionally substituted C 2 -C 6 heterohaloalkenyl, an optionally substituted C 2 -C 6 haloalkyny
  • R 13 and/or R 14 is an optionally substituted Cj-C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 8 heteroalkyl, an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, or an optionally substituted C 3 - C 8 cycloalkynyl.
  • R 13 and/or R 14 is an optionally substituted Ci- C 8 alkyl, an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl,, an optionally substituted C 2 -C 8 heteroalkyl an optionally substituted C 2 -C 8 heteroalkenyl, an optionally substituted C 2 -C 8 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkyl, an optionally substituted C 3 -C 8 cycloalkenyl, or an optionally substituted C 3 -C 8 cycloalkynyl.
  • R 13 and/or R 14 is selected from an optionally substituted C 2 -C 8 alkenyl, an optionally substituted C 2 -C 8 alkynyl, an optionally substituted C 2 -C 3 heteroalkenyl, an optionally substituted C 2 -C 3 heteroalkynyl, an optionally substituted C 3 -C 8 cycloalkenyl, and an optionally substituted d-C 8 cycloalkynyl.
  • R 13 and/or R 14 is selected from an optionally substituted methyl, ethyl propyl isopropyl, butyl, sec-butyl, and tert-butyl.
  • R 13 and/or R 14 is a halogen
  • R 1 is F or Cl.
  • R 13 and R 14 taken together with the nitrogen to which they are each bound to form a five to eight-membered heterocyclic ring.
  • R 15 is selected from H, a halogen, NO 2 , a cyano, an acyl, a d-C 3 alkyl optionally substituted with one or more halogens, a C 2 -C 3 alkenyl optionally substituted with one or more halogens, a C 2 -C 3 alkynyl optionally substituted with one or more halogens, a C ⁇ -C 2 alkoxy optionally substituted with one or more halogens, d-C 2 thioalkyl optionally substituted with one or more halogens, a C 2 thioalkenyl optionally substituted with one or more halogens, and a C 2 thioalkynyl optionally substituted with one or more halogens.
  • R 1 and R 17 are each independently selected from H, a d-d alkyl optionally substituted with one or more halogens, C 2 -C 5 alkenyl optionally substituted with one or more halogens, C 2 -C 5 alkynyl optionally substituted with one or more halogens, and a carbocyclic ring optionally substituted with one or more R 15 ; and [0111]
  • X and Y are each independently selected from a methylene optionally substituted with an oxime or with one or more halogens, a d-C 2 alkyl, optionally substituted with one or more halogens, a C 2 alkenyl optionally substituted with one or more halogens, a C 2 -C 6 alkynyl optionally substituted with one or more halogens, O, S, NR 18 , and benzyl optionally substituted with one or more fluorines.
  • X and/or Y is a carbonyl. In certain embodiments, X is a carbonyl. In certain embodiment, X and Y together form and olefin. [0112] In certain embodiments, if X is methylene, then Y is selected from NR 18 , O and S; if Y is methylene, then X is selected from NR 18 , O and S; and R 18 is selected from H a - alkyl, a C 2 -C 5 alkenyl, and a C 2 -C 5 alkynyl.
  • the identities of those two or more particular groups are selected independently and, thus, may be the same or different from one another.
  • certain compounds of the invention comprise two or more R 15 groups. The identities of those two or more R 15 groups are each selected independently. Thus, in certain embodiments, those R 15 groups are all the same as one another; in certain embodiments, those R 15 groups are all different from one another; and in certain embodiments, some of those R 15 groups are the same as one another and some are different from one another. This independent selection applies to any group that is present in a compound more than once.
  • Certain compounds of the present inventions may exist as stereoisomers including, but not limited to, optical isomers.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers.
  • two diastereomers which have a different configuration at only one chiral center are referred to herein as “epimers.”
  • racemate refers to a mixture of equal parts of enantiomers.
  • the compounds of the present invention may be chiral, and it is intended that any enantiomers, as separated, pure or partially purified enantiomers or racemic mixtures thereof are included within the scope of the invention.
