WO2010105048A9 - Thiazolidinedione analogues - Google Patents

Thiazolidinedione analogues Download PDF

Info

Publication number
WO2010105048A9
WO2010105048A9 PCT/US2010/026971 US2010026971W WO2010105048A9 WO 2010105048 A9 WO2010105048 A9 WO 2010105048A9 US 2010026971 W US2010026971 W US 2010026971W WO 2010105048 A9 WO2010105048 A9 WO 2010105048A9
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
halo
ring
aliphatic
Prior art date
Application number
PCT/US2010/026971
Other languages
French (fr)
Other versions
WO2010105048A1 (en
Inventor
Gerard R. Colca
Scott D. Larsen
Steven P. Tanis
Timothy Parker
Robert Gadwood
Original Assignee
Metabolic Solutions Development Company
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 filed Critical Metabolic Solutions Development Company
Publication of WO2010105048A1 publication Critical patent/WO2010105048A1/en
Publication of WO2010105048A9 publication Critical patent/WO2010105048A9/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems

Definitions

  • the present invention provides a pharmaceutical composition that includes selective thiazolidinedione analogs for use in treating and preventing diabetes, hypertension, diabetes, and inflammatory diseases.
  • Peroxisome Proliferator Activated Receptors are members of the nuclear hormone receptor super-family, which 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.
  • PPAR ⁇ is a key regulator of adipocyte differentiation and lipid metabolism. PPAR ⁇ is also found in other cell types including fibroblasts, myocytes, breast cells, human bone- marrow precursors, and macrophages/monocytes. In addition, PPAR ⁇ has been shown in macrophage foam cells in atherosclerotic plaques.
  • Thiazolidinediones such as pioglitazone
  • PPAR ⁇ ligands The finding that thiazolidinedones might mediate their therapeutic effects through direct interactions with PPAR ⁇ helped to establish the concept that PPAR ⁇ is a key regulator of glucose and lipid homeostasis.
  • compounds that involve the activation of PPAR ⁇ such as pioglitazone, also trigger sodium reabsorption and other unpleasant side effects.
  • the invention relates to compounds that have reduced binding and activation of the nuclear transcription factor PPAR ⁇ when compared with high affinity PPAR ⁇ ligands such as pioglitazone.
  • Compounds exhibiting PPAR ⁇ activity induce transcription of genes that favor sodium reabsorption
  • the compounds of this invention have reduced binding or activation of the nuclear transcription factor PPAR ⁇ when compared with traditional high affinity PPAR ⁇ ligands (e.g., pioglitazone), do not augment sodium reabsorption, and are therefore more useful in treating hypertension, diabetes, and inflammatory diseases.
  • the compounds having reduced PPAR ⁇ activity exhibit fewer side effects than compounds having higher levels of PPAR ⁇ activity.
  • the reduced PPAR ⁇ binding and reduced activity exhibited by these compounds are particularly useful for treating hypertension, diabetes, and inflammatory diseases both as single agents and in combination with other classes of antihypertensive agents.
  • traditional high affinity PPAR ⁇ ligands e.g., pioglitazone
  • these compounds are also useful for the treatment and prevention of diabetes and other inflammatory diseases.
  • the present invention provides a pharmaceutical composition useful in treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula I:
  • R 1 and R* is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo;
  • R 2 is H and R 2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO 2 )NH 2 ,
  • each R A independently is optionally substituted C 1-6 alkyl
  • each R B is independently optionally substituted C 1-12 alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted phenyl; or any two of R B , combined with the atoms to which they are attached, form an optionally substituted 5 to 7 membered ring; or R 2 and R 2 together may form oxo; R 3 is H; and Ring A is phenyl.
  • Another aspect of the present invention provides methods of treating hypertension, diabetes, and inflammatory diseases with a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.
  • compositions comprising a compound of Formula I and at least one diuretic, such as hydrocholothiazide.
  • Other aspects provide pharmaceutical compositions useful for treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula I and one or more agents that limit the activity of the renin-angiotensin system such as angiotensin concerting enzyme (ACE) inhibitors, e.g., ramipril, captopril, enalapril, or the like, and/or angiotensin II receptor blockers (ARBs), e.g., candesartan, losartan, olmesartan, or the like; and/or renin inhibitors.
  • ACE angiotensin concerting enzyme
  • ARBs angiotensin II receptor blockers
  • Still other aspects provide a useful pharmaceutical composition for treating hypertension, diabetes, and/or inflammatory diseases comprising a compound of Formula I and one or more compounds that reduce hypertension, e.g., ⁇ -adrenergic receptor blockers or calcium channel blockers, e.g., amlodipine, by mediating an alternate biological target.
  • a useful pharmaceutical composition for treating hypertension, diabetes, and/or inflammatory diseases comprising a compound of Formula I and one or more compounds that reduce hypertension, e.g., ⁇ -adrenergic receptor blockers or calcium channel blockers, e.g., amlodipine, by mediating an alternate biological target.
  • This invention also provides pharmaceutical combinations containing a compound of Formula I and a lipid lowering agent.
  • Compounds of Formula I because of their PPAR ⁇ - sparing properties and beneficial effects on lipids (e.g., reducing triglycerides and elevating HDL cholesterol), are particularly useful in combination with 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 invention relates to insulin sensitizers that have reduced binding and reduced activation of the nuclear transcription factor PPAR ⁇ and therefore produce reduced sodium reabsorption and fewer dose-limiting side effects.
  • compounds of Formula I are substantially more effective for treatment and prevention of diabetes and other metabolic inflammation mediated diseases including all aspects of insulin resistance associated with metabolic syndrome such as dyslipidemia and central obesity.
  • the compounds of Formula I are also useful for treating other inflammatory diseases such as rheumatoid arthritis, lupus, myasthenia gravis, vasculitis, Chronic Obstructive Pulmonary Disease (COPD), and inflammatory bowel disease as well as neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, acute allergic reactions, transplant rejections, central obesity, dyslipidemia, prediabetes and diabetes.
  • COPD Chronic Obstructive Pulmonary Disease
  • the present invention provides pharmaceutical compositions comprising a compound of Formula I and metformin.
  • the invention provides pharmaceutical compositions comprising a compound of Formula I, a second agent and a pharmaceutically acceptable carrier, wherein the second agent is selected from dipeptidyl peptidase IV (DPP-4) inhibitors, e.g., sitagliptin, vildagliptin, or the like; statins, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof; GLP-I and -2 agonists; or combinations thereof.
  • DPP-4 dipeptidyl peptidase IV
  • statins i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin,
  • the invention provides a combination of compound of Formula I and a glucocorticoid agonist which is useful for treating a number of inflammatory diseases and conditions including therapies of suppressing the immune response, preventing transplant rejections, and treating autoimmune diseases.
  • exemplary diseases and conditions include rheumatoid arthritis, lupus, myasthenia gravis, muscular dystrophy vasculitis, multiple sclerosis, Chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel disease, treatment of acute allergic reactions, and transplant rejection.
  • COPD Chronic Obstructive Pulmonary Disease
  • 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.
  • glucocorticoid agonist refers to steroid hormones characterized by their ability to bind with the Cortisol receptor.
  • glucocorticoid agonists include, but are not limited to, Hydrocortisone, Cortisone acetate, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, Fludrocortisone acetate, Deoxycorticosterone acetate (DOCA), and Aldosterone.
  • 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., 1-8, 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 (Le., 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,
  • substituents such as halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or
  • 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-SO 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 (alky
  • 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.,
  • cycloalkylaminocarbonyl amino [e.g., aliphaticamino, cycloaliphaticamino,
  • heterocycloaliphaticamino or aliphaticsulfonylamino
  • sulfonyl e.g.,
  • substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl,
  • (sulfonylamino)alkenyl such as (alkyl-SO 2 -amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.
  • 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-SCV, aliphaticamino-SOa-, or cycloaliphatic- SO 2 -], 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(O)-R Y or -C(O)-N(R X ) 2 , when used terminally, and -C(O)- N(R X )- or -N(R X )-C(O)- when used internally, wherein R x and R ⁇ 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 ⁇ 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 -, where R x has the same meaning as defined above.
  • an "aryl” group used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” 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 benzofused 2-3 membered carbocyclic rings.
  • a benzofused group includes phenyl fused with two or more C 4-S 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-SO 2 - or amino-SCV
  • 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 p,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 CM 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 Q -4 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. l]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-S ⁇ 2 -
  • sulfinyl e.g.,
  • heterocycloaliphatic encompasses heterocycloalkyl groups and heterocycloalkenyl groups, each of which being optionally substituted as set forth below.
  • a “heterocycloalkyl” group 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[fc]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-di
  • 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).
  • Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature.
  • 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[&]furyl, benzo[&]thiophenyl, quinolinyl, or isoquinolinyl).
  • heterocycloaliphatic moieties e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[&]furyl, benzo[&]thiophenyl, quinolinyl, or isoquinolinyl.
  • heteroaryl examples include azetidinyl, pyridyl, 1H- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b] furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo- 1,2,5-thiadiazolyl, or 1,8
  • monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, 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[&]furyl, benzo[&]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[fc]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;
  • cycloaliphatic (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliphatic )carbonyl; ((cycloaliphatic)aliphatic)carbonyl;
  • heterocycloaliphatic aliphatic
  • carbonyl or (heteroaraliphatic)carbonyl]
  • sulfonyl e.g., aliphaticsulfonyl or aminosulfonyl
  • sulf ⁇ nyl 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]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and
  • alkylsulfonyl heteroaryl
  • hydroxyalkyl heteroaryl
  • alkoxyalkyl heteroaryl
  • heterocycloaliphatic heteroaryl
  • cycloaliphatic heteroaryl
  • nitrogenalkyl heteroaryl
  • (cyanoalkyl)heteroaryl (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl; or (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].
  • heteroaralkyl group refers to an aliphatic group (e.g., a CM alkyl group) that is substituted with a heteroaryl group.
  • 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.
  • a "bridged bicyclic ring system” refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged.
  • 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.l]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,
  • heteroarylcarbonylamino heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • an "acyl” group refers to a formyl group or R X -C(O)- (such as alkyl-C(O)-, also referred to as “alkylcarbonyl”) where R x and "alkyl” have been defined previously.
  • 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)- The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
  • an "alkoxy” group 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 ⁇ 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(O)H,
  • haloaliphatic refers to an aliphatic group substituted with 1-3 halogen.
  • haloalkyl includes the group -CF 3 .
  • a "mercapto” group refers to -SH.
  • a "sulfo" group refers to -SO 3 H or -SC> 3 R X when used terminally or
  • a "sulfamide” group refers to the structure -NR X -S(O) 2 -NR Y R Z when used terminally and -NR X -S(O) 2 -NR Y - when used internally, wherein R x , R ⁇ , and R z have been defined above.
  • a "sulfamoyl” group refers to the structure -O-S(O) 2 -NR Y R Z wherein R ⁇ and R z have been defined above.
  • a "sulfonamide” group refers to the structure -S(O) 2 -NR X R Y or
  • 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.
  • sulfinyl refers to -S(O)-R X when used terminally and -
  • Exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like.
  • a "sulfonyl” group refers to -S(O) 2 -R X when used terminally and
  • sulfonyl groups include aliphatic-S(O) 2 -, aryl-S(O)2-, (cycloaliphatic(aliphatic))-S(O)2-,
  • a "sulfoxy" group refers to -O-SO-R X or -SO-O-R X , when used terminally and -O-S(O)- or -S(O)-O- when used internally, where R x has been defined above.
  • halogen or halo group refers to fluorine, chlorine, bromine or iodine.
  • an "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(O)(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(O)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(O)O- or alkyl-OC(O)-
  • alkylcarboxyaryl e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-
  • an "aliphatic chain” refers to a branched or straight aliphatic group
  • a straight aliphatic chain has the structure -[CH 2 ] V -, 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, at least one Q is an aliphatic group.
  • the term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.
  • substituted or unsubstituted compounds of the invention can 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.
  • the variables R 1 , R 2 , R 3 , and R 4 , and other variables contained in Formulae described herein encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables R 1 , R 2 , R3, and 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 Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "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 l4 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.
