WO2012178142A1 - Composés épargnant les ppar et combinaisons pour le traitement du diabète et d'autres maladies métaboliques - Google Patents

Composés épargnant les ppar et combinaisons pour le traitement du diabète et d'autres maladies métaboliques Download PDF

Info

Publication number
WO2012178142A1
WO2012178142A1 PCT/US2012/043926 US2012043926W WO2012178142A1 WO 2012178142 A1 WO2012178142 A1 WO 2012178142A1 US 2012043926 W US2012043926 W US 2012043926W WO 2012178142 A1 WO2012178142 A1 WO 2012178142A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen
alkyl
compound
optionally substituted
alkoxy
Prior art date
Application number
PCT/US2012/043926
Other languages
English (en)
Inventor
Gerard R. Colca
Steven P. Tanis
Scott D. Larsen
Original Assignee
Metabolic Solutions Development Company, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Metabolic Solutions Development Company, Llc filed Critical Metabolic Solutions Development Company, Llc
Publication of WO2012178142A1 publication Critical patent/WO2012178142A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring

Definitions

  • the present invention provides indole compounds, analogs thereof, and
  • compositions containing such compounds for use in treating and/or preventing diabetes or other metabolic disease states (e.g., obesity and dyslipidemia).
  • diabetes or other metabolic disease states e.g., obesity and dyslipidemia.
  • PPARs Peroxisome Proliferator Activated Receptors
  • PPARs are members of the nuclear hormone receptor super family that are ligand-activated transcription factors regulating gene expression. PPARs have been implicated in autoimmune diseases and other diseases, i.e. diabetes mellitus, cardiovascular and gastrointestinal disease, and Alzheimer's disease.
  • PPARy is a key regulator of adipocyte differentiation and lipid metabolism. PPARy is also found in other cell types including fibroblasts, myocytes, breast cells, human bone- marrow precursors, and macrophages/monocytes. In addition, PPARy has been shown in macrophage foam cells in atherosclerotic plaques.
  • Thiazolidinedione compounds developed originally for the treatment of type-2 diabetes, generally exhibit high-affinity as PPARy ligands. The finding that
  • thiazolidinediones might mediate their therapeutic effects through direct interactions with PPARy helped to establish the concept that PPARy is a key regulator of glucose and lipid homeostasis.
  • compounds that involve the activation of PPARy also trigger sodium reabsorption and other unpleasant side effects.
  • Brown adipose tissue (BAT) is responsible for cold- and diet-induced thermogenesis that significantly contributes to the control of body temperature and energy expenditure.
  • the present invention relates to compounds that have reduced binding and/or activation of the nuclear transcription factor PPARy. Contrary to the teachings of the literature, PPARy sparing compounds of the present invention are able to stimulate the differentiation of BAT and increase the amount of UCP1 protein.
  • the compounds of this invention have reduced binding and/or activation of the nuclear transcription factor PPARy, do not augment sodium re-absorption, and are useful in treating or preventing diabetes and other metabolic diseases such as obesity or dyslipidemia.
  • the compounds having lower PPARy activity exhibit fewer side effects than compounds having higher levels of PPARy activity.
  • these compounds are particularly useful for treating and/or preventing diabetes and other metabolic diseases both as a single therapeutic agent or in combination with other agents that affect cellular cyclic nucleotide levels including phosphodiesterase inhibitors, adrenergic agonists, or various hormones.
  • the present invention provides a compound of Formula I:
  • R a and R is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or R la and R lb taken together form oxo;
  • X 1 is -O- or -CH2-, or -CH-;
  • imm is a single bond or a double bond when X 1 is -CH- and one of R la and R lb is absent;
  • Ring A is selected from
  • R is selected from hydrogen or C1-3 alkyl
  • R J is selected from hydrogen, C 1-3 alkyl optionally substituted with 1-3 halo, or C1.3 alkoxy optionally substituted with 1-3 halo
  • R 4 is -Z A R A wherein Z A is independently selected from a bond, a C1.3 alkylidene chain, or -C(O)-; and R A is selected from hydrogen, C 1-3 alkyl, or phenyl optionally substituted with C1-3 alkyl or C1.3 alkoxy.
  • R 2 is selected from hydrogen, methyl, or ethyl.
  • R is hydrogen. In other examples, R is methyl.
  • R 3 is Q.3 alkoxy optionally substituted with 1-3 halo.
  • R 3 is -OCH 3 or -OCF 3 .
  • R 4 is -Z A R A , wherein Z A is independently selected from a bond or -C(O)-; and R A is selected from hydrogen, C1.3 alkyl, or phenyl optionally substituted with C1.3 alkyl or C1.3 alkoxy.
  • R 4 is -Z A R A , wherein Z A is independently selected from a bond or -C(O)-; and R A is selected from hydrogen, d-3 alkyl, or phenyl substituted with -OCH 3 or -OCH 2 CH 3 .
  • R 4 is hydrogen, -C3 ⁇ 4, -CH 2 CH 3 , or -C(0)-CH 3 .
  • R 4 is -Z A R A , wherein Z A is -C(O)-; and R A is phenyl optionally substituted with Q-3 alkyl or d-3 alkoxy.
  • R 4 is -Z A R A , wherein Z A is -C(0)-; and R A is phenyl substituted at its para position with C 1-3 alkyl or C ⁇ alkoxy.
  • R 2 is selected from hydrogen, methyl, or ethyl.
  • R 2 is hydrogen. In other examples, R 2 is methyl.
  • R is C 1.3 alkoxy optionally substituted with 1-3 halo.
  • R 3 is -OCH 3 or -OCF 3 .
  • R la and R lb is hydrogen and the other is selected from hydrogen, -CH 3 , -CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 .
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, as described above, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a second active pharmaceutical ingredient.
  • the pharmaceutical composition further comprises a dipeptidyl peptidase IV (DPP-4) inhibitor, e.g., sitagliptin, vildagliptin, or the like;
  • HMG-CoA reductase inhibitor e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof; GLP-1 or -2 agonists; or any combination thereof.
  • statin e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof; GLP-1 or -2 agonists; or any combination thereof.
  • Another aspect of the present invention provides a method of treating or reducing the symptoms of diabetes comprising administering to a patient a compound of Formula I or a pharmaceutical composition, as described above.
  • Another aspect of the present invention provides a method of treating or delaying the onset of obesity comprising administering to a patient a compound of Formula I or a pharmaceutical composition, as described above.
  • the obesity being treated is central obesity.
  • Some implementations of this method further comprise restricting the diet of the patient, performing additional physical exercise, or any combination thereof.
  • Another aspect of the present invention provides a method of treating or reducing the symptoms of dyslipidemia comprising administering to a patient a compound of Formula I or a pharmaceutical composition, as described above.
  • the present invention provides novel PPARy-sparing compounds
  • the present invention provides a compound of Formula I:
  • R la and R lb is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or R la and R lb taken together form oxo;
  • X 1 is -O- or -CH 2 -, or -CH-; is a single bond or a double bond when X 1 is -CH- and one of R 1
  • R 4 is -Z A R A wherein Z A is independently selected from a bond, a Ci -3 alkylidene chain, or -C(O)-; and R A is selected from hydrogen, alkyl, or phenyl optionally substituted with C 1-3 alkyl or Ci. 3 alkoxy.
  • PPARy-sparing compounds of the present invention effectively stimulate BAT stores, and are useful for treating obesity and other metabolic diseases such as diabetes.
  • compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • aliphatic encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.
  • an "alkyl” group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 1-3, 1-8, 1-6, or 1-4) carbon atoms.
  • An alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl.
  • An alkyl group can be substituted (i.e., optionally substituted) with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
  • substituents such as halo, phospho, cycloaliphatic [e.g., cycloalky
  • heterocycloalkylalkyl carbonylamino
  • heteroarylcarbonylamino heteroarylcarbonylamino
  • amino e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino
  • sulfonyl e.g.,
  • substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-S0 2 -amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.
  • carboxyalkyl such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl
  • cyanoalkyl hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (al
  • an "alkenyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be straight or branched. Examples of an alkenyl group include, but are not limited to allyl, isoprenyl, 2-butenyl, and 2-hexenyl.