  • diastereomers when a double bond or a fully or partially saturated ring system or more than one center of asymmetry or a bond with restricted rotatability is present in the molecule diastereomers may be formed. It is intended that any diastereomers, as separated, pure or partially purified diastereomers or mixtures thereof are included within the scope of the invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and it is intended that any tautomeric forms, which the compounds are able to form, are included within the scope of the present invention. Thus, as one skilled in the art knows, certain aryls may exist in tautomeric forms. The invention also includes tautomers, enantiomers and other stereoisomers of the compounds of Formula I.
  • R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • the compounds of Formula I when existing as a diastereomeric mixture, may be separated into diastereomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • a suitable solvent for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • any enantiomer of a compound of Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration or through enantioselective synthesis.
  • enantiomeric enrichment refers to the increase in the amount of one enantiomer as compared to the other.
  • the ee with respect to the first enantiomer is 40%.
  • the ee with respect to the first enantiomer is 80%.
  • An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred.
  • Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column.
  • the invention provides compounds selected from:
  • a compound of Formula I is a selective H ⁇ F-4 ⁇ receptor modulator. In certain embodiments, a compound of Formula I is a selective HNF-4 ⁇ receptor agonist. In certain embodiments, a compound of Formula I is a selective HNF-4 ⁇ receptor antagonist. In certain embodiments, a compound of Formula I is a selective HNF-4 ⁇ receptor partial agonist. In certain embodiments, a compound of Formula I is a tissue-specific selective HNF-4 ⁇ receptor modulator. In certain embodiments, a compound of Formula I is a gene-specific selective HNF-4 ⁇ receptor modulator. In certain embodiments, a compound of Formula I is a selective HNF-4 ⁇ receptor binding compound.
  • the present invention provides selective HNF-4 ⁇ receptor modulators. In certain embodiments, the invention provides selective HNF-4 ⁇ receptor binding agents. In certain embodiments, the invention provides methods of making and methods of using selective HNF-4 ⁇ receptor modulators and/or selective HNF-4 ⁇ binding agents. In certain embodiments, selective HNF-4 ⁇ modulators are agonists, partial agonists, and/or antagonists for the HNF-4 ⁇ receptor. In certain embodiments, the invention provides compounds that are selective for an HNF-4 ⁇ receptor relative to a retinoic X receptor (RXR). In certain embodiments, the invention provides compounds that are selective for an HNF-4 receptor relative to an RXR by at least 8 times.
  • RXR retinoic X receptor
  • the invention provides a salt conesponding to any of the compounds provided herein.
  • the invention provides a salt corresponding to a selective HNF-4 ⁇ modulator.
  • the invention provides a salt conesponding to a selective HNF-4 ⁇ receptor binding agent.
  • a salt is obtained by reacting a compound with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as
  • compounds of the present invention comprising one or more silicon atoms possess certain desired properties, including, but not limited to, greater stability and/or longer half-life in a patient, when compared to the same compound in which none of the carbon atoms have been replaced with a silicon atom.
  • Protecting groups that may be used in the present invention include those that are commonly known to those skilled in the art, such groups include, but are not limited to TBDMS, TBS and Benzyl.
  • compounds of the present invention are capable of modulating activity of HNF-4 ⁇ receptors in a "co-transfection” assay (also called a “cis-trans” assay), which has been discussed previously. See e.g., Evans et al., Science, 240:889-95 (1988); U.S. Patent Nos. 4,981,784 and 5,071,773; Pathirana et al., Mol Pharm. 47:630-35 (1995)). Modulating activity in a co-transfection assay has been shown to conelate with in vivo modulating activity. Thus, in certain embodiments, such assays are predictive of in vivo activity. See, e.g., Berger et al, J.
  • cDNA encoding an intracellular receptor e.g., HNF-4 ⁇ receptor
  • a constitutive promoter e.g., the SV 40 promoter
  • cDNA encoding a reporter protein such as firefly luciferase (LUC)
  • LEC firefly luciferase
  • Both co-transfection plasmids are co-transfected into the same cells.