  • thiazolidinedione compounds of the present invention are uniquely effective in treating hypertension, diabetes, and inflammatory diseases and possess a reduced interaction with PPAR ⁇ .
  • metabolic inflammation is a central cause of the numerous key diseases including hypertension, diabetes, and inflammatory diseases. It is further believed that thiazolidinediones of the present invention function to prevent hypertension, diabetes, and inflammatory diseases via a mitochondrial mechanism. Furthermore since the dose limiting side effects due to PPAR ⁇ interaction are reduced in compounds of the present invention when compared to compounds such as pioglitazone; especially stereoselective isomers, the compounds of Formula I are highly useful for treating hypertension, diabetes, and inflammatory diseases.
  • the compounds of Formula I are useful in treating or preventing all of the disease states wherein metabolic inflammation is the basis of the pathology.
  • the compounds of Formula I when used in combination with a glucocorticoid agonist can be used for treating inflammatory diseases.
  • the present invention provides compounds and pharmaceutical compositions that are useful for treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula I:
  • R 1 and R 4 are independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo.
  • R 2 is -H and R 2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO 2 )NH 2 , -O-CH(R A )OC(O)R B , -O-CH(R A )OP(O)(OR B ) 2 , -O-P(O)(OR B ) 2 , or
  • each R A is independently -H or an optionally substituted C 1-6 alkyl
  • each R B is independently -H, optionally substituted C 1-12 alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted phenyl, or any two of R B , taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring, or R 2 and R' 2 taken together form oxo
  • R 3 is H or optionally substituted C 1-3 aliphatic
  • Ring A is
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is phenyl and R 1 is attached to the ortho or para position of Ring A.
  • Ring A is phenyl, R 1 is attached to the ortho or para position of Ring A, and R 1 is -H or halo; or R 1 is -C 1-6 aliphatic or -C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
  • R 1 is -C 1-6 alkoxy optionally substituted with 1-3 halo.
  • R 1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
  • Ring A is phenyl and R 1 is attached to the meta or para position of Ring A.
  • Ring A is phenyl, R 1 is attached to the meta position of Ring A.
  • Ring A is phenyl, R 1 is attached to the meta position of Ring A, and R 1 is -H or halo; or R 1 is -C 1-6 aliphatic or -C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
  • R 1 is -C 1-6 aliphatic optionally substituted with 1-3 halo.
  • R 1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert-butyl, each of which is optionally substituted with 1-3 halo.
  • R 1 is -C 1-6 alkoxy optionally substituted with 1-3 halo.
  • R 1 is methoxy, ethoxy, propoxy, butoxy, iso-propoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
  • R 1 is -H, -Cl, -F, -Br, -CH 3 , -CH 2 CH 3 , -CF 3 , -OCHF 2 , or -OCF 3 .
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is N-(N-[0097] In some embodiments, Ring A is N-(N-[0097] In some embodiments, Ring A is N-(N-[0097]
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ring A is pyridine-2-yl or pyridine-3-yl
  • R 1 is -H or halo; or R 1 is -C 1-6 aliphatic, or -C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
  • R 1 is -H.
  • R[ is -C 1-6 aliphatic optionally substituted with 1-3 halo.
  • R 1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert-butyl, each of which is optionally substituted with 1-3 halo.
  • R 1 is -C 1-6 alkoxy optionally substituted with 1-3 halo.
  • R 1 is methoxy, ethoxy, propoxy, butoxy, iso-propoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
  • Ring A is pyridine-2-yl or pyridine-3-yl
  • R 4 is independently -H or halo.
  • Ring A d it b tit nts R 1 and R 4 form
  • Ring A and its substituents R 1 and R 4 form ,
  • R 2 is -OH. In others, R 2 is -O-acyl, -O-aroyl or -O- heteroaroyl. And in some instances, R 2 and R' 2 together form oxo. In other embodiments, R 2 is -H, -OH,
  • R 3 is -H or -CH 3 .
  • Another aspect of the present invention provides a compound of Formula (IA):
  • each of R 1 and R 4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo;
  • R' 2 is -H and R 2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO 2 )NH 2 , -O-CH(R A )OC(O)R B , -O-CH(R A )OP(O)(OR B ) 2 , -O-P(O)(OR B ) 2 , or
  • each R A is independently -H or an optionally substituted Q -6 alkyl
  • each R B is independently -H, optionally substituted C 1-I2 alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted phenyl, or any two of R B , taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring, or R 2 and R' 2 taken together form oxo
  • R 3 is H
  • Ring A is phenyl.
  • R 1 is attached to the ortho or para position of Ring A.
  • R 1 is attached to the ortho or para position of Ring A, and R 1 is -H or halo; or R 1 is -C 1-6 aliphatic or -C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
  • R 1 is -C 1- ⁇ alkoxy optionally substituted with 1-3 halo.
  • R 1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
  • R 1 is attached to the meta or para position of Ring A.
  • R 1 is attached to the meta position of Ring A.
  • R 1 is attached to the meta or para position of Ring A, and R 1 is -H or halo; or R 1 is -C 1-6 aliphatic or -C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
  • R 1 is -C 1-6 aliphatic optionally substituted with 1-3 halo.
  • R 1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert-butyl, each of which is optionally substituted with 1-3 halo.
  • R 1 is -C 1-6 alkoxy optionally substituted with 1-3 halo.
  • R 1 is methoxy, ethoxy, propoxy, butoxy, iso-propoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
  • R 1 is -H, -Cl, -F, -Br, -CH 3 , -CH 2 CH 3 , -CF 3 , -OCHF 2 , or
  • R 4 is -H, methyl, ethyl, methoxy, ethoxy, iso-propoxy, -CF 3 , -OCHF 2 or -OCF3.
  • R 4 is H.
  • Ring A and its substituents R 1 and R 4 form
  • R 2 is hydroxy. In others, R 2 is -O-acyl, -O-aroyl or
  • R 2 is -O-CH(R A )-O-C(O)R B
  • R A is -H, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2
  • R B is -H or R B is -C 1-6 alkyl, -C 3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
  • R 2 is -O-CH(R A )OP(O)(OR B ) 2
  • R A is -H, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2
  • R B is -H or R B is -C 1-6 alkyl, -C 3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
  • R 2 is -O- P(O)(OR B ) 2
  • R B is -C 1-4 alkyl optionally substituted with 1-3 halo, or two R B groups together with the atoms to which they are attached form an optionally substituted 5-7 membered ring.
  • R 2 is -0-SO 2 NH 2 .
  • R 2 is , and R B is -H or an optionally substituted C 1-4 alkyl.
  • R 2 and R 2 together form oxo.
  • R 1 is H. In some embodiments, R 1 is halo, such as F or Cl. In some embodiments, R 1 is an aliphatic optionally substituted with 1-3 halo. For instance, R 1 is trifluoromethyl. In some embodiments, R 1 is alkoxy. For instance, R 1 is methoxy, ethoxy, or -O-isopropyl. In still other embodiments, R 1 is alkoxy substituted with 1-3 halo. For instance, R 1 is -OCHF 2 or -OCF 3 . In each of the foregoing embodiments, R 1 can be substituted at the ortho, meta, or para position on the phenyl ring. In certain embodiments, R 1 is substituted at the para or meta position on the phenyl ring.
  • R 4 is H. In some embodiments, R 4 is halo, such as F or Cl. In some embodiments, R 4 is an aliphatic optionally substituted with 1-3 halo. For instance, R 4 is trifluoromethyl. In some embodiments R 4 is alkoxy. For instance, R 4 is methoxy, ethoxy, or -O-isopropyl. In still other embodiments, R 4 is alkoxy substituted with 1-3 halo. For instance, R 4 is -OCHF 2 or -OCF 3 . In each of the foregoing embodiments, R 4 can be substituted at the ortho, meta, or para position of the phenyl ring.
  • R 4 is substituted at the para or meta position on the phenyl ring.
  • R 1 and R 4 are different substituents.
  • R t and R 4 are the same substituent.
  • R 4 is other than H.
  • each of R 1 and R 4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo, provided that when one of R 1 and R 4 is H then the other is not ethyl.
  • each of R ( and R 4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo, provided that when one of R 1 and R 4 is H then the other is not ethyl substituted at the 4 poistion of the phenyl.
  • R 2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O- heteroaroyl, -0(SO 2 )NH 2 , -O-CH(R A )OC(O)R B , -O-CH(R A )OP(O)(OR B ) 2 , -O-P(O)(OR B ) 2 , or , wherein each R A is -H or optionally substituted C 1-6 alkyl, each R B is -H or optionlly substituted C 1-I2 alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted phenyl, wherein each of R A and R B is defined above.
  • R 2 is hydroxy
  • R 2 is an optionally substituted straight or branched C 1-6 alkyl, an optionally substituted straight or branched C 2-6 alkenyl, or an optionally substituted straight or branched C 2-6 alkynyl.
  • R 2 is a C 1-6 aliphatic optionally substituted with 1-2 hydroxy, carboxy or halo.
  • R 2 is a C 1-6 alkyl optionally substituted with hydroxy,
  • R 2 is a C 1-6 alkyl optionally substituted with -O-acyl, -O-aroyl, -0-heteroaroyl.
  • R 2 is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is optionally substituted with hydroxy. In several additional embodiments , R 2 is methyl or ethyl, each of which is substituted with hydroxy.
  • R 2 is -O-acyl, -O-aroyl or -O-heteroaryoyl.
  • R 2 is -O-acetyl, -O-hexanoyl, -O-benzoyl, -O-pivaloyl, -O- imidazolyl, -O-succinoyl, -O-thiazoloyl or -O-pyridinoyl, each of which is optionally substituted.
  • R 2 is -O-C(O)-imidazol-1-yl.
  • R 2 is -O-CH(R A )-O-C(O)-R B .
  • R 2 is -O-CH(R A )OP(O)(OR B ) 2 .
  • R 2 is -O-P(O)(OR B ) 2 .
  • R 2 is -0-S(O 2 )NH 2 .
  • two R B groups together with the atoms to which they are attached form an optionally substituted 5 to 7 membered cycloaliphatic or
  • heterocycloaliphatic ring
  • R 2 is , wherein R B is defined above.
  • R' 2 is H.
  • R 2 and R' 2 together form oxo.
  • R 2 is H and the carbon atom to which R 2 and R 2 are attached has an R configuration.
  • R' 2 is H and the carbon atom to which R' 2 and R 2 are attached has an S configuration.
  • R 2 is H and the carbon atom to which R 2 and R 2 are attached is racemic.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formulae I or IA and a pharmaceutically acceptable carrier.
  • Another aspect of the present invention provides a compound of Formulae ⁇ , HA, or
  • Another aspect of the present invention provides a compound of Formulae ⁇ , ILA, or IIB and a pharmaceutically acceptable carrier.
  • present invention include a single unit dosage form having from about 1 mg to about 200 mg
  • a compound of Formula I , II, ILA or IIB e.g., from about 10 mg to about 120 mg, from
  • form oxo include:
  • Exemplary compounds of Formula I or Formula IA, wherein R 2 is -OH and the carbon atom to which R 2 and R 2 are attached has an S configuration include:
  • Exemplary compounds of Formula I or Formula IA, wherein R 2 is -OH and the carbon atom to which R 2 and R' 2 are attached has an R configuration include:
  • Exemplary compounds of Formula I or Formula IA, wherein R 2 is -OH include:
  • Exemplary compounds of Formula I or Formula IA, wherein R 2 is -O-acyl, -O-aroyl or -O-heteroaroyl include
  • Exemplary compounds of Formula I or Formula IA, wherein R 2 is R 2 is -O-CH(R A )- O-C(O)R B , wherein R A and R B are defined above, include:
  • Exemplary compounds of Formula I or Formula IA, wherein R 2 is R 2 is -O- CH(R A )OP(O)(OR B ) 2 , wherein R A and R B are defined above, include:
  • Exemplary compounds of Formula I or Formula IA, wherein R 2 is -0-P(O)(OR ) 2 , wherein R B is defined above, include:
  • Exemplary compounds of Formula I or Formula IA, wherein R 2 is -0-SO 2 NH 2 include:
  • Another aspect of the present invention provides a compound of Formula (IB):
  • each of R 1 and R 4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo;
  • R 3 is H. In others, R 3 is methyl.