  • alkenyl group can be optionally substituted with one or more substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or
  • heterocycloalkenyl aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,
  • heteroarylcarbonylamino heteroaralkylcarbonylamino alkylaminocarbonyl
  • heteroarylaminocarbonyl amino [e.g., aliphaticamino, cycloaliphaticamino,
  • heterocycloaliphaticamino or aliphaticsulfonylamino
  • sulfonyl e.g.,
  • substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl,
  • an "alkynyl” group refers to an aliphatic carbon group that contains 2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has at least one triple bond.
  • An alkynyl group can be straight or branched. Examples of an alkynyl group include, but are not limited to, propargyl and butynyl.
  • An alkynyl group can be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanyl or cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl or cycloaliphaticsulfinyl], sulfonyl [e.g., aliphatic-SC>2-, aliphaticamino-S0 2 -, or
  • cycloaliphatic-S02-] amido e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino,
  • heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl urea, thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic)carbonyl or
  • heterocycloaliphatic carbonyl
  • amino e.g., aliphaticamino
  • sulfoxy e.g., sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.
  • an “amido” encompasses both “aminocarbonyl” and
  • carbonylamino when used alone or in connection with another group refer to an amido group such as -N(R x )-C(0)-R Y or -C(0)-N(R x ) 2 , when used terminally, and -C(0)-N(R x )- or -N(R x )-C(0)- when used internally, wherein R x and R Y can be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic.
  • amido groups examples include alkylamido (such as alkylcarbonylamino or
  • alkylaminocarbonyl (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.
  • an "amino" group refers to -NR X R Y wherein each of R x and R Y is independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,
  • amino groups include alkylamino, dialkylamino, or arylamino.
  • amino is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NR X -.
  • R x has the same meaning as defined above.
  • aralkyl refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in a bicyclic or tricyclic ring system is aromatic.
  • the bicyclic and tricyclic groups include benzo fused 2-3 membered carbocyclic rings.
  • a benzofused group includes phenyl fused with two or more C4.8 carbocyclic moieties.
  • An aryl is optionally substituted with one or more substituents including aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic; heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
  • cycloaliphatic)oxy (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., (aliphatic)carbonyl; (cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;
  • sulfonyl e.g., aliphatic-S0 2 - or amino-S0 2 -
  • sulfinyl e.g., aliphatic-S(O)- or cycloaliphatic-S(O)-
  • sulfanyl e.g., aliphatic-S-]
  • cyano halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl.
  • an aryl can be unsubstituted.
  • Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl,
  • aminocarbonyl)aryl (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g.,
  • (sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;
  • an "araliphatic” such as an "aralkyl” group refers to an aliphatic group (e.g., a C M alkyl group) that is substituted with an aryl group.
  • "Aliphatic,” “alkyl,” and “aryl” are defined herein.
  • An example of an araliphatic such as an aralkyl group is benzyl.
  • an "aralkyl” group refers to an alkyl group (e.g., a C alkyl group) that is substituted with an aryl group. Both “alkyl” and “aryl” have been defined above.
  • An example of an aralkyl group is benzyl.
  • An aralkyl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
  • substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g., cyclo
  • heteroaralkyloxy aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
  • heteroarylcarbonylamino or heteroaralkylcarbonylamino] cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • a "bicyclic ring system” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common).
  • Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.
  • a "cycloaliphatic” group encompasses a “cycloalkyl” group and a “cycloalkenyl” group, each of which being optionally substituted as set forth below.
  • a "cycloalkyl” group refers to a saturated carbocyclic mono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,
  • bicyclo[2.2.2]octyl bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.
  • a "cycloalkenyl” group refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds.
  • Examples of cycloalkenyl groups include cyclopentenyl, 1 ,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1 ]nonenyl.
  • a cycloalkyl or cycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic,
  • sulfonyl e.g., alkyl-S0 2 - and aryl-S0 2 -
  • sulfinyl e.g.
  • heterocycloaliphatic encompasses a heterocycloalkyl group and a heterocycloalkenyl group, each of which being optionally substituted as set forth below.
  • heterocycloalkyl refers to a 3-10 membered mono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic) saturated ring structure, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof).
  • heterocycloalkyl group examples include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1 ,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1 -aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-d
  • heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be categorized as heteroaryls.
  • a "heterocycloalkenyl” group refers to a mono- or bicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structure having one or more double bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, O, or S).
  • a heterocycloalkyl or heterocycloalkenyl group can be optionally substituted with one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
  • substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
  • heteroaryloxy e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)
  • heterocycloaliphaticcarbonylamino ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino] nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl,
  • sulfonyl e.g., alkylsulfonyl or arylsulfonyl
  • sulfinyl
  • a “heteroaryl” group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof) and in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring systems is aromatic.
  • a heteroaryl group includes a benzofused ring system having 2 to 3 rings.
  • a benzofused group includes benzo fused with one or two 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[6]furyl, benzo[6]thiophenyl, quinolinyl, or isoquinolinyl).
  • heterocycloaliphatic moieties e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[6]furyl, benzo[6]thiophenyl, quinolinyl, or isoquinolinyl.
  • heteroaryl examples include azetidinyl, pyridyl, lH-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[l,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-l,2,5-thiadiazolyl
  • monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
  • 1,3,4-thiadiazolyl 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.
  • Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
  • bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[6]furyl, benzo[6]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[6]furyl, bexo[6]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.
  • Bicyclic heteroaryls are numbered according to standard chemical nomenclature.
  • a heteroaryl is optionally substituted with one or more substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;
  • heterocycloaliphatic (heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;
  • heterocycloaliphatic aliphatic
  • carbonyl or (heteroaraliphatic)carbonyl]
  • sulfonyl e.g., aliphaticsulfonyl or aminosulfonyl
  • sulfinyl e.g., aliphaticsulfinyl
  • sulfanyl e.g., aliphaticsulfanyl
  • a heteroaryl can be unsubstituted.
  • Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl];
  • aminoheteroaryl e.g., ((alkylsulfonyl)amino)heteroaryl and
  • alkylsulfonyl heteroaryl
  • hydroxyalkyl heteroaryl
  • alkoxyalkyl heteroaryl
  • heterocycloaliphatic heteroaryl
  • cycloaliphatic heteroaryl
  • nitrogenalkyl heteroaryl
  • heteroalkyl (cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl, and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].
  • heteroaryl group refers to an alkyl group (e.g., a C 1-4 alkyl group) that is substituted with a heteroaryl group. Both “alkyl” and “heteroaryl” have been defined above.
  • a heteroaralkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,
  • substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (he
  • alkylcarbonyloxy aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino
  • heteroarylcarbonylamino heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • cyclic moiety and “cyclic group” refer to mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which has been previously defined.
  • bridged bicyclic ring system refers to a bicyclic
  • bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, l-azabicyclo[2.2.2]octyl, 3- azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0 3 ' 7 ]nonyl.
  • a bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,
  • substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycl
  • heteroaralkyloxy aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
  • an "acyl” group refers to a formyl group or R x -C(0)- (such as alkyl-C(O)-, also referred to as "alkylcarbonyl”) where R x and "alkyl" have been defined previously.
  • Acetyl and pivaloyl are examples of acyl groups.
  • an “aroyl” or “heteroaroyl” refers to an aryl-C(O)- or a
  • heteroaryl-C(O)- respectively.
  • the aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
  • alkoxy refers to an alkyl-O- group where “alkyl” has been defined previously.
  • a “carbamoyl” group refers to a group having the structure
  • R x and R Y have been defined above and R z can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
  • a "carboxy” group refers to -COOH, -COOR x , -OC(0)H,
  • haloaliphatic refers to an aliphatic group substituted with 1-3 halogen.
  • haloalkyl includes the group -CF 3 .
  • mercapto refers to -SH.
  • a "sulfo" group refers to -SO3H or -S0 3 R when used terminally or -S(0) 3 - when used internally.
  • sulfamide refers to the structure -NR x -S(0) 2 -NR Y R z when
  • a "sulfamoyl” group refers to the structure -0-S(0) 2 -NR R wherein R and R have been defined above.
  • a "sulfonamide” group refers to the structure -S(0) 2 -NR R or -NR x -S(0) 2 -R z when used terminally; or -S(0) 2 -NR x - or -NR X -S(0) 2 - when used internally, wherein R x , R Y , and R z are defined above.
  • sulfanyl group refers to -S-R x when used terminally and -S- when used internally, wherein R x has been defined above.
  • sulfanyls include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like.
  • a "sulfinyl” group refers to -S(0)-R when used terminally and -S(O)- when used internally, wherein R x has been defined above.
  • exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(0)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like.
  • a "sulfonyl” group refers to-S(0) 2 -R x when used terminally and -S(0) 2 - when used internally, wherein R x has been defined above.
  • exemplary sulfonyl groups include aliphatic-S(0)2-, aryl-S(0) 2 -, (cycloaliphatic(aliphatic))-S(0) 2 -,
  • a "sulfoxy" group refers to -0-SO-R x or -SO-0-R x , when used terminally and -O-S(O)- or -S(0)-0- when used internally, where R x has been defined above.
  • halogen or halo group refers to fluorine, chlorine, bromine or iodine.
  • alkoxycarbonyl which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as alkyl-O-C(O)-.
  • alkoxyalkyl refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.
  • phospho refers to phosphinates and phosphonates.
  • phosphinates and phosphonates include -P(0)(R p ) 2 , wherein R p is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino.
  • aminoalkyl refers to the structure (R x ) 2 N-alkyl-.
  • cyanoalkyl refers to the structure (NC)-alkyl-.
  • urea refers to the structure -NR x -CO-NR Y R z and a
  • thiourea refers to the structure -NR X -CS-NR Y R Z when used terminally and
  • the term “vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
  • the term “geminal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.
  • terminal refers to the location of a group within a substituent.
  • a group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure.
  • Carboxyalkyl i.e., R x O(0)C-alkyl is an example of a carboxy group used terminally.
  • a group is internal when the group is present in the middle of a substituent of the chemical structure.
  • Alkylcarboxy e.g., alkyl-C(0)0- or alkyl-OC(O)-
  • alkylcarboxyaryl e.g., alkyl-C(0)0-aryl- or alkyl-O(CO)-aryl-
  • carboxy groups used internally are examples of carboxy groups used internally.
  • an "aliphatic chain” refers to a branched or straight aliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).
  • a straight aliphatic chain has the structure -[ ⁇ 1 ⁇ 2] ⁇ -, where v is 1-12.
  • a branched aliphatic chain is a straight aliphatic chain that is substituted with one or more aliphatic groups.
  • a branched aliphatic chain has the structure -[CQQ] V - where Q is independently a hydrogen or an aliphatic group; however, Q shall be an aliphatic group in at least one instance.
  • the term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.
  • variables R la , R lb , R 2a , R b , R 3 , R 4 , and other variables contained in Formula I, described herein encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables R la , R lb , R 2a , R 2b , R 3 , R 4 , and other variables contained therein can be optionally substituted with one or more substituents described herein.
  • Each substituent of a specific group is further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl.
  • an alkyl group can be substituted with alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl.
  • the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl.
  • the two alkoxy groups can form a ring together with the atom(s) to which they are bound.
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • Specific substituents are described above in the definitions and below in the description of compounds and examples thereof.
  • an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • a ring substituent such as a heterocycloalkyl
  • substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
  • stable or chemically feasible refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • an "effective amount” is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy
  • patient refers to a mammal, including a human.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers
  • stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C- enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.
  • an "adrenergic agonist” refers to any compound having agonistic activity toward any adrenergic receptor (e.g., ⁇ , ⁇ 2 , ⁇ 3 ).
  • adrenergic receptor e.g., ⁇ , ⁇ 2 , ⁇ 3
  • This usage also applies to subtypes of beta agonists, (e.g., 'beta- 1 -adrenergic agonist' is used interchangeable with ' ⁇ - adrenergic agonist' and/or ' agonist').
  • the term "delaying the onset" of a disease refers to a delay of symptoms of a disease, wherein the delay caused by the administration of a therapeutic agent (e.g., compound or pharmaceutical composition).
  • a therapeutic agent e.g., compound or pharmaceutical composition.
  • the delay of symptoms need not last for the duration of the patient's life, although the delay may last for this duration.
  • Compounds of the present invention possess a reduced interaction with PPARy and are uniquely effective in treating, preventing, or reducing the symptoms of diabetes and/or other metabolic diseases such as obesity and dyslipidemia.
  • R la and R lb is independently selected from hydrogen, -OH, C alkyl optionally substituted with 1-3 halo, or C alkoxy optionally substituted with 1-3 halo, or R la and R lb taken together form oxo;
  • X 1 is -O- or
  • -CE-2- or -CH-; is a single bond or a double bond when X 1 is -CH- and one of R la and R lb is absent; ring A is selected from
  • R 2 is selected from hydrogen or C 1-3 alkyl
  • R 3 is selected from hydrogen, C 1-3 alkyl optionally substituted with 1-3 halo, or C 1-3 alkoxy optionally substituted with 1-3 halo
  • R 4 is -Z A R A wherein Z A is independently selected from a bond, a C 1-3 alkylidene chain, or -C(O)-; and R A is selected from hydrogen, C 1-3 alkyl, or phenyl optionally substituted with C 1-3 alkyl or C 1-3 alkoxy.
  • ring A is
  • R 3 is C 1-3 alkoxy optionally substituted with 1-3 halo.
  • R 3 is -OCH 3 or -OCF 3 .
  • R 4 is -Z A R A , wherein Z A is independently selected from a bond or -C(O)-; and R A is selected from hydrogen, C 1-3 alkyl, or phenyl optionally substituted with C 1-3 alkyl or C 1-3 alkoxy.
  • R 4 is -Z A R A , wherein Z A is independently selected from a bond or -C(O)-; and R A is selected from hydrogen, Ci -3 alkyl, or phenyl substituted with -OCH 3 or -OCH 2 CH 3 .
  • R 4 is hydrogen, -CH 3 , -CH 2 CH 3 , or -C(0)-CH 3 .
  • R 4 is -Z A R A , wherein Z A is -C(O)-; and R A is phenyl optionally substituted with Ci -3 alkyl or C 1-3 alkoxy.
  • R 4 is -Z A R A , wherein Z A is -C(O)-; and R A is phenyl substituted at its para position with C 1-3 alkyl or C1.3 alkoxy.
  • R is selected from hydrogen, methyl, or ethyl.
  • R 2 is hydrogen. In other examples, R 2 is methyl.
  • R is Cu 3 alkoxy optionally substituted with 1-3 halo.
  • R 3 is -OCH 3 or -OCF3.
  • R la and R lb is hydrogen and the other is selected from hydrogen, -CH 3 , -CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 .