  • Expression of the first co-transfection plasmid results in production of the intracellular receptor protein.
  • Activation of that intracellular receptor protein results in production of a receptor- dependant activation factor for the promoter of the second co-transfection plasmid.
  • That receptor-dependant activation factor in turn results in expression of the reporter protein encoded on the second co-transfection plasmid.
  • reporter protein expression is linked to activation of the receptor.
  • that reporter activity can be conveniently measured (e.g., as increased luciferase production).
  • Certain co-transfection assays can be used to identify agonists, partial agonists, and/or antagonists of intracellular receptors.
  • to identify agonists co-transfected cells are exposed to a test compound. If the test compound is an agonist or partial agonist, reporter activity is expected to be higher compared to co-transfected cells in the absence of the test compound.
  • to identify antagonists the cells are exposed to a known agonist (e.g., the natural ligand for the receptor) in the presence and absence of a test compound. If the test compound is an antagonist, reporter activity is expected to be lower than that of cells exposed only to the known agonist.
  • compounds of the invention are used to detect the presence, quantity and/or state of receptors in a sample.
  • samples are obtained from a patient.
  • compounds are radio- or isotopically-labeled.
  • compounds of the present invention that selectively bind HNF-4 ⁇ receptors may be used to determine the presence or amount of such receptors in a sample, such as cell homogenates and lysates.
  • the present invention provides for use of both CARLA and mammalian-2-hybrid assays, to characterize the in vitro profile of compounds of the invention on a HNF-4 ⁇ receptor.
  • Techniques for formulation and administration of compounds of the present invention may be found for example, in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.
  • a pharmaceutical agent comprising one or more compounds of the present invention is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • a pharmaceutical agent comprising one or more compounds of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
  • a liquid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • a pharmaceutical agent comprising one or more compounds of the present invention is a solid (e.g., a powder, tablet, and/or capsule).
  • a solid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a depot preparation. Certain of such depot preparations are typically longer acting than non-depot preparations.
  • such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a delivery system.
  • delivery systems include, but are not limited to, liposomes and emulsions.
  • Certain delivery systems are useful for preparing certain pharmaceutical agents including those comprising hydrophobic compounds.
  • certain organic solvents such as dimethylsulfoxide are used.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises one or more tissue-specific delivery molecules designed to deliver the pharmaceutical agent to specific tissues or cell types.
  • pharmaceutical agents include liposomes coated with a tissue-specific antibody.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase.
  • co- solvent systems are used for hydrophobic compounds.
  • a non-limiting example of such a co-solvent system is the NPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM , and 65% w/v polyethylene glycol 300.
  • the proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a sustained-release system.
  • a non- limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months.
  • compositions used in pharmaceutical agent of the present invention may be provided as pharmaceutically acceptable salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises an active ingredient in a therapeutically effective amount.
  • the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • a phannaceutical agent comprising one or more compounds of the present invention is formulated as a prodrug.
  • prodrugs are useful because they are easier to administer than the conesponding active form.
  • a prodrug may be more bioavailable (e.g., through oral administration) than is the conesponding active form.
  • a prodrug may have improved solubility compared to the conesponding active form.
  • a prodrug is an ester.
  • such prodrugs are less water soluble than the conesponding active form.
  • such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility.
  • the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid.
  • the carboxylic acid containing compound is the conesponding active form.
  • a prodrug comprises a short peptide (polyaminoacid) bound to an acid group.
  • the peptide is metabolized to form the conesponding active form.
  • a pharmaceutical agent comprising one or more compounds of the present invention is useful for treating a conditions or disorder in a mammalian, and particularly in a human patient.
  • Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous).
  • pharmaceutical intrathecals are administered to achieve local rather than systemic exposures.
  • pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area).
  • a pharmaceutical agent comprising one or more compounds of the present invention is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.).