  • Ring A is N-(N-[00151] In some embodiments, Ring A is N-(N-[00151] In some embodiments, Ring A is N-(N-[00151]
  • Ring A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is -H or halo; or R 1 is -C 1-6 alkyl or -C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
  • R is -H, -Cl, -F, -Br, -CH 3 , -CH 2 CH 3 , -CF 3 , -OCHF 2 , or -OCF 3 .
  • R 1 is H.
  • R 1 is ethyl.
  • R 4 is -H, methyl, ethyl, methoxy, ethoxy, iso-propoxy, -CF 3 ,
  • R 4 is -H.
  • Ring A and its substituents R 1 and R 4 form
  • R 2 is -O-acyl, -0-aroyl, or -O-heteroaroyl.
  • R 2 is -O-CH(R A )-O-C(O)R B
  • R A is -H, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2
  • R B is -H or R B is -C 1-6 alkyl, -C 3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
  • R 2 is -0-CH(R A )OP(0)(OR B ) 2
  • R A is -H, -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2
  • R B is -H or R B is -C 1-6 alkyl, -C 3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
  • R 2 is -O-P(O)(OR B ) 2
  • R B is -C 1-4 alkyl optionally substituted with 1-3 halo, or two R B groups together with the atoms to which they are attached form an optionally substituted 5-7 membered ring.
  • R 2 is -0-SO 2 NH 2 .
  • R 2 is , and R B is -H or an optionally substituted C 1-4 alkyl.
  • R 1 is H. In some embodiments, R 1 is halo, such as F or Cl. In some embodiments, R 1 is an aliphatic optionally substituted with 1-3 halo. For instance, R 1 is methyl, ethyl or trifluoromethyl. In some embodiments, R 1 is alkoxy. For instance, R 1 is methoxy, ethoxy, or -O-isopropyl. In still other embodiments, R 1 is alkoxy substituted with 1-3 halo. For instance, R 1 is -OCHF 2 or -OCF 3 . In each of the foregoing embodiments, R 1 can be substituted at the ortho, meta, or para position on the pyridine ring. In certain embodiments, R 1 is substituted at the ortho or meta position on the pyridine ring.
  • R 4 is H.
  • R 4 is H and R 1 is C 1 .3 alkyl.
  • R 4 is halo, such as F or Cl.
  • R 4 is an aliphatic optionally substituted with 1-3 halo.
  • R 4 is trifluoromethyl.
  • R 4 is alkoxy.
  • R 4 is methoxy, ethoxy, or -O-isopropyl.
  • R 4 is alkoxy substituted with 1-3 halo.
  • R4 is -OCHF 2 or -OCF 3 .
  • R 4 can be substituted at the ortho, meta, or para position relative to the N of the pyridine ring.
  • R 4 is substituted at the para or meta position on the pyridine ring.
  • R 1 and R 4 are different substituents.
  • R 1 and R 4 are the same substituent.
  • each of R 1 and R 4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo.
  • R 2 is -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO 2 )NH 2 , -O- CH(R A )OC(O)R B , -O-CH(R A )OP(O)(OR A ) 2 , -O-P(O)(OR A ) 2
  • R A is -H or optionally substituted C 1-6 alkyl
  • R B is -H or optionally substituted C 1-12 alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted phenyl; or any two of R B , combined with the atoms to which they are attached, may form an optionally substituted 5 to 7 membered ring.
  • R 2 is -O-acyl, -O-aroyl or -O-heteroaryoyl.
  • R 2 is -O-acetyl, -O-hexanoyl, -O-benzoyl, -O-pivaloyl, -O- imidazolyl, -O-thiazoloyl or -O-pyridinoyl, each optionally substituted.
  • R 2 is -0-C(0)-imidazol-1-yl.
  • R 2 is -O-CH(R A ) -0-C(O)- R B .
  • R 2 is -O-CH(R A )OP(O)(OR B ) 2 .
  • R 2 is -O-P(O)(OR B ) 2 .
  • R 2 is -O S(O 2 )NH 2 .
  • R 2 is a 1,3-dioxolan-2-one of the Formula , wherein R A and R B are as described previously.
  • R' 2 is H.
  • R 2 is H and R 2 has an R configuration.
  • R 2 is H and R 2 has an S configuration.
  • R' 2 is H and R 2 is racemic.
  • R 1 or R 4 when one of R 1 or R 4 is H, the other is not ethyl.
  • the invention provides a pharmaceutical composition which includes compounds of the Formula
  • R 2 is H, R 1 , R 3 , and R 4 are defined above in Formula IB, Ring A is 2-pyridinyl or 3- pyridinyl and R 2 is -O-Q wherein Q is -acyl, -aroyl or -heteroaryoyl.
  • Q is -acetyl, -hexanoyl, -benzoyl, -pivaloyl, -succinoyl, each optionally substituted.
  • Q is acetyl
  • Q is hexanoyl
  • Q is benzoyl
  • Q is pivaloyl
  • Q is succinoyl
  • composition further comprises a pharmaceutically acceptable carrier.
  • a pharmaceutical composition to include a compound of Formula III, IIIA, or IIIB:
  • R' 2 is H
  • R 1 , R 2 , R 3 , R 4 and Ring A are defined above in Formula IB.
  • compositions according to the present invention includes a single unit dosage form having about 1 mg to about 200 mg of a compound of Formula IB, IV, IVA or IVB, e.g., between about 10 mg to about 120 rag, between about 10 mg to about 100 mg, or about 15 mg to about 60 mg.
  • the compound of Formula IB, III, IIIA or IIIB includes:
  • the compound of Formula BB, III, IIIA or IIIB includes:
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula IB, HI, ⁇ iA or HIB wherein the compound has a PPAR ⁇ activity of 50% or less relative to the activity of rosiglitazone when dosed to produce circulating levels greater than 3 ⁇ M or having a PPAR ⁇ activity of 10 times less than pioglitazone at the same dosage.
  • Another aspect of the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula IB, HC, III A or IIIB.
  • the compositions of several alternative methods further comprise a pharmaceutically acceptable carrier.
  • Another aspect of the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula III or IIIA, wherein said compound has a purity of about 70% e.e. or more.
  • the method treating hypertension, diabetes, and
  • inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula III or IIIA, 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 antihypertensive agents or other drugs.
  • One aspect of the present invention provides pharmaceutical composition comprising a compound of Formula IB, III, IIIA or IIIB and at least one diuretic, such as hydrochlorothiazide, chlorothaladone, chlorothiazide, or combinations thereof.
  • Other aspects provide pharmaceutical compositions useful for treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula IB, III, IIIA or IIIB and one or more agents that limit the activity of the renin-angiotensin system such as angiotensin concerting enzyme inhibitors, i.e. ACE inhibitors, e.g.
  • ARBs e.g.candesartan, losartan, olmesartan, or the like
  • renin inhibitors e.g.candesartan, losartan, olmesartan, or the like
  • Still other aspects provide a useful pharmaceutical composition for treating hypertension, diabetes, and inflammatory diseases comprising of a compound of Formula IB, III, IIIA or IIIB and compounds that limit hypertension, diabetes, and inflammatory diseases by alternate means including ⁇ -adrenergic receptor blockers, and calcium channel blockers (e.g., amlodipine).
  • compositions that are useful for lowering lipids comprising compounds of Formula IB, III, HLA or IIIB and one or more statin, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof.
  • statin i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof.
  • Another aspect of the present invention provides a combination of a compound of Formula IB, IQ, IIIA or IIIB with one or more antihypertensive agents including diuretics (for example hydrochlorothiazide, chlorothaladone, chlorothiazide), angiotensive converting enzyme inhibitors, e.g., ACE inhibitors, e.g., ramipril, captopril, enalapril, combinations thereof, or the like; angiotensin II receptor blockers, i.e., ARBs, e.g., losartan, olmesartan, telmisartan, combinations thereof, or the like; renin inhibitors; ⁇ -adrenergic receptor blockers, statins, or combinations thereof.
  • diuretics for example hydrochlorothiazide, chlorothaladone, chlorothiazide
  • angiotensive converting enzyme inhibitors e.g., ACE inhibitors, e.g
  • the invention provides compounds of Formula IV
  • Q is acyl, aroyl, heteroaroyl, SO 2 NH 2 , CH(R A )OC(O)R B , CH(R A )OP(O)(OR A ) 2 ,
  • R A is -H or optionally substituted C 1-6 alkayl
  • R B is -H or optionally substituted C 1-12 alkyl, optionally substituted C 3-8 cycloalkyl or optionally substituted phenyl, wherein each substituent is optionally substituted
  • any two of R B combined with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring.
  • Q is -acetyl, -hexanoyl, -benzoyl, -pivaloyl, -succinoyl, each optionally substituted.
  • Q is acetyl
  • Q is hexanoyl
  • Q is benzoyl
  • Q is pivaloyl
  • Q is succinoyl
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, IA, IB, II, ILA, ILB, ILL, ILIA, IILB, or IV, wherein the compound has a PPAR ⁇ activity of 50% or less relative to the activity of rosiglitazone when dosed to produce circulating levels greater than 3 ⁇ M or having a PPAR ⁇ activity of 10 times less than pioglitazone at the same dosage.
  • Another aspect of the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula I, IA, IB, II, ILA, LIB, III, IILA, LILB, or IV.
  • a pharmaceutical composition comprising a compound of Formula I, IA, IB, II, ILA, LIB, III, IILA, LILB, or IV.
  • the compositions of several alternative methods further comprise a pharmaceutically acceptable carrier.
  • Another aspect of the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula II or UA, wherein said compound has a purity of about 70 e.e.% or more.
  • the method treating hypertension, diabetes, and
  • inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula II or ILA 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 antihypertensive agents or other drugs.
  • One aspect of the present invention provides pharmaceutical composition comprising a compound of Formula I, IA, IB, II, IIA, IIB, III, HIA, 1HB, or IV and at least one diuretic, such as hydrochlorothiazide,
  • chlorothaladone chlorothiazide, or combinations thereof.
  • Other aspects provide
  • compositions useful for treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula I, IA, IB, LI, ILA, ILB, LLI, ILIA, LLlB, or IV and one or more agents that limit the activity of the renin-angiotensin system such as angiotensin concerting enzyme (ACE) inhibitors, e.g., ramipril, captopril, enalapril, or the like, and/or angiotensin II receptor blockers (ARBs), e.g., candesartan, losartan, olmesartan, or the like; and/or renin inhibitors.
  • ACE angiotensin concerting enzyme
  • ARBs angiotensin II receptor blockers
  • Still other aspects provide a useful pharmaceutical composition for treating hypertension, diabetes, and inflammatory diseases comprising of a compound of Formula I, IA, LB, LI, LlA, HB, III, LlLA, LlIB, or IV and one or more compounds that reduce hypertension, diabetes, and/or inflammatory diseases including, for example, ⁇ -adrenergic receptor blockers, calcium channel blockers, e.g., amlodipine, or a combination thereof.
  • compositions that are useful for lowering lipids comprising compounds of Formula I, IA, LB, H, HA, HB, III, HIA, HIB, or IV and one or more statin, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any statin, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any statin, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin
  • Another aspect of the present invention provides a combination of a compound of Formula I, LA, LB, H, LlA, LIB, HI, LlLA, HLB, or IV with one or more antihypertensive agents including diuretics (for example hydrochlorothiazide, chlorothaladone, chlorothiazide), angiotensive converting enzyme (ACE) inhibitors, e.g., ramipril, captopril, enalapril, combinations thereof, or the like; angiotensin Ll receptor blockers (ARBs), e.g., losartan, olmesartan, telmisartan, combinations thereof, or the like; renin inhibitors; ⁇ -adrenergic receptor blockers, statins, or any combination thereof.