  • the compound of Formula I is selected from a compound of Formul
  • X la is -O- or -CH 2 - and each of R la , R lb , R 2 , and R 4 , are defined above.
  • the compound of Formula I is selected from a compound of
  • X la is -O- or -CH 2 - and each of R la , R 2 , and R 4 , are defined above.
  • Examples of compounds of Formula I include those provided in Table A: Table A: Exemplary compounds of Formula I.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein each of R la and R lb is independently selected from hydrogen, -OH, C 1 -4 alkyl optionally substituted with 1-3 halo, or CM alkoxy optionally substituted with 1-3 halo, or R la and R lb taken together form oxo;
  • X 1 is -O- or -CH2-, or -CH-;
  • mrm is a single bond or a double bond when X 1 is -CH- and one of R la and R is absent;
  • R 2 is selected from hydrogen or Cu alkyl
  • R 3 is selected from hydrogen, C1.3 alkyl optionally substituted with 1-3 halo, or C 1-3 alkoxy optionally substituted with 1-3 halo
  • R 4 is -Z A R A wherein Z A is independently selected from a bond, a C 1-3 alkylidene chain, or -C(O)-; and R A is selected from hydrogen, C 1-3 alkyl, or phenyl optionally substituted with C1.3 alkyl or C 1.3 alkoxy, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a compound of Formula IIA, IIB, IV A, or IVB, wherein said compound has a purity of about 70 e.e. % or more.
  • the pharmaceutical composition comprises a compound of Formula IIA, IIB, IVA, or IVB, wherein the compound has a purity of about 80 % e.e. or more (e.g., 90 % e.e. or more, 95 % e.e. or more, 97 % e.e. or more, or 99 % e.e. or more).
  • compositions of the present invention can also comprise one or more additional pharmaceutical agents or other drugs.
  • the pharmaceutical composition further comprises a diuretic, such as hydrochlorothiazide, chlorothaladone, chlorothiazide, or combinations thereof.
  • the pharmaceutical composition further comprises one or more agents that limit the activity of the rennin- angiotensin system such as angiotensin concerting enzyme inhibitors, i.e., ACE inhibitors, e.g.
  • the pharmaceutical composition further comprises a compound that limits hypertension by alternate means including ⁇ -adrenergic receptor blockers, and calcium channel blockers, e.g., amlodipine.
  • the pharmaceutical composition further comprises one or more statins, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof.
  • statins i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof.
  • the pharmaceutical composition further comprises a GLP analogue and/or a DPP4 inhibitor.
  • the pharmaceutical composition further comprises a phosphodiesterase inhibitor in combination with a beta-adrenergic agonist and at least one additional weight loss drug.
  • weight loss drugs include appetite suppressants (e.g., Meridia, or the like), fat absorption inhibitors (e.g., Xenical, or the like), or compounds that augment sympathomimetic activity such as ephedrine or its various salts.
  • compositions according to the present invention include a single unit dosage form having about 1 mg to about 200 mg of a compound of Formula I, e.g., between about 10 mg to about 120 mg, between about 10 mg to about 100 mg, or about 15 mg to about 60 mg.
  • Another aspect of the present invention provides a method of treating, preventing, or reducing the symptoms of diabetes comprising administering to a patient a compound of Formula I or a pharmaceutical composition as described herein.
  • Another aspect of the present invention provides a method for inducing remission of the symptoms of diabetes mellitus in a patient comprising administering to the patient a compound of Formula I or a pharmaceutical composition as described herein.
  • the present invention also provides methods of treating or delaying the onset, i.e., preventing, of diabetes mellitus in a patient comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt), and administering a GLP analogue.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof e.g., an alkali earth metal salt
  • the administration of the compound of Formula I can occur prior to, after, or concurrent with the administration of the GLP analogue.
  • the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a GLP analogue, wherein the administration further comprises administering a compound of Formula I prior to administering a GLP analogue.
  • a pharmaceutically acceptable salt thereof e.g., an alkali earth metal salt
  • the administration of the compound of Formula I although beginning prior to the administration of the GLP analogue, continues for at least some duration of time wherein the GLP analogue is co-administered.
  • the administration of the compound of Formula I ceases once the administration of a GLP analogue begins.
  • the administration of the compound of Formula I begins prior to the administration of a GLP analogue and continues for at least the duration of time in which the GLP analogue is administered.
  • the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a GLP analogue, wherein the administration further comprises administering a compound or compound salt of Formula I concurrently with the administering of a GLP analogue.
  • a pharmaceutically acceptable salt thereof e.g., an alkali earth metal salt
  • the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a GLP analogue, wherein the administration further comprises administering a compound of Formula I after administering a GLP analogue.
  • a pharmaceutically acceptable salt thereof e.g., an alkali earth metal salt
  • the administration of the compound of Formula I although starting after the administration of the GLP analogue, continues for at least some duration of time wherein the GLP analogue is co-administered.
  • the administration of the GLP analogue ceases once the administration of a compound of Formula I begins.
  • the administration of GLP analogue begins prior to the administration of the compound of Formula I GLP analogue and continues for at least the duration of time in which the compound of Formula I is administered.
  • the present invention also provides methods of treating or preventing diabetes mellitus in a patient comprising administering a compound of Formula I or a
  • compositions or compounds of Formula I can occur prior to, after, or concurrent with the administration of the DPP4 inhibitor.
  • the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a DPP4 inhibitor, wherein the administration further comprises administering a compound or compound salt of Formula I prior to administering a DPP4 inhibitor.
  • a pharmaceutically acceptable salt thereof e.g., an alkali earth metal salt
  • the administration of the compound of Formula I although beginning prior to the administration of the DPP4 inhibitor, continues for at least some duration of time wherein the DPP4 inhibitor is co-administered.
  • the administration of the compound of Formula I ceases once the administration of a DPP4 inhibitor begins.
  • the administration of the compound of Formula I begins prior to the administration of a DPP4 inhibitor and continues for at least the duration of time in which the DPP4 inhibitor is administered.
  • the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor, wherein the administration further comprises
  • the method of treating or preventing diabetes mellitus in a patient comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., an alkali earth metal salt); and a DPP4 inhibitor, wherein the administration further comprises administering a compound of Formula I after administering a DPP4 inhibitor.
  • a pharmaceutically acceptable salt thereof e.g., an alkali earth metal salt
  • the administration of the compound of Formula I although starting after the administration of the DPP4 inhibitor, continues for at least some duration of time wherein the DPP4 inhibitor is co-administered.
  • the administration of the DPP4 inhibitor ceases once the administration of a compound of Formula I begins.
  • DPP4 inhibitor begins prior to the administration of the compound of Formula I and continues for at least the duration of time in which the compound of Formula I is administered.
  • Another aspect of the present invention provides a method of treating or preventing diabetes mellitus in a patient comprising administering a pharmaceutical composition comprising a compound of Formula I and GLP analogue (e.g., GLP-1 analogue).
  • GLP analogue e.g., GLP-1 analogue
  • Another aspect of the present invention provides a method of treating or preventing diabetes mellitus in a patient comprising administering a pharmaceutical composition comprising a compound of Formula I and a DPP4 inhibitor.
  • Several methods further comprise the administration of an agent that increases a cyclic nucleotide level (e.g., increases cellular cAMP levels) in a patient.