  • such dosage units comprise a selective a HNF-4 ⁇ receptor modulator in a dose from about 1 ⁇ g/kg of body weight to about 50 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective a HNF-4 ⁇ receptor modulator in a dose from about 2 ⁇ g/kg of body weight to about 25 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective a HNF-4 ⁇ receptor modulator in a dose from about 10 ⁇ g/kg of body weight to about 5 mg/kg of body weight. In certain embodiments, pharmaceutical agents are administered as needed, once per day, twice per day, three times per day, or four or more times per day.
  • a pharmaceutical agent comprising a compound of the present invention is prepared for oral administration.
  • a pharmaceutical agent is formulated by combining one or more compounds of the present invention with one or more pharmaceutically acceptable carriers. Certain of such carriers enable compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient.
  • pharmaceutical agents for oral use are obtained by mixing one or more compounds of the present invention and one or more solid excipient.
  • Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpy ⁇ olidone (PVP).
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical agents are formed to obtain tablets or dragee cores.
  • disintegrating agents e.g., cross-linked polyvinyl pynolidone, agar, or alginic acid or a salt thereof, such as sodium alginate
  • dragee cores are provided with coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pynolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to tablets or dragee coatings.
  • pharmaceutical agents for oral administration are push-fit capsules made of gelatin.
  • Such push-fit capsules comprise one or more compounds of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • pharmaceutical agents for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more compounds of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • pharmaceutical agents are prepared for buccal administration.
  • a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical agent comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • Certain pharmaceutical agents for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • Certain pharmaceutical agents for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical agents for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dexfran.
  • such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • a pharmaceutical agent is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • a pharmaceutical agent is prepared for administration by inhalation. Certain of such pharmaceutical agents for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer.
  • Such pharmaceutical agents comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator may be formulated.
  • Certain of such formulations comprise a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.
  • a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema.
  • a pharmaceutical agent comprises known ingredients, such as cocoa butter and/or other glycerides.
  • a pharmaceutical agent is prepared for topical administration.
  • Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams.
  • Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as EucerinTM, available from Beiersdorf (Cincinnati, Ohio).
  • Suitable cream bases include, but are not limited to, NiveaTM Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose CreamTM, available from Johnson & Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and LubridermTM, available from Pfizer (Morris Plains, New Jersey).
  • the formulation, route of administration and dosage for a pharmaceutical agent of the present invention can be chosen in view of a particular patient's condition. (See e.g., Fingl et al 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).
  • a pharmaceutical agent is administered as a single dose.
  • a pharmaceutical agent is administered as a series of two or more doses administered over one or more days.
  • a pharmaceutical agent of the present invention is administered to a patient between about 0.1% and 500%, more preferably between about 25% and 75% of an established human dosage. Where no human dosage is established, a suitable human dosage may be infened from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies.
  • a daily dosage regimen for a patient comprises an oral dose of between 0.1 mg and 2000 mg of a compound of the present invention. In certain embodiments, a daily dosage regimen is administered as a single daily dose.
  • a daily dosage regimen is administered as two, three, four, or more than four doses.
  • a pharmaceutical agent of the present invention is administered by continuous intravenous infusion. In certain of such embodiments, from 0.1 mg to 500 mg of a composition of the present invention is administered per day.
  • a pharmaceutical agent of the invention is administered for a period of continuous therapy. For example, a pharmaceutical agent of the present invention may be administered over a period of days, weeks, months, or years.
  • Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect. In certain embodiments, dosage amount and interval between doses are adjusted to maintain a desired concentration on compound in a patient.
  • dosage amount and interval between doses are adjusted to provide plasma concentration of a compound of the present invention at an amount sufficient to achieve a desired effect.
  • the plasma concentration is maintained above the minimal effective concentration (MEC).
  • pharmaceutical agents of the present invention are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time.
  • the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present invention.
  • a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • one or more pharmaceutical agents of the present invention are co-administered with one or more other pharmaceutical agents.
  • such one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical agents of the present invention.
  • such one or more other pharmaceutical agents are designed to treat a different disease or condition as the one or more pharmaceutical agents of the present invention.
  • such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical agents of the present invention.
  • one or more pharmaceutical agents of the present invention is co-administered with another pharmaceutical agent to treat an undesired effect of that other pharmaceutical agent.