  • diuretics for example hydrochlorothiazide, chlorothaladone, chlorothiazide
  • ACE angiotensive converting enzyme
  • ARBs angiotensin
  • the compounds of Formula I, IA, IB, ⁇ , UA, IIB, IH, IIIA, IIIB, or IV may be readily synthesized from commercially available or known starting materials by known methods. Exemplary synthetic routes to produce compounds of Formula I, IA, IB, ⁇ , HA,
  • the starting material Ia is reduced to form the aniline Ib.
  • the aniline Ib is diazotized in the presence of hydrobromic acid, acrylic acid ester, and a catalyst such as cuprous oxide to produce the alpha-bromo acid ester Ic.
  • the alpha-bromo acid ester Ic is cyclized with thiourea to produce racemic thiazolidinedione Id.
  • Compounds of Formula II can be separated from the racemic mixture using any suitable process such as HPLC.
  • R 2 is an oxo group or -O-Q and R 3 is hydrogen.
  • the starting material 2a is reacted with 4- hydroxybenzaldehyde under basic conditions (e.g., aq. NaOH) to give a mixture of regioisomeric alcohols 2b that were separated by chromatography.
  • the regioisomeric alcohols 2b is reacted with 2,4-thiazolidine dione using pyrrolidine as base to give compound 2c.
  • Cobalt catalyzed reduction with sodium borohydride affords compound 2d, which is oxidized, for example, with phosphorus pentoxide in the presence of dimethyl sulfoxide, to give the ketone 2e.
  • compounds of Formula I wherein R 2 is -O-Q may be prepared from the hydroxy compound 2d using known methods of alkylation, acylation, sulfonation or phosphorylation.
  • the present invention provides compounds that are useful as treatments for hypertension, diabetes, and inflammatory diseases.
  • 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.
  • certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof.
  • 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 1-4 alkyl) 4 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.
  • the pharmaceutically acceptable 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 emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • 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 emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions
  • 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
  • the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a
  • composition comprising a compound of Formula I, II, IIA or IIB, preferably a mammal, in need thereof.
  • composition is that amount effective for treating or lessening the severity of hypertension, diabetes, and inflammatory diseases.
  • compositions may be administered using any amount and any route of administration effective for treating or lessening the severity of hypertension, diabetes, and inflammatory diseases.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, 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
  • 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.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other 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
  • 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.
  • 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.
  • buffering agents 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 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.
  • the present invention provides a method of treating or reducing the severity of hypertension, diabetes, and inflammatory diseases.
  • Another aspect of the invention relates to treating hypertension, diabetes, and inflammatory 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, IIA or KB.
  • 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.
  • Example 1 5-[4-(2-oxo-2-phenylethoxy)benzyl]-1,3-thiazolidine-2,4-dione.
  • Step 1 Preparation of 4-(2-hydroxy-2-phenylethoxy)benzaldehyde.
  • Step 2 Preparation of 5-[4-(2-hydroxy-2-phenylethoxy)benzylidene]-1,3- thiazolidine-2,4-dione.
  • Step 3 Preparation of 5-[4-(2-hydroxy-2-phenyl €thoxy)b €nzyl]-1,3-thiazolidine- 2,4-dione.
  • Step 4 Preparation of 5-[4-(2-oxo-2-phenyIethoxy)benzyl]-1,3-thiazolidine-2,4- dione.
  • Example 2 Preparation of 5- ⁇ 4-[2-(4-fluorophenyl)-2-oxoethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione.
  • Step 1 Preparation of 4-[2-(fluorophenyl)-2-hydroxyethoxy]benzaldehyde
  • Step 2 Preparation of 5- ⁇ 4-[2-(4-fluorophenyl)-2-hydroxyethoxy]benzylidene ⁇ - 1,3-thiazolidine-2, 4-dione
  • Step 3 Preparation of 5- ⁇ 4-[2-(4-fluorophenyl)- 2-hydroxyethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione
  • Step 4 Preparation of 5- ⁇ 4-[2-(4-fluorophenyl)-2-oxoethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione
  • Example 3 Preparation of 5- ⁇ 4-[2-(2-fluorophenyl)- 2-oxoethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione.
  • Step 3 Preparation of 5- ⁇ 4-[2-(2-fluorophenyl)- 2-hydroxyethoxy]benzylidene ⁇ - 1,3-thiazolidine-2, 4-dione.
  • Step 4 Preparation of 5- ⁇ 4-[2-(2-fluorophenvl)- 2-hydroxyethoxy]benzyl ⁇ - 1,3- thiazolidine-2,4-dione.
  • Step 1 Preparation of 2-(3-fluorophenyl)oxirane
  • Step 2 Preparation of 4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzaldehyde
  • Step 3 Preparation of 5- ⁇ 4-[2-(3-fluorophenyl)- 2-hydroxyethoxy]benzylidene ⁇ - 1,3-thiazolidine-2, 4-dione
  • Step 4 Preparation of 5- ⁇ 4-[2-(3-fluorophenyl)- 2-hydroxyethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione
  • Step 5 Preparation of 5- ⁇ 4-[2-(3-fluorophenyI)- 2-oxoethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione
  • DMSO 0.5 mL
  • Example 5 Preparation of 5- ⁇ 4-[2-(3-methoxyphenyl) -2-oxoethoxy]benzyl ⁇ -1,3 -thiazolidine-2,4-dione.
  • Step 2 4-[2-hydroxy-2-(3-methoxyphe ⁇ yl)ethoxy]benzaldehyde
  • Step 3 5- ⁇ 4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzylidene ⁇ -1,3- thiazolidine-2,4-dione
  • Step 4 5- ⁇ 4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzyl ⁇ -1,3-thiazolidine-
  • Step 5 Preparation of 5- ⁇ 4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione
  • Example 6 Preparation of 5- ⁇ 4-[2-(2-methoxyphenyl) -2-oxoethoxy]benzyl ⁇ - 1,3-thiazolidine-2,4-dione.
  • Step 2 Preparation of 4-[2-hydroxy-2-(2- methoxyphenyl)ethoxy]benzaldehyde
  • Step 3 Preparation of (5Z)-5- ⁇ 4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy] benzylidene ⁇ -1,3-thiazolidine-2,4-dione
  • Step 4 5-(4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzyl ⁇ -1,3-thiazolidine-
  • Step 5 Preparation of 5- ⁇ 4-[2-(2-methoxyphenyl)-2-oxoethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione
  • Example 7 Preparation of 5- ⁇ 4-[2-(3-chlorophenyl)-2-oxoettioxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione.
  • reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried
  • Step 2 4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzaldehyde
  • Step 3 5- ⁇ 4-[2-(3-cMorophenyl)-2-hydroxyethoxy]benzylidene ⁇ -1,3- thiazolidine-2,4-dione
  • Step 4 5- ⁇ 4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzyl ⁇ -1,3-thiazolidine-2,4- dione
  • Step 5 Preparation of 5- ⁇ 4-[2-(3-chlorophenyl)-2-oxoethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione
  • Example 8 Preparation of 5- ⁇ 4-[2-(2-chlorophenyl)-2-oxoethoxy]benzyl ⁇ -1,3- thiazolidine-2,4-dione.
  • the title compound can be prepared as described in Example 7 using appropriate starting materials, such as 2-(2-chlorophenyl)oxirane.
  • activation of the PPAR ⁇ receptor is generally believed to be a selection criteria to select for molecules that may have anti-diabetic and insulin sensitizing pharmacology
  • 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 PPAR ⁇ .
  • the optimal compounds have at least a 10- fold reduced potency as compared to pioglitazone and less than 50% of the full activation produced by rosiglitazone in assays conducted in vitro for transactivation of the PPAR ⁇ receptor.
  • the assays are conducted by first evaluation of the direct interactions of the molecules with the ligand binding domain of PPAR ⁇ .
  • Antidiabetic Thiazolidinedione is a High Affinity Ligand for Peroxisome Proliferator- activated Receptor (PPAR) J. Biol. Chem.(1995) 270: 12953] but will use luciferase as a reporter as in Vosper et al. [Vosper, H., Khoudoli, GA, Palmer, CN (2003) The peroxisome proliferators activated receptor d is required for the differentiation of THP-I moncytic cells by phorbol ester. Nuclear Receptor 1 :9].
  • PPAR Peroxisome Proliferator- activated Receptor
  • 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, 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.
  • 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.
  • Examples 1, 2, 3, 4 and 5 exhibited a plasma insulin level of less than about 5 ng/ml and example 6 exhibited a plasma insulin level between about 15 and 20 ng/ml; examples 1, 2, 3, 4, and 5 exhibited a plasma triglyceride level of between about 100 and 200 mg/dl and example 6 exhibited a plasma triglyceride level between about 300 and 400 mg/dl; examples 1, 2, 3, 4, and 5 exhibited a plasma gluclose level of between about 350 and 425 mg/dl and example 6 exhibited a plasma gluclose level between about 450 and 525 mg/dl.
  • the PPAR ⁇ -sparing compounds of this invention will be more effective for the treatment of diseases caused by metabolic inflammation such as diabetes and metabolic syndrome by limiting the side effects attributable to direct and partial activation of nuclear transcription factors.
  • the compounds of the present invention exhibit reduced PPAR ⁇ activation, it is anticipated that these compounds are suitable for use in combination with other compounds having antidiabetic activity, such as metformin, DDP-4 inhibitors, or other antidibaetic agents that function by differing mechanisms to augment the actions or secretions of GLPl or insulin. Specifically because of the reduced PPAR ⁇ interaction, these compounds will also be useful for treating dyslipidemia associated with metabolic inflammatory diseases combining particularly well with lipid lowering statins such as atorvastatin or the like.

Abstract

The present invention relates to thiazolidinedione analogues that are useful for treating hypertension, diabetes, and inflammatory diseases. In other aspects, the present invention also presents methods of treating hypertension, diabetes, or other inflammatory diseases as well as pharmaceutical compositions that are useful for treating such diseases.

Description

THIAZOLIDINEDIONE ANALOGUES
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Application No.61/159,678, filed on March 12, 2009, and U.S. Application No. 61/161,258, filed on March 18, 2009. Each of these applications is incorporated by reference in its entirety.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention provides a pharmaceutical composition that includes selective thiazolidinedione analogs for use in treating and preventing diabetes, hypertension, diabetes, and inflammatory diseases.
BACKGROUND OF THE INVENTION
[0003] Over the past several decades, scientists have postulated that PPARγ is the generally accepted site of action for insulin sensitizing thiazolidinedione compounds.
[0004] Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor super-family, which 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.
[0005] PPARγ is a key regulator of adipocyte differentiation and lipid metabolism. PPARγ is also found in other cell types including fibroblasts, myocytes, breast cells, human bone- marrow precursors, and macrophages/monocytes. In addition, PPARγ has been shown in macrophage foam cells in atherosclerotic plaques.
[0006] Thiazolidinediones, such as pioglitazone, developed originally for the treatment of type-2 diabetes, generally exhibit high affinity as PPARγ ligands. The finding that thiazolidinedones might mediate their therapeutic effects through direct interactions with PPARγ helped to establish the concept that PPARγ is a key regulator of glucose and lipid homeostasis. However, compounds that involve the activation of PPARγ, such as pioglitazone, also trigger sodium reabsorption and other unpleasant side effects.
SUMMARY OF THE INVENTION
[0007] In general, the invention relates to compounds that have reduced binding and activation of the nuclear transcription factor PPARγ when compared with high affinity PPARγ ligands such as pioglitazone. Compounds exhibiting PPARγ activity induce transcription of genes that favor sodium reabsorption The compounds of this invention have reduced binding or activation of the nuclear transcription factor PPARγ when compared with traditional high affinity PPARγ ligands (e.g., pioglitazone), do not augment sodium reabsorption, and are therefore more useful in treating hypertension, diabetes, and inflammatory diseases. Advantageously, the compounds having reduced PPARγ activity exhibit fewer side effects than compounds having higher levels of PPARγ activity. Most specifically, the reduced PPARγ binding and reduced activity exhibited by these compounds, as compared with traditional high affinity PPARγ ligands (e.g., pioglitazone), are particularly useful for treating hypertension, diabetes, and inflammatory diseases both as single agents and in combination with other classes of antihypertensive agents. As hypertension and inflammatory diseases pose major risk factors in the onset of diabetes and pre-diabetes, these compounds are also useful for the treatment and prevention of diabetes and other inflammatory diseases.