  • the administration of these ingredients can be sequential (e.g., the compound of Formula I is administered first in time, and the agent is administered second in time) or simultaneous, i.e., both ingredients are administered at substantially the same time, or administered as a single pharmaceutical composition.
  • Several embodiments comprise the step of administering to a patient a
  • compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a phosphodiesterase inhibitor; and either a GLP analogue or a DPP4 inhibitor.
  • Other embodiments further comprise the administration of an agent that increases a cyclic nucleotide level in a patient (e.g., a ⁇ -adrenergic agonist).
  • the method of treating or preventing diabetes mellitus further comprises administering a co-therapy such as a third pharmaceutical agent, a restricted diet, increase the duration and/or exertion of a patient's physical activity, or any combination thereof.
  • a co-therapy such as a third pharmaceutical agent, a restricted diet
  • Another aspect of the present invention provides a method of treating and/or preventing diabetes mellitus comprising administering a pharmaceutical composition comprising a compound of Formula I, wherein said compound has a purity of about 70 e.e.% or more.
  • the method treating diabetes mellitus comprises administering a pharmaceutical composition comprising a compound of Formula I and either a GLP analogue or a DPP4 inhibitor, wherein the compound of Formula I has a purity of about 80% e.e. or more (e.g., 90% e.e. or more, 95% e.e. or more, 97% e.e. or more, or 99% e.e. or more).
  • Another aspect of the present invention provides a method of inducing remission of the symptoms of diabetes mellitus (e.g., type-2 diabetes mellitus) comprising administering a compound of Formula I or a pharmaceutically acceptable salt (e.g., an alkali earth metal salt) thereof; and a GLP (e.g., GLP-1) analogue.
  • a pharmaceutically acceptable salt e.g., an alkali earth metal salt
  • the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a GLP analogue to a patient having a HbAlC level of at least about 6.5 mmol/mol (e.g., at least about 7.0 mmol/mol or at least about 7.5 mmol/mol).
  • the patient suffers from type-2 diabetes.
  • the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a GLP analogue until the patient presents a HbAlC level of no more than about 6.0 mmol/mol (e.g., no more than about 5.9 mmol/mol).
  • a HbAlC level of no more than about 6.0 mmol/mol e.g., no more than about 5.9 mmol/mol.
  • the administration is arrested and the patient is deemed to be in state of remission.
  • the patient presents a HbAlC level of about 6.0 mmol or less, the
  • GLP analogue e.g., administration by injection, oral administration, nasal administration, or rectal administration
  • administration of the compound of Formula I or its salt continues substantially throughout the remission period.
  • the administration of both the GLP analogue e.g., administration by injection, oral
  • administration, nasal administration, or rectal administration and the administration of the compound of Formula I or its salt is also arrested throughout the remission period.
  • the return of an HbAlC level of about 6.0 or greater in a patient signals the end of the remission period, and the administration of the compound of Formula I and the GLP analogue resumes.
  • the administration that resumes at the conclusion of remission need not be identical (e.g., different compounds of Formula I, different dosages, different GLP analogues, or any combination thereof) to the administration that induced the preceding remission state.
  • the administration of the compound of Formula I can occur prior to, after, or concurrent with the administration of the GLP analogue in methods for inducing remission.
  • the compound of Formula I is administered after a patient is administered a GLP analogue.
  • the method of inducing remission of the symptoms of diabetes mellitus comprises administering to a patient a compound of Formula I or a pharmaceutically acceptable salt thereof; and a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, prior to the
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, concurrently with the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).
  • a GLP analogue e.g., Exenatide (e.g., Byetta)
  • Exendin-4 Liraglutide
  • Taspoglatide e.g., byetta
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, concurrently with the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).
  • a GLP analogue e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof.
  • the method of inducing remission of the symptoms of diabetes mellitus comprises administering to a patient a compound of Formula I or a pharmaceutically acceptable salt thereof; and a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).
  • a GLP analogue e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof.
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, prior to the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, concurrently with the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).
  • a GLP analogue e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof.
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the administration of a GLP analogue (e.g., Exenatide (e.g., Byetta), Exendin-4, Liraglutide, Taspoglatide, or any combination thereof).
  • Another aspect of the present invention provides a method of inducing remission of the symptoms of diabetes mellitus (e.g., type-2 diabetes mellitus) comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor.
  • a method of inducing remission of the symptoms of diabetes mellitus comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor.
  • the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor to a patient having a HbAlC level of at least about 6.5 mmol/mol (e.g., at least about 7.0 mmol/mol or at least about 7.5 mmol/mol).
  • the patient suffers from type-2 diabetes.
  • the method comprises administering a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor until the patient presents a HbAlC level of no more than about 6.0 mmol/mol (e.g., no more than about 5.9 mmol/mol).
  • a HbAlC level of no more than about 6.0 mmol/mol (e.g., no more than about 5.9 mmol/mol).
  • the administration is arrested and the patient is deemed to be in state of remission.
  • the remission period is concluded and the administration of the compound of Formula I and the DPP4 inhibitor resumes.
  • the administration that resumes at the conclusion of remission need not be identical (e.g., different compounds of Formula I, different dosages, different DPP4 inhibitors, or any combination thereof) to the administration that induced the preceding remission state.
  • the administration of the compound of Formula I can occur prior to, after, or concurrent with the administration of the DPP4 inhibitor in methods for inducing remission.
  • the compound of Formula I is administered after a patient is administered a DPP4 inhibitor.
  • the method of inducing remission of the symptoms of diabetes mellitus comprises administering to a patient a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof).
  • a DPP4 inhibitor e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, prior to the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof).
  • a DPP4 inhibitor e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
  • a DPP4 inhibitor e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof).
  • a DPP4 inhibitor e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
  • the compound of Formula I is administered after a patient is administered a DPP4 inhibitor.
  • the method of inducing remission of the symptoms of diabetes mellitus comprises administering to a patient a compound of Formula I or a pharmaceutically acceptable salt thereof; and a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof).
  • a DPP4 inhibitor e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, prior to the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof).
  • a DPP4 inhibitor e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
  • a DPP4 inhibitor e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
  • the method comprises administering to a patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, after the administration of a DPP4 inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof).
  • a DPP4 inhibitor e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, or any combination thereof.
  • Another aspect of the present invention provides a method of treating or preventing obesity (e.g., central obesity) and/or reducing bodyweight in a patient comprising
  • Several embodiments comprise the step of administering to a patient a compound of Formula I and an agent that increases a cyclic nucleotide level (e.g., increases cellular cAMP levels) in a patient.