  • one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the same time.
  • one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the different times.
  • one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared together in a single formulation.
  • one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared separately.
  • Examples of pharmaceutical agents that may be co-administered with a pharmaceutical agent of the present invention include, but are not limited to, analgesics (e.g., acetaminophen); anti-inflammatory agents, including, but not limited to non- steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-1 inhibitors, and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g..
  • biguanides glucosidase inhibitors, insulins, sulfonylureas, and thiazolidenediones
  • adrenergic modifiers diuretics
  • hormones e.g., anabolic steroids, androgen, estrogen, calcitonin, progestin, somatostan, and thyroid hormones
  • immunomodulators muscle relaxants; antihistamines; osteoporosis agents (e.g., biphosphonates, calcitonin, and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; poison oak or poison sumac products; antibodies; and vaccines.
  • the invention provides methods of treating a patient comprising administering one or more compounds of the present invention.
  • Compounds of the present invention including, but not limited to, pharmaceutically acceptable salts, solvates and hydrates, are expected to be effective in treating diseases or conditions that are mediated by HNF-4 ⁇ . Therefore, in certain embodiments, compounds of the invention are effective in treating conditions that are mediated by HNF-4 ⁇ , including, but not limited to, syndrome X, non-insulin dependent diabetes mellitus, cancer, obesity, cardiovascular disease and dyshpidemia.
  • a patient is treated prophylactically to reduce or prevent the occunence of a condition.
  • the present invention provides a method of lowering blood glucose levels in a mammal by administering to the patient a pharmaceutically effective amount of at least one compound of the present invention.
  • the patient is a mammal.
  • the patient is a human.
  • the present invention provides a method of lowering plasma triglycerides levels in a patient by administering to the mammal a pha ⁇ naceutically effective amount of at least one compound of the present invention.
  • the patient is a mammal.
  • the patient is a human.
  • the present invention provides a method of increasing insulin levels in a patient by administering to the mammal a pharmaceutically effective amount of at least one compound of the present invention.
  • the patient is a mammal.
  • the patient is a human.
  • Compound 25 was synthesized according to the procedure described in Example 1 using 4-hydroxyphenyl acetic acid and 3-bromomethyl-5,6J,8-tetrahydro- 5,5,8,8-tetramethylnaphtalene as alkylating reagent.
  • Biphenyl-2-yl-methanol (0.359g, 1.89 mmol), (4-Hydroxy-phenoxy)- acetic acid methyl ester (0.344 g, 1.89 mmol), triphenylphosphine (0.991 g, 3.77 mmol) and DEAD (0.647g, 3J8 mmol) are dissolved in THF (6.8 mL) and stined for 16 hours.
  • the reaction is acidified with .1 N HCl and extracted with ethyl acetate and washed with brine and dried over sodium sulfate. The organic layer is filtered and concentration gives an oil.
  • the reaction is partitioned between dichloromethane and water.
  • the organic layer is washed with brine and dried over sodium sulfate .
  • the organic layer is filtered and concenfration under reduced pressure yields a beige solid.
  • The. solid is stined with diethyl ether and the solid is filtered off to give the title compound. (1.17 g, 65 % yield) mass spectrum (m/e) 360.0(M+1).
  • the reaction is washed with brine and dried over sodium sulfate.
  • the reaction is filtered and the organics are removed under reduced pressure to obtain an oil.
  • the oil is flash columned using hexane : ethyl acetate (95:5) and gradually increasing the polarity with hexane : ethyl acetate (90 : 10) to give the title compound (1.78 g, 94 % yield).
  • E-4-(2-Biphenyl-2-yl-vinyl)-benzoic acid methyl ester (0.160g, 0.509 mmol) is dissolved in THF(2 L) and lithium hydroxide (0.036 g,l .52 mmol dissolved in water (1 mL) is added and the reaction is heated at 55° C.
  • the reaction is acidified with 1 ⁇ HCl and is extracted with ethyl acetate.
  • the organic layers are washed with brine and dried over sodium sulfate.