[0008] In one aspect, the present invention provides a pharmaceutical composition useful in treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein:
Each of R1 and R* is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo; R2 is H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2,
-O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(0RB)2 -O-P(O)(ORB)2, or
Figure imgf000003_0002
, wherein each RA independently is optionally substituted C1-6 alkyl, each RB is independently optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl or optionally substituted phenyl; or any two of RB, combined with the atoms to which they are attached, form an optionally substituted 5 to 7 membered ring; or R2 and R2 together may form oxo; R3 is H; and Ring A is phenyl. [0009] Another aspect of the present invention provides methods of treating hypertension, diabetes, and inflammatory diseases with a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.
[0010] Another aspect of this invention provides pharmaceutical compositions comprising a compound of Formula I and at least one diuretic, such as hydrocholothiazide. Other aspects provide pharmaceutical compositions useful for treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula I and one or more agents that limit the activity of the renin-angiotensin system such as angiotensin concerting enzyme (ACE) inhibitors, e.g., ramipril, captopril, enalapril, or the like, and/or angiotensin II receptor blockers (ARBs), e.g., candesartan, losartan, olmesartan, or the like; and/or renin inhibitors. Still other aspects provide a useful pharmaceutical composition for treating hypertension, diabetes, and/or inflammatory diseases comprising a compound of Formula I and one or more compounds that reduce hypertension, e.g., β-adrenergic receptor blockers or calcium channel blockers, e.g., amlodipine, by mediating an alternate biological target.
[0011] This invention also provides pharmaceutical combinations containing a compound of Formula I and a lipid lowering agent. Compounds of Formula I, because of their PPARγ- sparing properties and beneficial effects on lipids (e.g., reducing triglycerides and elevating HDL cholesterol), are particularly useful in combination with 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.
[0012] In another aspect, the invention relates to insulin sensitizers that have reduced binding and reduced activation of the nuclear transcription factor PPARγ and therefore produce reduced sodium reabsorption and fewer dose-limiting side effects. Thus, compounds of Formula I are substantially more effective for treatment and prevention of diabetes and other metabolic inflammation mediated diseases including all aspects of insulin resistance associated with metabolic syndrome such as dyslipidemia and central obesity. The compounds of Formula I are also useful for treating other inflammatory diseases such as rheumatoid arthritis, lupus, myasthenia gravis, vasculitis, Chronic Obstructive Pulmonary Disease (COPD), and inflammatory bowel disease as well as neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, acute allergic reactions, transplant rejections, central obesity, dyslipidemia, prediabetes and diabetes. [0013] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I and metformin.
[0014] In still another aspect, the invention provides pharmaceutical compositions comprising a compound of Formula I, a second agent and a pharmaceutically acceptable carrier, wherein the second agent is selected from dipeptidyl peptidase IV (DPP-4) inhibitors, e.g., sitagliptin, vildagliptin, or the like; statins, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof; GLP-I and -2 agonists; or combinations thereof.
[0015] In still another aspect, the invention provides a combination of compound of Formula I and a glucocorticoid agonist which is useful for treating a number of inflammatory diseases and conditions including therapies of suppressing the immune response, preventing transplant rejections, and treating autoimmune diseases. Exemplary diseases and conditions, include rheumatoid arthritis, lupus, myasthenia gravis, muscular dystrophy vasculitis, multiple sclerosis, Chronic Obstructive Pulmonary Disease (COPD), inflammatory bowel disease, treatment of acute allergic reactions, and transplant rejection.
DETAILED DESCRIPTION
[0016] As used herein, the following definitions shall apply unless otherwise indicated.
[0017] I. DEFINITIONS
[0018] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0019] As described herein, 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.
[0020] As used herein, the term "glucocorticoid agonist" refers to steroid hormones characterized by their ability to bind with the Cortisol receptor. Examples of glucocorticoid agonists include, but are not limited to, Hydrocortisone, Cortisone acetate, Prednisone, Prednisolone, Methylprednisolone, Dexamethasone, Betamethasone, Triamcinolone, Beclometasone, Fludrocortisone acetate, Deoxycorticosterone acetate (DOCA), and Aldosterone.
[0021] As used herein the term "aliphatic" encompasses the terms alkyl, alkenyl, alkynyl, each of which being optionally substituted as set forth below.
[0022] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1-12 (e.g., 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 (Le., 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,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl,
heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g., aliphatic-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkyls include carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.
[0023] As used herein, 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. An 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.,
(aliphatic)carbonyl, (cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyOcarbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino,
heterocycloaliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g.,
alkyl-SO2-, cycloaliphatic-SO2-, or aryl-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl,
(sulfonylamino)alkenyl (such as (alkyl-SO2-amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl, or haloalkenyl.
[0024] As used herein, 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-SCV, aliphaticamino-SOa-, or cycloaliphatic- SO2-], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino,
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, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.
[0025] As used herein, an "amido" encompasses both "aminocarbonyl" and
"carbonylamino". These terms when used alone or in connection with another group refer to an amido group such as -N(RX)-C(O)-RY or -C(O)-N(RX)2, when used terminally, and -C(O)- N(RX)- or -N(RX)-C(O)- when used internally, wherein Rx and Rγ can be aliphatic, cycloaliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaraliphatic.
Examples of amido groups include alkylamido (such as alkylcarbonylamino or
alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.
[0026] As used herein, an "amino" group refers to -NRXRY wherein each of Rx and Rγ 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,
((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or
(heteroaraliphatic)carbonyl, each of which being defined herein and being optionally substituted. Examples of amino groups include alkylamino, dialkylamino, or arylamino. When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NRX-, where Rx has the same meaning as defined above.
[0027] As used herein, an "aryl" group used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" 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 benzofused 2-3 membered carbocyclic rings. For example, a benzofused group includes phenyl fused with two or more C4-S 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;
(heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or
(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-SO2- or amino-SCV]; 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. Alternatively, an aryl can be unsubstituted.
[0028] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g., (alkoxycarbonyl)aryl,
((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g.,
(aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl [e.g.,
((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl; (alkoxy)aryl;
(sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;
(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl;
(((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl;
((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl ; (cy anoalkyl)aryl;
(hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m- alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heterocycloaliphatic)- o-(alkyl))aryl.
[0029] As used herein, an "araliphatic" such as an "aralkyl" group refers to an aliphatic group (e.g., a CM 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.
[0030] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a Q-4 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,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyOcarbonylamino, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyOcarbonylamino, (heterocycloalkylalkyOcarbonylamino,
heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0031] As used herein, 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.
[0032] As used herein, a "cycloaliphatic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which being optionally substituted as set forth below.
[0033] As used herein, 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.
[0034] A "cycloalkenyl" group, as used herein, 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. l]nonenyl.
[0035] 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.,
(aliphatic)carbonylamino, (cycloaliphatic)carbonylamino,
((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl,
((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-S02- and aryl-Sθ2-], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alky 1-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0036] As used herein, the term "heterocycloaliphatic" encompasses heterocycloalkyl groups and heterocycloalkenyl groups, each of which being optionally substituted as set forth below. [0037] As used herein, a "heterocycloalkyl" group 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). Examples of a heterocycloalkyl group 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[fc]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03'7]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures, such as tetrahydroisoquinoline, which would be categorized as heteroaryls.
[0038] A "heterocycloalkenyl" group, as used herein, 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).
Monocyclic and bicyclic heterocycloaliphatics are numbered according to standard chemical nomenclature.
[0039] 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,
heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, ((cycloaliphatic)
aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino,
(heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic) aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (cycloaliphatic)carbonyl,
((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0040] A "heteroaryl" group, as used herein, 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. For example, 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[&]furyl, benzo[&]thiophenyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl, pyridyl, 1H- indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b] furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo- 1,2,5-thiadiazolyl, or 1,8-naphthyridyl.
[0041] Without limitation, monocyclic heteroaryls include furyl, thiophenyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, 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.
[0042] Without limitation, bicyclic heteroaryls include indolizyl, indolyl, isoindolyl, 3H- indolyl, indolinyl, benzo[&]furyl, benzo[&]thiophenyl, quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl, benzo[fc]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.
[0043] 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;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [ e.g., aliphaticcarbonyl; (cycloaliphatic )carbonyl; ((cycloaliphatic)aliphatic)carbonyl;
(araliphatic)carbonyl; (heterocycloaliphatic )carbonyl;
((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl or aminosulfonyl]; sulfϊnyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, a heteroaryl can be unsubstituted. [0044] Non-limiting examples of substituted heteroaryls include (halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and
((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl,
((alkylcarbonyl)amino)heteroaryl, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,
(((heteroaryl)amino)carbonyl)heteroaryl, ((heterocycloaliphatic)carbonyl)heteroaryl, and ((alkylcarbonyl)amino)heteroaryl] ; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl;
(sulfamoyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,
(alkylsulfonyl)heteroaryl] ; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl;
(hydroxy )heteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl)amino)alkyl]heteroaryl;
(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl; (nitroalkyl)heteroaryl;
(((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl;
(cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl; or (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].
[0045] A "heteroaraliphatic (such as a heteroaralkyl group) as used herein, refers to an aliphatic group (e.g., a CM alkyl group) that is substituted with a heteroaryl group.
"Aliphatic," "alkyl," and "heteroaryl" have been defined above.
[0046] A "heteroaralkyl" group, as used herein, refers to an alkyl group (e.g., a C1-4 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,
alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyOcarbonylamino, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalky^carbonylamino, (heterocycloalkylalky^carbonylamino,
heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0047] As used herein, "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. [0048] As used herein, a "bridged bicyclic ring system" refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of 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.l]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[3.3.1.03'7]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,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,
heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[0049] As used herein, an "acyl" group refers to a formyl group or RX-C(O)- (such as alkyl-C(O)-, also referred to as "alkylcarbonyl") where Rx and "alkyl" have been defined previously. Acetyl and pivaloyl are examples of acyl groups.
[0050] As used herein, an "aroyl" or "heteroaroyl" refers to an aryl-C(O)- or a
heteroaryl-C(O)-. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
[0051] As used herein, an "alkoxy" group refers to an alkyl-O- group where "alkyl" has been defined previously.
[0052] As used herein, a "carbamoyl" group refers to a group having the structure
-O-CO-NRXRY or -NRX-CO-O-RZ, wherein Rx and Rγ have been defined above and Rz can be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.
[0053] As used herein, a "carboxy" group refers to -COOH, -COORX, -OC(O)H,
-OC(O)RX, when used as a terminal group; or -OC(O)- or -C(O)O- when used as an internal group.
[0054] As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogen. For instance, the term haloalkyl includes the group -CF3.
[0055] As used herein, a "mercapto" group refers to -SH. [0056] As used herein, a "sulfo" group refers to -SO3H or -SC>3RX when used terminally or
-S(O)3- when used internally.
[0057] As used herein, a "sulfamide" group refers to the structure -NRX-S(O)2-NRYRZ when used terminally and -NRX-S(O)2-NRY- when used internally, wherein Rx, Rγ, and Rz have been defined above.
[0058] As used herein, a "sulfamoyl" group refers to the structure -O-S(O)2-NRYRZ wherein Rγ and Rz have been defined above.
[0059] As used herein, a "sulfonamide" group refers to the structure -S(O)2-NRXRY or
-NRX-S(O)2-RZ when used terminally; or -S(O)2-NRX- or -NRX -S(O)2- when used internally, wherein Rx, Rγ, and Rz are defined above.
[0060] As used herein a "sulfanyl" group refers to -S-Rx when used terminally and -S- when used internally, wherein Rx has been defined above. Examples of sulfanyls include aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like.
[0061] As used herein a "sulfinyl" group refers to -S(O)-RX when used terminally and -
S(O)- when used internally, wherein Rx has been defined above. Exemplary sulfinyl groups include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-, cycloalkyl-S(O)-, heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like.