  • the administration of these ingredients can be sequential (e.g., the compound of Formula I is administered first in time, and the agent is administered second in time) or simultaneous, i.e., both ingredients are administered at substantially the same time.
  • Several embodiments comprise the step of administering to a patient a
  • composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a phosphodiesterase inhibitor; and an agent that increases a cyclic nucleotide level in a patient (e.g., a ⁇ -adrenergic agonist).
  • an agent that increases a cyclic nucleotide level in a patient e.g., a ⁇ -adrenergic agonist.
  • Another aspect of the present invention provides a method of treating or preventing diabetes in a patient comprising administering a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Formula I and an agent that increases a cyclic nucleotide level in a patient.
  • Several methods comprise the step of administering to a patient a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a phosphodiesterase inhibitor; and an agent that increases a cyclic nucleotide level in a patient (e.g., a ⁇ -adrenergic agonist).
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a phosphodiesterase inhibitor; and an agent that increases a cyclic nucleotide level in a patient (e.g., a ⁇ -adrenergic agonist).
  • the method of treating or preventing diabetes further comprises administering a co-therapy such as a third pharmaceutical agent, a restricted diet, increase the duration and/or exertion of a patient's physical activity, or any combination thereof.
  • a co-therapy such as a third pharmaceutical agent, a restricted diet
  • Another aspect of the present invention provides a method of treating and/or preventing diabetes comprising administering a pharmaceutical composition comprising a compound of Formula I wherein said compound has a purity of about 70 e.e.% or more.
  • the method treating obesity and/or reducing a patient's bodyweight comprises administering a pharmaceutical composition comprising a compound of Formula I wherein the compound has a purity of about 80% e.e. or more (e.g., 90% e.e. or more, 95% e.e. or more, 97% e.e. or more, or 99% e.e. or more).
  • the present invention provides a method of treating or reducing the severity of central obesity.
  • the method of treating obesity e.g., central obesity
  • reducing bodyweight in a patient, or treating diabetes further comprises administering a co-therapy such as a third pharmaceutical agent (e.g., weight loss drugs (e.g., appetite suppressants (e.g., Meridia, or the like), fat absorption inhibitors (e.g., Xenical, or the like), or compounds that augment sympathomimetic activity such as ephedrine or its various salts)), a restricted diet, increase the duration and/or exertion of a patient's physical activity, or any combination thereof.
  • a co-therapy such as a third pharmaceutical agent
  • a third pharmaceutical agent e.g., weight loss drugs (e.g., appetite suppressants (e.g., Meridia, or the like), fat absorption inhibitors (e.g., Xenical, or the like), or compounds that augment sympathomimetic activity such as ep
  • Another aspect of the present invention provides a method of treating, preventing, or reducing the symptoms of dyslipidemia comprising administering to a patient a compound of Formula I or a pharmaceutical composition as described herein.
  • Another aspect of the present invention provides a method of lowering lipids in a patient comprising administering to a patient a compound of Formula I or a pharmaceutical composition as described herein.
  • the compounds of Formula I may be readily synthesized from commercially available or known starting materials by known methods. Exemplary synthetic routes to produce compounds of Formula I are provided in the Schemes below.
  • 3-hydroxybenzaldehyde is treated with a triphenylphosphene reagent to generate 4-(3-hydroxyphenyl)but-3-en-2-one, which undergoes hydrogenation to form 4-(3-hydroxyphenyl)butan-2-one.
  • 4-(3-hydroxyphenyl)butan-2-one is reacted with R 3 substituted phenylhydrazine 1-1 to generate the indole intermediate 1-2.
  • Intermediate 1-2 is reacted with the ester 1-3 to generate intermediate 1-4.
  • Intermediate 1-4 may undergo deprotection to generate compound 1-5, or intermediate 1-4 may be further functionalized to generate intermediate 1-6 before undergoing deprotection to generate compound 1-7, wherein compounds 1-5 and 1-7 are compounds of Formula I.
  • o-iodoxybenzoic acid (IBX).
  • Treatment with an alpha-triphenylphosphenium ester of formula 3-4 provides the olefin intermediate 3-5.
  • Intermediate 3-5 can then be immediately hydrolyzed to the corresponding acid 3-6, or further functionalized at the ring nitrogen of the indole scaffold to produce a compound of 3-7 which can then be hydrolyzed to the corresponding acid of formula 3-8, wherein compounds 3-7 and 3-8 are compounds of Formula I.
  • the present invention provides compounds that are useful as treatments for obesity and/or reducing a patient's bodyweight.
  • compositions comprising any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • a pharmaceutically acceptable derivative or a prodrug includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • compositions of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁇ C M alkyl ⁇ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or
  • composition its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose a
  • excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • oils such as peanut oil, cottonseed oil; safflower oil; ses
  • an "effective amount" of the compound or pharmaceutically acceptable composition is that amount effective for treating, preventing, or lessening the severity of metabolic diseases such as obesity, i.e., weight loss, diabetes, and/or neurodegenerative diseases (e.g., Alzheimer's disease, dementia, or the like).
  • metabolic diseases such as obesity, i.e., weight loss, diabetes, and/or neurodegenerative diseases (e.g., Alzheimer's disease, dementia, or the like).
  • compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of obesity and/or obesity related diseases.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the particular agent, its mode of administration, and the like.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors known in the medical arts.
  • patient means an animal, for example, a mammal, and more specifically a human.
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the compounds of the invention may be
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the compounds of the invention are useful as treatments for metabolic diseases.
  • the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
  • the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects).
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as "appropriate for the disease, or condition, being treated”.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • compositions for coating an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • the present invention in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device.
  • the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121, each of which is incorporated by reference.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Another aspect of the invention relates to treating metabolic diseases in a biological sample or a patient (e.g., in vitro or in vivo), which method comprises administering to the patient, or contacting said biological sample with a pharmaceutical composition comprising a compound of Formula I, II, III, or IV.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.02 mmol). Stirred at RT for 2 hours. HPLC indicates reaction is complete. Quenched with saturated NH 4 C1 and partitioned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic phases were dried (Na 2 S0 ), filtered and evaporated in vacuo. The residue was chromatographed on a small Biotage column eluting with 0-5% MeOH/DCM. Fractions containing product were combined and evaporated in vacuo.
  • N,N-Diisopropylethylamine (0.293 mL, 1.68 mmol), 5,5-Dimethylcyclohexane-l,3-dione (235 mg, 1.68 mmol) and Tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.06 mmol).
  • HPLC indicates reaction is complete. Quenched with saturated NH4CI and partitioned between DCM and water. The aqueous phase was extracted twice with DCM. The combined organic phases were dried (Na 2 S0 4 ), filtered and evaporated in vacuo. The residue was chromatographed on a small Biotage column eluting with 0-5% MeOH/DCM. Fractions containing product were combined and evaporated in vacuo.
  • Tetrakis(triphenylphosphine)palladium(0) (3.80 mg, 0.00328 mmol) was added and purged again with N 2 and left to stir at RT overnight.