  • the organic layer is filtered and concentration under reduced pressure gives the title compound .
  • mass spectrum (m/e) 299.2 (M-1)
  • CN-1 cells African green monkey kidney fibroblasts
  • DMEM Dulbecco's Modified Eagle Medium
  • CH-FBS charcoal resin-stripped fetal bovine serum
  • the CV-1 cells were transiently transfected by FuGENE 6 transfection reagent in 175 cm2 flask with the following plasmids: pCMX- HNF-4 ⁇ DF (3ug/flask), apoAl-LUC reporter (lug/flask), and filler DNA (pcDNA; 3ug/flask).
  • the receptor plasmid, pCMX-HNF-4 ⁇ DF contains the rat HNF-4 ⁇ l under constitutive control of the CMV promoter, as-more fully described in J.D. Fraser et al, "DNA binding and transcription activation specificity of hepatocyte nuclear factor
  • the reporter plasmid contains the cDNA for firefly luciferase (LUC) under control of a multimerized HNF-4 ⁇ response element (the A site from the apo Al promoter) linked to the TK minimal promoter. See e.g., Fraser et al. supra. Twenty four after transfection the cells are harvested and plated in 96 well plates at 10,000 cells/well. Media containing one of the modulator compounds of the present
  • LGO 100695 has the following structure:
  • Antagonist activity was determined by testing the amount of LUC expression in the presence of no exogenous compound (just the endogenous ligand) as HNF-4 ⁇ receptor agonist. The concentration of a test compound that inhibited 50% of LUC expression was quantified (IC50). In addition, the efficacy of antagonists was determined as a function (%) of
  • HNF-4 ⁇ receptor modulator compounds of present invention Agonist, partial agonist, antagonist activity of HNF-4 ⁇ receptor modulator compounds of present invention. Efficacy (%) for HNF-4 ⁇ agonist was determined by comparing activity (e.g., luciferase production) of putative agonist to that LGO 100695. Efficacy (%) for HNF-4 ⁇ antagonist was determined by the percentage amount by which the luciferase production is reduced (maximum concentration of antagonist) from the luciferase production without compound.
  • the present invention includes any combination of the various species and subgeneric groupings falling within the generic disclosure. This invention therefore includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.
  • description of the various embodiments and processing conditions have been provided, the scope of the invention is not to be limited thereto or thereby. Modifications and alterations of the present, invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. [0284] Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific examples which have been presented merely to illustrate certain embodiments of the present invention.

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Abstract

L'invention se rapporte à des composés qui modulent les récepteurs du facteur nucléaire hépatocyte 4α (HNF-4α). Cette invention concerne également des compositions pharmaceutiques contenant lesdits composés, ainsi que des procédés pour utiliser les composés et compositions pharmaceutiques pour moduler les récepteurs du facteur HNF-4α ainsi que des processus dont la médiation est assurée par les récepteurs du facteur HNF-4α. La présente invention concerne en outre des procédés pour produire les composés et compositions pharmaceutiques, ainsi que des produits intermédiaires utilisés pour les synthétiser.