[0062] As used herein, a "sulfonyl" group refers to -S(O)2-RX when used terminally and
-S(O)2- when used internally, wherein Rx has been defined above. Exemplary sulfonyl groups include aliphatic-S(O)2-, aryl-S(O)2-, (cycloaliphatic(aliphatic))-S(O)2-,
cycloaliphatic-S(O)2-, heterocycloaliphatic-S(O)2-, heteroaryl-S(O)2-,
(cycloaliphatic(amido(aliphatic)))-S(O)2- or the like.
[0063] As used herein, a "sulfoxy" group refers to -O-SO-RX or -SO-O-RX, when used terminally and -O-S(O)- or -S(O)-O- when used internally, where Rx has been defined above.
[0064] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.
[0065] As used herein, an "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)-.
[0066] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl has been defined above.
[0067] As used herein, a "carbonyl" refer to -C(O)-.
[0068] As used herein, an "oxo" refers to =0. [0069] As used herein, the term "phospho" refers to phosphinates and phosphonates.
Examples of phosphinates and phosphonates include -P(O)(RP)2, wherein Rp is aliphatic, alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy aryl, heteroaryl, cycloaliphatic or amino.
[0070] As used herein, an "aminoalkyl" refers to the structure (Rx)2N-alkyl-.
[0071] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.
[0072] As used herein, a "urea" group refers to the structure -NRX-CO-NRYRZ and a
"thiourea" group refers to the structure -NRX-CS-NRYRZ when used terminally and
-NRX-CO-NRY- or -NRX-CS-NRY- when used internally, wherein Rx, Rγ, and Rz have been defined above.
[0073] As used herein, a "guanidine" group refers to the structure -N=C(N(RXRY))N(RXRY) or -NRX-C(=NRX)NRXRY wherein Rx and Rγ have been defined above.
[0074] As used herein, the term "amidino" group refers to the structure -C=(NRX)N(RXRY) wherein Rx and Rγ have been defined above.
[0075] In general, 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.
[0076] In general, 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.
[0077] The terms "terminally" and "internally" refer 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., RxO(O)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(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.
[0078] As used herein, 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 -[CH2]V-, 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, at least one Q is an aliphatic group. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.
[0079] The phrase "optionally substituted" is used interchangeably with the phrase
"substituted or unsubstituted." As described herein, compounds of the invention can 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. As described herein, the variables R1, R2, R3, and R4, and other variables contained in Formulae described herein encompass specific groups, such as alkyl and aryl. Unless otherwise noted, each of the specific groups for the variables R1, R2, R3, and R4, 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. For instance, 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. As an additional example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atom(s) to which they are bound.
[0080] In general, the term "substituted," whether preceded by the term "optionally" or not, 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. Unless otherwise indicated, 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, can be bound to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, i.e., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds.
[0081] The phrase "stable or chemically feasible," as used herein, 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. In some embodiments, 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.
[0082] As used herein, 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 Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.
[0083] Unless otherwise stated, 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
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or l4C-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.
[0084] Chemical structures and nomenclature are derived from ChemDraw, version 11.0.1 , Cambridge, MA.
[0085] π. PHARMACEUTICAL COMPOSITIONS
[0086] It is commonly believed that efficacious insulin sensitizing compounds must have high PPARγ activity, and conversely, that compounds having reduced PPARγ activity would yield reduced insulin sensitizing activity. Contrary to this belief, thiazolidinedione compounds of the present invention are uniquely effective in treating hypertension, diabetes, and inflammatory diseases and possess a reduced interaction with PPARγ.
[0087] Without wishing to be bound by theory, it is believed that metabolic inflammation is a central cause of the numerous key diseases including hypertension, diabetes, and inflammatory diseases. It is further believed that thiazolidinediones of the present invention function to prevent hypertension, diabetes, and inflammatory diseases via a mitochondrial mechanism. Furthermore since the dose limiting side effects due to PPARγ interaction are reduced in compounds of the present invention when compared to compounds such as pioglitazone; especially stereoselective isomers, the compounds of Formula I are highly useful for treating hypertension, diabetes, and inflammatory diseases.
[0088] Additionally, since the thiazolidinedione analogues of the present invention function via a mitochondrial mechanism, the compounds of Formula I are useful in treating or preventing all of the disease states wherein metabolic inflammation is the basis of the pathology.
[0089] Furthermore since the dose limiting side effects due to PPARγ interaction are reduced in compounds of the present invention; especially stereoselective isomers, the compounds of Formula I when used in combination with a glucocorticoid agonist can be used for treating inflammatory diseases.
[0090] 1. Compounds
[0091] The present invention provides compounds and pharmaceutical compositions that are useful for treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula I:
Figure imgf000019_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1 and R4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo. R2 is -H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2, -O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or
Figure imgf000020_0001
each RA is independently -H or an optionally substituted C1-6 alkyl; each RB is independently -H, optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted phenyl, or any two of RB, taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring, or R2 and R'2 taken together form oxo; R3 is H or optionally substituted C1-3 aliphatic; and Ring A is
or
Figure imgf000020_0002
Figure imgf000020_0003
[0092] In several embodiments, Ring A is
Figure imgf000020_0004
[0093] In other embodiments, Ring A is phenyl and R1 is attached to the ortho or para position of Ring A. For instance, Ring A is phenyl, R1 is attached to the ortho or para position of Ring A, and R1 is -H or halo; or R1 is -C1-6 aliphatic or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo. In some embodiments, R1 is -C1-6 alkoxy optionally substituted with 1-3 halo. For example, R1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
[0094] In other embodiments, Ring A is phenyl and R1 is attached to the meta or para position of Ring A. For instance, Ring A is phenyl, R1 is attached to the meta position of Ring A. In some embodiments, Ring A is phenyl, R1 is attached to the meta position of Ring A, and R1 is -H or halo; or R1 is -C1-6 aliphatic or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo. For example, R1 is -C1-6 aliphatic optionally substituted with 1-3 halo. In other examples, R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert-butyl, each of which is optionally substituted with 1-3 halo. And, in some examples, R1 is -C1-6 alkoxy optionally substituted with 1-3 halo. For instance, R1 is methoxy, ethoxy, propoxy, butoxy, iso-propoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo. [0095] In some embodiments, when Ring A is phenyl, R1 is -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CF3, -OCHF2, or -OCF3.
[0096] In other embodiments, Ring A is
Figure imgf000021_0001
[0097] In some embodiments, Ring A is
Figure imgf000021_0002
or
Figure imgf000021_0003
[0098] For example, Ring A is
Figure imgf000021_0005
[0099] In another example, Ring A is
Figure imgf000021_0004
[00100] In some embodiments, when Ring A is pyridine-2-yl or pyridine-3-yl, R1 is -H or halo; or R1 is -C1-6 aliphatic, or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo. For instance, R1 is -H. In other instances, R[ is -C1-6 aliphatic optionally substituted with 1-3 halo. For example, R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert-butyl, each of which is optionally substituted with 1-3 halo. In some instances, R1 is -C1-6 alkoxy optionally substituted with 1-3 halo. For example, R1 is methoxy, ethoxy, propoxy, butoxy, iso-propoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
[00101] In several embodiments, when Ring A is pyridine-2-yl or pyridine-3-yl, R4 is independently -H or halo.
[00102] In some embodiments, Ring A d it b tit nts R1 and R4 form
Figure imgf000022_0001
[00103] In other embodiments, Ring A and its substituents R1 and R4 form
Figure imgf000022_0002
,
[00104] In some embodiments, R2 is -OH. In others, R2 is -O-acyl, -O-aroyl or -O- heteroaroyl. And in some instances, R2 and R'2 together form oxo. In other embodiments, R2 is -H, -OH,
Figure imgf000022_0003
Figure imgf000023_0001
[00105] In some embodiments, R3 is -H or -CH3.
[00106] Another aspect of the present invention provides a compound of Formula (IA):
Figure imgf000023_0002
or a pharmaceutically acceptable salt thereof, wherein each of R1 and R4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo; R'2 is -H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2, -O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or
Figure imgf000023_0003
each RA is independently -H or an optionally substituted Q-6 alkyl; each RB is independently -H, optionally substituted C1-I2 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted phenyl, or any two of RB, taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring, or R2 and R'2 taken together form oxo; R3 is H; and Ring A is phenyl.
[00107] In some embodiments, in Formula IA, R1 is attached to the ortho or para position of Ring A. For example, R1 is attached to the ortho or para position of Ring A, and R1 is -H or halo; or R1 is -C1-6 aliphatic or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo. For example, R1 is -C1-δ alkoxy optionally substituted with 1-3 halo. In other examples, R1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo. [00108] In some embodiments, R1 is attached to the meta or para position of Ring A. For instance, R1 is attached to the meta position of Ring A. In some embodiments, R1 is attached to the meta or para position of Ring A, and R1 is -H or halo; or R1 is -C1-6 aliphatic or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo. For instance, R1 is -C1-6 aliphatic optionally substituted with 1-3 halo. In some examples, R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert-butyl, each of which is optionally substituted with 1-3 halo. In other instances, R1 is -C1-6 alkoxy optionally substituted with 1-3 halo. For example, R1 is methoxy, ethoxy, propoxy, butoxy, iso-propoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
[00109] In other embodiments, R1 is -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CF3, -OCHF2, or
-OCF3.
[00110] In several embodiments, in the compound of Formula IA, R4 is -H, methyl, ethyl, methoxy, ethoxy, iso-propoxy, -CF3, -OCHF2 or -OCF3. For example, R4 is H.
[00111] In other embodiments, Ring A and its substituents R1 and R4 form
Figure imgf000024_0001
[00112] In some embodiments, R2 is hydroxy. In others, R2 is -O-acyl, -O-aroyl or
-O-heteroaroyl. For example, R2 is -O-CH(RA)-O-C(O)RB, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6 alkyl, -C3-8cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo. In other embodiments, R2 is -O-CH(RA)OP(O)(ORB)2, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6 alkyl, -C3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo. And, in others, R2 is -O- P(O)(ORB)2, and RB is -C1-4 alkyl optionally substituted with 1-3 halo, or two RB groups together with the atoms to which they are attached form an optionally substituted 5-7 membered ring. In some embodiments, R2 is -0-SO2NH2. In some embodiments, R2 is
Figure imgf000025_0001
, and RB is -H or an optionally substituted C1-4 alkyl.
[00113] And, in some embodiments, R2 and R2 together form oxo.
[00114] In several embodiments, R1 is H. In some embodiments, R1 is halo, such as F or Cl. In some embodiments, R1 is an aliphatic optionally substituted with 1-3 halo. For instance, R1 is trifluoromethyl. In some embodiments, R1 is alkoxy. For instance, R1 is methoxy, ethoxy, or -O-isopropyl. In still other embodiments, R1 is alkoxy substituted with 1-3 halo. For instance, R1 is -OCHF2 or -OCF3. In each of the foregoing embodiments, R1 can be substituted at the ortho, meta, or para position on the phenyl ring. In certain embodiments, R1 is substituted at the para or meta position on the phenyl ring.
[00115] In several embodiments, R4 is H. In some embodiments, R4 is halo, such as F or Cl. In some embodiments, R4 is an aliphatic optionally substituted with 1-3 halo. For instance, R4 is trifluoromethyl. In some embodiments R4 is alkoxy. For instance, R4 is methoxy, ethoxy, or -O-isopropyl. In still other embodiments, R4 is alkoxy substituted with 1-3 halo. For instance, R4 is -OCHF2 or -OCF3. In each of the foregoing embodiments, R4 can be substituted at the ortho, meta, or para position of the phenyl ring. In certain embodiments, R4 is substituted at the para or meta position on the phenyl ring. In some embodiments, R1 and R4 are different substituents. In still other embodiments, Rt and R4 are the same substituent. In some embodiments when R1 is aliphatic, R4 is other than H.
[00116] In several embodiments, each of R1 and R4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo, provided that when one of R1 and R4 is H then the other is not ethyl.
[00117] In several embodiments, each of R( and R4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo, provided that when one of R1 and R4 is H then the other is not ethyl substituted at the 4 poistion of the phenyl.
[00118] In several embodiments, R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O- heteroaroyl, -0(SO2)NH2, -O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or
Figure imgf000026_0001
, wherein each RA is -H or optionally substituted C1-6 alkyl, each RB is -H or optionlly substituted C1-I2 alkyl, optionally substituted C3-8 cycloalkyl or optionally substituted phenyl, wherein each of RA and RB is defined above.