  • HPLC shows a new, major peak and LCMS confirms mass for the desired product. Partitioned between EtOAc and saturated NH4CI, and the aq. phase was extracted with EtOAc. Combined organic phases dried (Na 2 S0 4 ), filtered and evaporated in vacuo to give 64 mg yellow-orange oil. Chromatographed in two batches on small pipette columns. Fractions containing product were combined and evaporated in vacuo to give a light yellow solid. HPLC is 100 area% at both 210 and 254 ran, however, a faint, slightly higher Rf spot is evident on TLC. 1H-NMR consistent with desired contaminated with 1,3 -dimethyl barituric acid.
  • Tetrakis(triphenylphosphine)palladium(0) (2.87 mg, 0.00248 mmol) was added and purged again with N 2 and left to stir at RT overnight.
  • HPLC shows a major new peak and LCMS confirms that it is desired.
  • the reaction mixture was partitioned between EtOAc and saturated NH 4 C1, and the aq. phase was extracted with EtOAc.
  • the combined organic phases were dried (Na 2 S0 4 ), filtered and evaporated in vacuo. The residue was chromatographed several times on small pipette columns (eluting with ether and EtOAc with hexane in varying %s).
  • Example 13 Preparation of methyl (2R)-2-(3-(H,2-dimethyl-5- (trifluoromethoxy H-indol-3-yllmethv phenoxy)propanoate [Bl and (2R)-2-(3-(fl,2- dimethyl-5-(trifluoromethoxy)-lH-indol-3-yllmethyl>phenoxy ' )propanoic acid [CI
  • Example 14 Preparation of 2-ethoxy-3-(3-([l-(4-methoxybenzoyl)-2-methyl-5- ( trifluoromethoxy l H-indol-3-yll methyl ⁇ phenvDpropanoic acid
  • Tetrakis(triphenylphosphine)palladium(0) (1.65 mg, 0.00143 mmol) was added and purged again with N 2 , and left to stir at RT overnight.
  • HPLC shows a new, major peak and LCMS confirms mass for the desired product. Partitioned between EtOAc and saturated NH4CI, and the aq. phase was extracted with EtOAc. Combined organic phases dried (Na 2 S0 4 ), filtered and evaporated in vacuo to give 12 mg amber glass.
  • Assays useful for evaluating the biological properties of compounds of Formula I may be assayed using the following assay methods.
  • this invention finds that activation of this receptor should be a negative selection criterion. Molecules will be chosen from this chemical space because they have reduced, not just selective, activation of PPARy.
  • the optimal compounds have at least a
  • the assays are conducted by first evaluation of the direct interactions of the molecules with the ligand binding domain of PPARy. This can be performed with a commercial interaction kit that measures the direct interaction by florescence using rosiglitazone as a positive control.
  • PPARy binding is measured by a TR-FRET competitive binding assay using Invitrogen LanthaScreenTM TR-FRET PPARy Competitive Binding Assay (Invitrogen #4894).
  • This assay uses a terbium-labeled anti-GST antibody to label the GST tagged human PPARy ligand binding domain (LBD).
  • LBD GST tagged human PPARy ligand binding domain
  • a fluorescent small molecule pan-PPAR ligand tracer binds to the LBD causing energy transfer from the antibody to the ligand resulting in a high TR-FRET ratio.
  • Competition binding by PPARy ligands displace the tracer from the LBD causing a lower FRET signal between the antibody and tracer.
  • the TR-FRET ratio is determined by reading the fluorescence emission at 490 and 520 nm using a Synergy2 plate reader (BioTek).
  • the ability of compounds of the present invention to bind to PPARy may also be measured using a commercial binding assay (Invitrogen Corporation, Carlsbad, CA) that measures the test compounds ability to bind with PPAR-LBD/Fluormone PPAR Green complex. These assays are performed on three occasions with each assay using duplicate wells at each concentration of tested compound. The data are mean and SEM of the values obtained from the three experiments. Rosiglitazone or pioglitazone may be used as the positive control in each experiment. Compounds were added at the concentrations shown, which ranged from 0.1-100 micromolar.
  • PPARy activation in intact cells may be measured by a cell reporter assay using Invitrogen GeneBLAzer PPARy Assay (Invitrogen #1419).
  • This reporter assay uses the human PPARy ligand binding domain (LBD) fused to the GAL4 DNA binding domain (DBD) stably transfected into HEK 293H cells containing a stably expressed beta-lactamase reporter gene under the control of an upstream activator sequence.
  • LBD human PPARy ligand binding domain
  • DBD GAL4 DNA binding domain
  • beta-lactamase reporter gene under the control of an upstream activator sequence.
  • a PPARy agonist binds to the LBD of the GAL4/PPAR fusion protein, the protein binds to the upstream activator sequence activating the expression of beta-lactamase.
  • the cells are loaded with a FRET substrate for 2 hours and fluorescence emission FRET ratios are obtained at 460 and 530 nm in
  • Pioglitazone Endocrinology, 129:1915-1925.].
  • Compounds are formulated in 1% sodium carboxy methylcellulose, and 0.01% tween 20 and dosed daily by oral gavage. After 4 days of once daily treatment, blood samples are taken from the retro-orbital sinus and analyzed for glucose, triglycerides, and insulin as described in Hofmann et al. Doses of compounds that produce at least 80% of the maximum lowering of glucose, triglycerides, and insulin will not significantly increase the expression of a P2 in the liver of these mice.
  • Precursors of BAT are isolated from the interscapular adipose pad of either normal or diabetic mice and cultured in vitro as described below based on the modifications recited in Petrovic N, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Am. J. Physiol.
  • the brown fat pads are pooled and minced, digested for 45 minutes in isolation buffer containing 0.15% (wt/vol) collagenase.
  • the cell suspension is filtered through a 100 ⁇ nylon filter and centrifuged at 200 x g for 5 minutes.
  • the pellet containing the preadipocytes is resuspended in 1.2 ml/animal of DMEM containing 10% FBS, 10 mM HEPES, 25 ⁇ g/ml sodium ascorbate, 100 U/ml penicillin, and 100 ⁇ g/ml streptomycin.
  • the resuspended preadipocytes are distributed into 6 well plates and grown at 37 °C in an atmosphere of 10% C0 2 in air with 80% humidity. The medium is changed on the first day and then every second day until confluent.
  • the growth medium is aspirated, rinsed with PBS, and lysed with KHM buffer containing 1% Igepal CA-630, and a protease inhibitor cocktail.
  • the lysate is centrifuged at 8,000 x g for 5 minutes (4°C), the supernatant containing the cell lysate is collected and total protein analyzed using the BCA method.
  • 20 ⁇ g/lane of cell lysate is run on 10-20% Tris glycine gels under reducing conditions and the proteins transferred to PVDF membranes.
  • Western blotting is conducted using UCPl polyclonal 1° antibody, an HRP conjugated 2° antibody, and imaged using enhanced chemiluminescence reagents and imaging film. Densitometry is conducted on the scanned films using ImageJ software and analyzed using GraphPad Prism software.
  • a photoaffinity crosslinker was synthesized by coupling a carboxylic acid analog of pioglitazone to a p-azido-benzyl group containing ethylamine as in Amer. J. Physiol
  • crosslinker was iodinated carrier free using a modification of the Iodogen (Pierce) procedure and purified using open column chromatography (PerkinElmer). Specific crosslinking is defined as labeling that is prevented by the presence of competing drug.
  • Competitive binding assays are conducted in 50 mM Tris , pH 8.0. All crosslinking reactions are conducted in triplicate using 8 concentrations of competitor ranging from 0-25 uM. Each crosslinking reaction tube contains 20 ug of crude mitochondrial enriched rat liver membranes, 0.1 uCi of 125I-MSDC-1101, and ⁇ competitor drug with a final concentration of 1% DMSO.
  • the binding assay reaction is nutated at room temperature in the dark for 20 minutes and stopped by exposure to 180,000 uJoules. Following crosslinking, the membranes are pelleted at 20,000 * g for 5 minutes, the pellet is resuspended in Laemmli sample buffer containing 1% BME and run on 10-20% Tricine gels. Following
  • control compound is 5-(4-(2-(5-ethylpyridin-2-yl)-2- oxoethoxy)benzyl)thiazolidine-2,4-dione for each of the concentrations tested.
  • T/C data is test compound activity that is normalized with respect to the vehicle activity.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Obesity (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés I et des compositions pharmaceutiques qui sont utiles pour le traitement et/ou la prévention du diabète ou d'autres maladies métaboliques, éventuellement en combinaison avec une seconde thérapie, tel qu'un agent pharmaceutique actif ou une restriction alimentaire ou une augmentation de la durée de l'activité physique ou de l'effort dans celle-ci.
PCT/US2012/043926 2011-06-23 2012-06-25 Composés épargnant les ppar et combinaisons pour le traitement du diabète et d'autres maladies métaboliques WO2012178142A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161500401P 2011-06-23 2011-06-23
US61/500,401 2011-06-23