PCT/US2004/023788 2003-07-16 2004-07-16 Derives d'acide benzoique et phenylacetique utilises en tant que modulateurs des recepteurs du facteur hnf-4$g(a) WO2005009104A2 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1559422A1 (fr) * 2002-11-08 2005-08-03 Takeda Pharmaceutical Company Limited Agent de controle de la fonction recepteur
WO2005094810A2 (fr) * 2004-03-05 2005-10-13 Karo Bio Ab Nouvelles compositions pharmaceutiques
WO2010127264A3 (fr) * 2009-04-30 2010-12-23 Burnham Institute For Medical Research Antagonistes de hnf4α et procédés d'utilisation
WO2010127246A3 (fr) * 2009-04-30 2010-12-29 Burnham Institute For Medical Research Modulateurs de hnf4 et procédés d'utilisation
JP2012512893A (ja) * 2008-12-18 2012-06-07 メタボレックス， インコーポレイテッド Ｇｐｒ１２０受容体作動薬およびその使用
WO2012079154A1 (fr) * 2010-12-14 2012-06-21 Dalhousie University Modulateurs sélectifs des récepteurs des oestrogènes
JP2013544799A (ja) * 2010-10-27 2013-12-19 プロメティック・バイオサイエンシーズ・インコーポレイテッド がん治療のための化合物および組成物
JP2016017037A (ja) * 2014-07-04 2016-02-01 国立大学法人 東京大学 脂肪酸サロゲートを含むリゾホスファチジルセリン誘導体
EP3253745A4 (fr) * 2015-02-05 2018-06-27 Piramal Enterprises Limited Composés contenant une séquence de liaison carbone-carbone en tant qu'agonistes gpr120

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU8750298A (en) * 1997-08-28 1999-03-22 Ono Pharmaceutical Co. Ltd. Peroxisome proliferator-activated receptor controllers
GB0031109D0 (en) * 2000-12-20 2001-01-31 Glaxo Group Ltd Chemical compounds
NZ529351A (en) * 2001-06-07 2006-01-27 Lilly Co Eli Modulators of peroxisome proliferator activated receptors

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [Online] 11 March 1999 TAJIMA ET AL: 'Preparation of phenylalkanoic acid derivatives as peroxisome profilerator-activated receptor controllers', XP002994321 Database accession no. (1999:184126) & WO 99 11255 A1 *
DATABASE CAPLUS [Online] 19 December 2002 BROOKS ET AL: 'Preparation of substituted 3-phenyl1-2alkoxypropanic acids and analogs as modulators or peroxisome profilerator activated receptors for treatment of daibetes and related conditions', XP002994320 Database accession no. (2002:964313) & WO 02 100813 A2 *
DATABASE CAPLUS [Online] 27 June 2002 BESWICK ET AL: 'Thia-and oxazoles and their use as hPPAR delta agonists', XP002994319 Database accession no. (2002:487541) & WO 02 50048 A1 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7960369B2 (en) 2002-11-08 2011-06-14 Takeda Pharmaceutical Company Limited Receptor function regulator
EP1559422A4 (fr) * 2002-11-08 2010-02-24 Takeda Pharmaceutical Agent de controle de la fonction recepteur
EP1559422A1 (fr) * 2002-11-08 2005-08-03 Takeda Pharmaceutical Company Limited Agent de controle de la fonction recepteur
EP2385032A1 (fr) * 2002-11-08 2011-11-09 Takeda Pharmaceutical Company Limited Régulateur de fonction de récepteur GPR40
WO2005094810A2 (fr) * 2004-03-05 2005-10-13 Karo Bio Ab Nouvelles compositions pharmaceutiques
WO2005094810A3 (fr) * 2004-03-05 2006-01-12 Karobio Ab Nouvelles compositions pharmaceutiques
JP2012512893A (ja) * 2008-12-18 2012-06-07 メタボレックス， インコーポレイテッド Ｇｐｒ１２０受容体作動薬およびその使用
WO2010127264A3 (fr) * 2009-04-30 2010-12-23 Burnham Institute For Medical Research Antagonistes de hnf4α et procédés d'utilisation
WO2010127246A3 (fr) * 2009-04-30 2010-12-29 Burnham Institute For Medical Research Modulateurs de hnf4 et procédés d'utilisation
JP2013544799A (ja) * 2010-10-27 2013-12-19 プロメティック・バイオサイエンシーズ・インコーポレイテッド がん治療のための化合物および組成物
WO2012079154A1 (fr) * 2010-12-14 2012-06-21 Dalhousie University Modulateurs sélectifs des récepteurs des oestrogènes
JP2016017037A (ja) * 2014-07-04 2016-02-01 国立大学法人 東京大学 脂肪酸サロゲートを含むリゾホスファチジルセリン誘導体
EP3253745A4 (fr) * 2015-02-05 2018-06-27 Piramal Enterprises Limited Composés contenant une séquence de liaison carbone-carbone en tant qu'agonistes gpr120

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