[00119] In some embodiments, R2 is hydroxy.
[00120] In some embodiments, R2 is an optionally substituted straight or branched C1-6 alkyl, an optionally substituted straight or branched C2-6 alkenyl, or an optionally substituted straight or branched C2-6 alkynyl. In other embodiments, R2 is a C1-6 aliphatic optionally substituted with 1-2 hydroxy, carboxy or halo. In other embodiments, R2 is a C1-6 alkyl optionally substituted with hydroxy, In further embodiments, R2 is a C1-6 alkyl optionally substituted with -O-acyl, -O-aroyl, -0-heteroaroyl. In several other embodiments, R2 is a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl, each of which is optionally substituted with hydroxy. In several additional embodiments , R2 is methyl or ethyl, each of which is substituted with hydroxy.
[00121] In certain embodiments, R2 is -O-acyl, -O-aroyl or -O-heteroaryoyl.
[00122] In other embodiments, R2 is -O-acetyl, -O-hexanoyl, -O-benzoyl, -O-pivaloyl, -O- imidazolyl, -O-succinoyl, -O-thiazoloyl or -O-pyridinoyl, each of which is optionally substituted.
[00123] In some embodiments, R2 is -O-C(O)-imidazol-1-yl.
[00124] In certain embodiments, R2 is -O-CH(RA)-O-C(O)-RB.
[00125] In some embodiments, R2 is -O-CH(RA)OP(O)(ORB)2.
[00126] In some embodiments, R2 is -O-P(O)(ORB)2.
[00127] In other embodiments, R2 is -0-S(O2)NH2.
[00128] In some embodiments, two RB groups together with the atoms to which they are attached, form an optionally substituted 5 to 7 membered cycloaliphatic or
heterocycloaliphatic ring.
[00129] In some further embodiments, R2 is
Figure imgf000026_0002
, wherein RB is defined above.
[00130] In several embodiments, R'2 is H.
[00131] In some embodiments, R2 and R'2 together form oxo. [00132] In some embodiments, R2 is H and the carbon atom to which R2 and R2 are attached has an R configuration.
[00133] In some embodiments, R'2 is H and the carbon atom to which R'2 and R2 are attached has an S configuration.
[00134] In some embodiments, R2 is H and the carbon atom to which R2 and R2 are attached is racemic.
[00135] In some embodiments, when one of R1 or R4 is H, the other is not ethyl.
[00136] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formulae I or IA and a pharmaceutically acceptable carrier.
[00137] Another aspect of the present invention provides a compound of Formulae π, HA, or
ΠB:
II
IIA
Figure imgf000027_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4 and Ring A are defined above in Formula IA. [00138] Another aspect of the present invention provides a compound of Formulae π, ILA, or IIB and a pharmaceutically acceptable carrier. Exemplary compositions according to the
present invention include a single unit dosage form having from about 1 mg to about 200 mg
of a compound of Formula I , II, ILA or IIB, e.g., from about 10 mg to about 120 mg, from
about 10 mg to about 100 mg, or from about 15 mg to about 60 mg.
[00139] Exemplary compounds of Formula I or Formula IA, wherein R2 and R2 together
form oxo include:
Figure imgf000028_0002
Figure imgf000028_0001
[00140] Exemplary compounds of Formula I or Formula IA, wherein R2 is -OH and the carbon atom to which R2 and R2 are attached has an S configuration include:
Figure imgf000029_0001
[00141] Exemplary compounds of Formula I or Formula IA, wherein R2 is -OH and the carbon atom to which R2 and R'2 are attached has an R configuration include:
Figure imgf000030_0001
.
[00142] Exemplary compounds of Formula I or Formula IA, wherein R2 is -OH include:
Figure imgf000030_0002
Figure imgf000031_0001
[00143] Exemplary compounds of Formula I or Formula IA, wherein R2 is -O-acyl, -O-aroyl or -O-heteroaroyl include
Figure imgf000031_0002
Figure imgf000032_0001
Figure imgf000033_0001
[00144] Exemplary compounds of Formula I or Formula IA, wherein R2 is R2 is -O-CH(RA)- O-C(O)RB, wherein RA and RB are defined above, include:
Figure imgf000033_0002
[00145] Exemplary compounds of Formula I or Formula IA, wherein R2 is R2 is -O- CH(RA)OP(O)(ORB)2, wherein RA and RB are defined above, include:
Figure imgf000034_0001
[00146] Exemplary compounds of Formula I or Formula IA, wherein R2 is -0-P(O)(OR )2, wherein RB is defined above, include:
Figure imgf000034_0002
Figure imgf000035_0001
[00147] Exemplary compounds of Formula I or Formula IA, wherein R2 is -0-SO2NH2 include:
Figure imgf000035_0002
[00148] Other exemplary compounds of Formula I or Formula IA include:
Figure imgf000035_0003
or
[00149] Another aspect of the present invention provides a compound of Formula (IB):
Figure imgf000036_0002
(IB)
or a pharmaceutically acceptable salt thereof, wherein each of R1 and R4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo; R2 is -H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2, -O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or
Figure imgf000036_0003
; each RA is independently -H or an optionally substituted C1-6 alkyl; each RB is independently -H, optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted phenyl, or any two of RB, taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring, or R2 and R2 taken together form oxo; R3 is H or optionally substituted C 1-3 aliphatic; and Ring A is
Figure imgf000036_0004
[00150] In several embodiments, R3 is H. In others, R3 is methyl.
[00151] In some embodiments, Ring A is
Figure imgf000037_0001
[00152] In other embodiments, Ring A is
Figure imgf000037_0002
[00153] In some of these embodiments of compounds of Formula IB, R1 is -H or halo; or R1 is -C1-6 alkyl or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo. For example, R, is -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CF3, -OCHF2, or -OCF3. In other examples, R1 is H. In some examples, R1 is ethyl.
[00154] In some embodiments, R4 is -H, methyl, ethyl, methoxy, ethoxy, iso-propoxy, -CF3,
-OCHF2 or -OCF3. For example, R4 is -H.
[00155] In some embodiments, Ring A and its substituents R1 and R4 form
Figure imgf000037_0003
[00156] In other embodiments, R2 is -O-acyl, -0-aroyl, or -O-heteroaroyl. For example, R2 is -O-CH(RA)-O-C(O)RB, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6 alkyl, -C3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo. In other examples, R2 is -0-CH(RA)OP(0)(ORB)2, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6 alkyl, -C3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo. In some embodiments, R2 is -O-P(O)(ORB)2, and RB is -C1-4 alkyl optionally substituted with 1-3 halo, or two RB groups together with the atoms to which they are attached form an optionally substituted 5-7 membered ring. In some embodiments, R2 is -0-SO2NH2. In other embodiments, R2 is
Figure imgf000038_0001
, and RB is -H or an optionally substituted C1-4 alkyl.
[00157] In several embodiments, R1 is H. In some embodiments, R1 is halo, such as F or Cl. In some embodiments, R1 is an aliphatic optionally substituted with 1-3 halo. For instance, R1 is methyl, ethyl or trifluoromethyl. In some embodiments, R1 is alkoxy. For instance, R1 is methoxy, ethoxy, or -O-isopropyl. In still other embodiments, R1 is alkoxy substituted with 1-3 halo. For instance, R1 is -OCHF2 or -OCF3. In each of the foregoing embodiments, R1 can be substituted at the ortho, meta, or para position on the pyridine ring. In certain embodiments, R1 is substituted at the ortho or meta position on the pyridine ring.
[00158] In several embodiments, R4 is H.
[00159] In some embodiments, R4 is H and R1 is C1.3 alkyl.
[00160] In some embodiments, R4 is halo, such as F or Cl. In some embodiments, R4 is an aliphatic optionally substituted with 1-3 halo. For instance, R4 is trifluoromethyl. In some embodiments R4 is alkoxy. For instance, R4 is methoxy, ethoxy, or -O-isopropyl. In still other embodiments, R4 is alkoxy substituted with 1-3 halo. For instance, R4 is -OCHF2 or -OCF3. In each of the foregoing embodiments, R4 can be substituted at the ortho, meta, or para position relative to the N of the pyridine ring. In certain embodiments, R4 is substituted at the para or meta position on the pyridine ring. In some embodiments, R1 and R4 are different substituents. In still other embodiments, R1and R4 are the same substituent. In several embodiments, each of R1 and R4 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic and alkoxy are optionally substituted with 1-3 of halo.
[00161] In several embodiments, R2 is -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2, -O- CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORA)2, -O-P(O)(ORA)2
or
Figure imgf000038_0002
1 wherein each RA is -H or optionally substituted C1-6 alkyl, RB is -H or optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl or optionally substituted phenyl; or any two of RB, combined with the atoms to which they are attached, may form an optionally substituted 5 to 7 membered ring.
[00162] In certain embodiments, R2 is -O-acyl, -O-aroyl or -O-heteroaryoyl. [00163] In other embodiments, R2 is -O-acetyl, -O-hexanoyl, -O-benzoyl, -O-pivaloyl, -O- imidazolyl, -O-thiazoloyl or -O-pyridinoyl, each optionally substituted.
[00164] In some embodiments, R2 is -0-C(0)-imidazol-1-yl.
[00165] In certain embodiments, R2 is -O-CH(RA) -0-C(O)- RB.
[00166] In some embodiments, R2 is -O-CH(RA)OP(O)(ORB)2.
[00167] In some embodiments, R2 is -O-P(O)(ORB)2.
[00168] In other embodiments, R2 is -O S(O2)NH2.
[00169] In some further embodiments, R2 is a 1,3-dioxolan-2-one of the Formula
Figure imgf000039_0001
, wherein RA and RB are as described previously.
[00170] In several embodiments, R'2 is H.
[00171] In some embodiments, R2 is H and R2 has an R configuration.
[00172] In some embodiments, R2 is H and R2 has an S configuration.
[00173] In some embodiments, R'2 is H and R2 is racemic.
[00174] In some embodiments, when one of R1 or R4 is H, the other is not ethyl.
[00175] In further embodiments, the invention provides a pharmaceutical composition which includes compounds of the Formula
Figure imgf000039_0002
or
Figure imgf000039_0003
wherein R2 is H, R1, R3, and R4 are defined above in Formula IB, Ring A is 2-pyridinyl or 3- pyridinyl and R2 is -O-Q wherein Q is -acyl, -aroyl or -heteroaryoyl.
[00176] In further embodiments, Q is -acetyl, -hexanoyl, -benzoyl, -pivaloyl, -succinoyl, each optionally substituted.
[00177] In certain embodiments, Q is acetyl.
[00178] In certain embodiments, Q is hexanoyl.
[00179] In certain embodiments, Q is benzoyl.
[00180] In certain embodiments, Q is pivaloyl.
[00181] In certain embodiments, Q is succinoyl.
[00182] In several embodiments, the composition further comprises a pharmaceutically acceptable carrier. [00183] Another aspect of the present invention provides a pharmaceutical composition to include a compound of Formula III, IIIA, or IIIB:
Figure imgf000040_0001
or a pharmaceutically acceptable salt thereof, wherein R'2 is H, and R1, R2, R3, R4 and Ring A are defined above in Formula IB.
[00184] Exemplary compositions according to the present invention includes a single unit dosage form having about 1 mg to about 200 mg of a compound of Formula IB, IV, IVA or IVB, e.g., between about 10 mg to about 120 rag, between about 10 mg to about 100 mg, or about 15 mg to about 60 mg.
In some embodiments, the compound of Formula IB, III, IIIA or IIIB includes:
Figure imgf000041_0001
[00186] In some embodiments, the compound of Formula BB, III, IIIA or IIIB includes:
Figure imgf000041_0002
Figure imgf000042_0001
[00187] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula IB, HI, πiA or HIB wherein the compound has a PPARγ activity of 50% or less relative to the activity of rosiglitazone when dosed to produce circulating levels greater than 3 μM or having a PPARγ activity of 10 times less than pioglitazone at the same dosage.