Publications (1)

Publication Number Publication Date
WO2012178142A1 true WO2012178142A1 (fr) 2012-12-27

Family

ID=46545454

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/043926 WO2012178142A1 (fr) 2011-06-23 2012-06-25 Composés épargnant les ppar et combinaisons pour le traitement du diabète et d'autres maladies métaboliques

Country Status (1)

Country Link
WO (1) WO2012178142A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024017851A1 (fr) 2022-07-18 2024-01-25 The University Court Of The University Of Glasgow Inhibiteurs du métabolisme du pyruvate mitochondrial pour le traitement de la leucémie myéloïde chronique

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
WO2002008188A1 (fr) * 2000-07-25 2002-01-31 Merck & Co., Inc. Indoles n-substitues utiles pour le traitement du diabete
WO2003084916A2 (fr) * 2002-04-05 2003-10-16 Warner-Lambert Company Llc Composes modulant l'activite ppar et leurs procedes de preparation
WO2005009958A1 (fr) * 2003-07-17 2005-02-03 Plexxikon, Inc. Composes ayant une activite sur des ppar
EP1537078A1 (fr) * 2002-08-29 2005-06-08 Merck & Co., Inc. Indoles a activite antidiabetique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5304121A (en) 1990-12-28 1994-04-19 Boston Scientific Corporation Drug delivery system making use of a hydrogel polymer coating
US5886026A (en) 1993-07-19 1999-03-23 Angiotech Pharmaceuticals Inc. Anti-angiogenic compositions and methods of use
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
WO2002008188A1 (fr) * 2000-07-25 2002-01-31 Merck & Co., Inc. Indoles n-substitues utiles pour le traitement du diabete
WO2003084916A2 (fr) * 2002-04-05 2003-10-16 Warner-Lambert Company Llc Composes modulant l'activite ppar et leurs procedes de preparation
EP1537078A1 (fr) * 2002-08-29 2005-06-08 Merck & Co., Inc. Indoles a activite antidiabetique
WO2005009958A1 (fr) * 2003-07-17 2005-02-03 Plexxikon, Inc. Composes ayant une activite sur des ppar

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
"Handbook of Chemistry and Physics", article "Periodic Table of the Elements"
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS
ACTON J J ET AL: "Benzoyl 2-methyl indoles as selective PPARgamma modulators", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 15, no. 2, 17 January 2005 (2005-01-17), pages 357 - 362, XP027800994, ISSN: 0960-894X, [retrieved on 20050117] *
AMER. J. PHYSIOL, vol. 256, pages E252 - E260
BIOCHEMICAL PHARMACOLOGY, vol. 52, 1996, pages 639 - 701
DIABETES, vol. 58, 2009, pages 1526 - 1531
E. W. MARTIN: "Remington's Pharmaceutical Sciences", 1980, MACK PUBLISHING CO.
FREIREICH ET AL., CANCER CHEMOTHER. REP., vol. 50, 1966, pages 219
GUAN, Y. ET AL., NAT. MED., vol. 11, 2005, pages 861 - 866
HOFMANN, C.; LOMEZ, K.; COLCA, J.R.: "Glucose transport deficiency corrected by treatment with the oral anti-hyperglycemic agent Pioglitazone", ENDOCRINOLOGY, vol. 129, 1991, pages 1915 - 1925
JOHN J. ACTON ET AL, JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 13, 9 July 2009 (2009-07-09), pages 3846 - 3854, XP055037372, ISSN: 0022-2623, DOI: 10.1021/jm900097m *
LIU K ET AL: "Selective PPARgamma modulators with improved pharmacological profiles", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 15, no. 10, 16 May 2005 (2005-05-16), pages 2437 - 2440, XP027801708, ISSN: 0960-894X, [retrieved on 20050516] *
M. EINSTEIN ET AL: "The Differential Interactions of Peroxisome Proliferator-Activated Receptor Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities", MOLECULAR PHARMACOLOGY, vol. 73, no. 1, 1 January 2007 (2007-01-01), pages 62 - 74, XP055037373, ISSN: 0026-895X, DOI: 10.1124/mol.107.041202 *
MATSUSUE K; HALUZIK M; LAMBERTG; YIM S-H; OKSANA GAVRILOVA 0; WARD JM; BREWER B; REITMAN ML; GONZALEZ FJ: "Liver-specific disruption of PPAR in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes", J. CLIN. INVEST., vol. 111, 2003, pages 737
N. ENGL. J. MED., vol. 360, 2009, pages 1500 - 1508
PETROVIC ET AL., AM. J. PHYSIOL. ENDOCRINOL. META., vol. 295, 2008, pages E287 - E296
PETROVIC N; SHABALINA IG; TIMMONS JA; CANNON B; NEDERGAARD J, AM. J. PHYSIOL. ENDOCRINOL. METAB., vol. 295, 2008, pages E287 - E296
PHYSIOL REV., vol. 84, 2004, pages 277 - 359
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
SCIENTIFIC TABLES, GEIGY PHARMACEUTICALS, 1970, pages 537
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS
TRAVIS S. HUGHES ET AL: "Ligand and Receptor Dynamics Contribute to the Mechanism of Graded PPAR[gamma] Agonism", STRUCTURE, vol. 20, no. 1, 1 January 2012 (2012-01-01), pages 139 - 150, XP055037371, ISSN: 0969-2126, DOI: 10.1016/j.str.2011.10.018 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024017851A1 (fr) 2022-07-18 2024-01-25 The University Court Of The University Of Glasgow Inhibiteurs du métabolisme du pyruvate mitochondrial pour le traitement de la leucémie myéloïde chronique

Similar Documents

Publication Publication Date Title
US9155729B2 (en) Thiazolidinedione analogues
US8067450B2 (en) Thiazolidinedione analogues for the treatment of metabolic diseases
US20120322728A1 (en) Ppar-sparing thiazolidinediones and combinations for the treatment of diabetes mellitus and other metabolic diseases
US20120316138A1 (en) Ppar-sparing thiazolidinediones and combinations for the treatment of obesity and other metabolic diseases
WO2011075514A1 (fr) Thiazolidinediones épargnant les ppar et associations pour le traitement de maladies neurodégénératives
WO2011084453A1 (fr) Sels de thiazolidinedione épargnant les ppar pour le traitement des maladies métaboliques
EP2560615A1 (fr) Analogues de thiazolidinedione
EP3024816B1 (fr) Composés réduisant l'activité ou la liaison de ppar pour le traitement de maladies métaboliques
US8304441B2 (en) Thiazolidinedione analogues for the treatment of metabolic diseases
WO2012178142A1 (fr) Composés épargnant les ppar et combinaisons pour le traitement du diabète et d'autres maladies métaboliques
WO2012177956A1 (fr) Composés réduisant l'activité ou la liaison-de ppar et combinaisons pour le traitement du diabète et d'autres maladies métaboliques
AU2013200104B2 (en) Thiazolidinedione analogues for the treatment of metabolic inflammation mediated disease

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12737378

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12737378

Country of ref document: EP

Kind code of ref document: A1