[00188] Another aspect of the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula IB, HC, III A or IIIB. The compositions of several alternative methods further comprise a pharmaceutically acceptable carrier.
[00189] Another aspect of the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula III or IIIA, wherein said compound has a purity of about 70% e.e. or more. For example, the method treating hypertension, diabetes, and
inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula III or IIIA, 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).
[00190] Pharmaceutical compositions of the present invention can also comprise one or more additional antihypertensive agents or other drugs. One aspect of the present invention provides pharmaceutical composition comprising a compound of Formula IB, III, IIIA or IIIB and at least one diuretic, such as hydrochlorothiazide, chlorothaladone, chlorothiazide, or combinations thereof. Other aspects provide pharmaceutical compositions useful for treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula IB, III, IIIA or IIIB and one or more agents that limit the activity of the renin-angiotensin system such as angiotensin concerting enzyme inhibitors, i.e. ACE inhibitors, e.g. ramipril, captopril, enalapril, or the like, and/or angiotensin II receptor blockers, i.e. ARBs, e.g.candesartan, losartan, olmesartan, or the like; and/or renin inhibitors. Still other aspects provide a useful pharmaceutical composition for treating hypertension, diabetes, and inflammatory diseases comprising of a compound of Formula IB, III, IIIA or IIIB and compounds that limit hypertension, diabetes, and inflammatory diseases by alternate means including β-adrenergic receptor blockers, and calcium channel blockers (e.g., amlodipine).
[00191] This invention also provides pharmaceutical compositions that are useful for lowering lipids comprising compounds of Formula IB, III, HLA or IIIB and one or more statin, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any pharmaceutically acceptable combination thereof.
[00192] Another aspect of the present invention provides a combination of a compound of Formula IB, IQ, IIIA or IIIB with one or more antihypertensive agents including diuretics (for example hydrochlorothiazide, chlorothaladone, chlorothiazide), angiotensive converting enzyme inhibitors, e.g., ACE inhibitors, e.g., ramipril, captopril, enalapril, combinations thereof, or the like; angiotensin II receptor blockers, i.e., ARBs, e.g., losartan, olmesartan, telmisartan, combinations thereof, or the like; renin inhibitors; β-adrenergic receptor blockers, statins, or combinations thereof.
[00193] In one aspect, the invention provides compounds of Formula IV
Figure imgf000044_0001
wherein Q is acyl, aroyl, heteroaroyl, SO2NH2, CH(RA)OC(O)RB, CH(RA)OP(O)(ORA)2 ,
P(O)(ORB)2 or
Figure imgf000044_0002
,wherein each RA is -H or optionally substituted C1-6 alkayl, RB is -H or optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl or optionally substituted phenyl, wherein each substituent is optionally substituted; and any two of RB, combined with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring.
[00194] In some embodiments, Q is -acetyl, -hexanoyl, -benzoyl, -pivaloyl, -succinoyl, each optionally substituted.
[00195] In certain embodiments, Q is acetyl.
[00196] In certain embodiments, Q is hexanoyl.
[00197] In certain embodiments, Q is benzoyl.
[00198] In certain embodiments, Q is pivaloyl.
[00199] In certain embodiments, Q is succinoyl.
[00200] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of Formula I, IA, IB, II, ILA, ILB, ILL, ILIA, IILB, or IV, wherein the compound has a PPARγ activity of 50% or less relative to the activity of rosiglitazone when dosed to produce circulating levels greater than 3 μM or having a PPARγ activity of 10 times less than pioglitazone at the same dosage.
[00201] Another aspect of the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula I, IA, IB, II, ILA, LIB, III, IILA, LILB, or IV. The compositions of several alternative methods further comprise a pharmaceutically acceptable carrier.
[00202] Another aspect of the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula II or UA, wherein said compound has a purity of about 70 e.e.% or more. For example, the method treating hypertension, diabetes, and
inflammatory diseases comprising administering a pharmaceutical composition comprising a compound of Formula II or ILA 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).
[00203] Pharmaceutical compositions of the present invention can also comprise one or more additional antihypertensive agents or other drugs. One aspect of the present invention provides pharmaceutical composition comprising a compound of Formula I, IA, IB, II, IIA, IIB, III, HIA, 1HB, or IV and at least one diuretic, such as hydrochlorothiazide,
chlorothaladone, chlorothiazide, or combinations thereof. Other aspects provide
pharmaceutical compositions useful for treating hypertension, diabetes, and inflammatory diseases comprising a compound of Formula I, IA, IB, LI, ILA, ILB, LLI, ILIA, LLlB, or IV and one or more agents that limit the activity of the renin-angiotensin system such as angiotensin concerting enzyme (ACE) inhibitors, e.g., ramipril, captopril, enalapril, or the like, and/or angiotensin II receptor blockers (ARBs), e.g., candesartan, losartan, olmesartan, or the like; and/or renin inhibitors. Still other aspects provide a useful pharmaceutical composition for treating hypertension, diabetes, and inflammatory diseases comprising of a compound of Formula I, IA, LB, LI, LlA, HB, III, LlLA, LlIB, or IV and one or more compounds that reduce hypertension, diabetes, and/or inflammatory diseases including, for example, β-adrenergic receptor blockers, calcium channel blockers, e.g., amlodipine, or a combination thereof.
[00204] This invention also provides pharmaceutical compositions that are useful for lowering lipids comprising compounds of Formula I, IA, LB, H, HA, HB, III, HIA, HIB, or IV and one or more statin, i.e., HMG-CoA reductase inhibitor, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, simvastatin, rosuvastatin, pravastatin, or any
pharmaceutically acceptable combination thereof.
[00205] Another aspect of the present invention provides a combination of a compound of Formula I, LA, LB, H, LlA, LIB, HI, LlLA, HLB, or IV with one or more antihypertensive agents including diuretics (for example hydrochlorothiazide, chlorothaladone, chlorothiazide), angiotensive converting enzyme (ACE) inhibitors, e.g., ramipril, captopril, enalapril, combinations thereof, or the like; angiotensin Ll receptor blockers (ARBs), e.g., losartan, olmesartan, telmisartan, combinations thereof, or the like; renin inhibitors; β-adrenergic receptor blockers, statins, or any combination thereof. [00206] in. GENERAL SYNTHETIC SCHEMES
[00207] The compounds of Formula I, IA, IB, π, UA, IIB, IH, IIIA, IIIB, or IV may be readily synthesized from commercially available or known starting materials by known methods. Exemplary synthetic routes to produce compounds of Formula I, IA, IB, π, HA,
IIB, HI, IIIA, IIIB, or IV are provided below in Schemes 1 and 2 below.
Scheme 1:
Figure imgf000046_0001
[00208] Referring to Scheme 1, the starting material Ia is reduced to form the aniline Ib. The aniline Ib is diazotized in the presence of hydrobromic acid, acrylic acid ester, and a catalyst such as cuprous oxide to produce the alpha-bromo acid ester Ic. The alpha-bromo acid ester Ic is cyclized with thiourea to produce racemic thiazolidinedione Id. Compounds of Formula II can be separated from the racemic mixture using any suitable process such as HPLC.
[00209] In Scheme 2 below, R2 is an oxo group or -O-Q and R3 is hydrogen.
Scheme 2:
Figure imgf000047_0001
[00210] Referring to Scheme 2, the starting material 2a is reacted with 4- hydroxybenzaldehyde under basic conditions (e.g., aq. NaOH) to give a mixture of regioisomeric alcohols 2b that were separated by chromatography. The regioisomeric alcohols 2b is reacted with 2,4-thiazolidine dione using pyrrolidine as base to give compound 2c. Cobalt catalyzed reduction with sodium borohydride affords compound 2d, which is oxidized, for example, with phosphorus pentoxide in the presence of dimethyl sulfoxide, to give the ketone 2e. Alternatively, compounds of Formula I wherein R2 is -O-Q, may be prepared from the hydroxy compound 2d using known methods of alkylation, acylation, sulfonation or phosphorylation.
[00211] IV. USES, FORMULATIONS, AND ADMINISTRATION
[00212] As discussed above, the present invention provides compounds that are useful as treatments for hypertension, diabetes, and inflammatory diseases.
[00213] Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. [00214] It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative or a prodrug thereof. According to the present invention, 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.
[00215] As used herein, 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.
[00216] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds 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. Other pharmaceutically acceptable 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 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.
[00217] As described above, the pharmaceutically acceptable 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 emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the
pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of 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 acetate; powdered tragacanth; malt; gelatin; talc; 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.
[00218] In yet another aspect, the present invention provides a method of treating hypertension, diabetes, and inflammatory diseases comprising administering a
pharmaceutical composition comprising a compound of Formula I, II, IIA or IIB, preferably a mammal, in need thereof.
[00219] According to the invention an "effective amount" of the compound or
pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of hypertension, diabetes, and inflammatory diseases.
[00220] The pharmaceutical compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of hypertension, diabetes, and inflammatory diseases.
[00221] The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, 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. The expression "dosage unit form" as used herein 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. The term "patient", as used herein, means an animal, for example, a mammal, and more specifically a human.
[00222] The pharmaceutically acceptable 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. In certain embodiments, 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. Alternatively, the compounds of the invention may be
administered orally or parenterally at dosage levels of between 10 mg/kg and about 120 mg/kg.
[00223] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00224] 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00225] 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. [00226] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other 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.
[00227] 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.
[00228] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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 and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[00229] 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.
[00230] 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. In such solid dosage forms 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. In the case of capsules, tablets and pills, 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.
[00231] 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. Additionally, 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. [00232] As described generally above, the compounds of the invention are useful as treatments for hypertension, diabetes, and inflammatory diseases.
[00233] The activity, or more importantly, reduced PPARγ activity of a compound utilized in this invention as a treatment of hypertension, diabetes, and inflammatory diseases may be assayed according to methods described generally in the art and in the examples herein.
[00234] It will also be appreciated that 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. It will also be appreciated that 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). As used herein, 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".
[00235] 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. Preferably 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.
[00236] The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
Accordingly, 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. In still another aspect, 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.
[00237] According to yet another embodiment, the present invention provides a method of treating or reducing the severity of hypertension, diabetes, and inflammatory diseases.
[00238] Another aspect of the invention relates to treating hypertension, diabetes, and inflammatory 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, IIA or KB. The term "biological sample", as used herein, 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.
[00239] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
[00240] V. EXAMPLES
[00241] Example 1: 5-[4-(2-oxo-2-phenylethoxy)benzyl]-1,3-thiazolidine-2,4-dione.
Figure imgf000055_0001
[00242] Step 1. Preparation of 4-(2-hydroxy-2-phenylethoxy)benzaldehyde.
[00243] To 2-(4-fluorophenyl)oxirane (6.50 g, 54.0 mmol) was added toluene (85 mL), 4-hydroxybenzaldehyde (9.89 g, 81.0 mmol), PEG4000 (polyethylene glycol, 1.15 g) and IM NaOH (85 mL) and the stirring mixture was heated at 78 °C overnight. After cooling to RT the reaction mixture was extracted with EtOAc, and the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on a medium silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing predominandy the higher Rf spot were combined and evaporated in vacuo to give 1.85g (14%) of the title compound as a yellow oil. Fractions containing predominantly the lower Rf spot were combined and evaporated in vacuo to give 0.64g of the regioisomer as a colorless, viscous oil. Mixed fractions were combined and rechromatographed eluting with 30% EtOAc/hexanes. Fractions containing the higher Rf material were combined and evaporated in vacuo to give an additional 2.64 g (20%) of the title compound as a colorless oil. Fractions containing die lower Rf material were combined and evaporated in vacuo to give an additional 1.82 g of the regioisomer as a colorless viscous oil.
[00244] Step 2: Preparation of 5-[4-(2-hydroxy-2-phenylethoxy)benzylidene]-1,3- thiazolidine-2,4-dione.
[00245] To a stirring solution of 4-[(2S)-2-hydroxy-2-phenylethoxy]benzaldehyde (2.63 g, 10.8 mmol) in absolute EtOH (75 mL) was added 2,4-thiazolidinedione (1.27 g, 10.8 mmol) and piperidine (0.54 mL, 5.4 mmol), and the resulting solution was heated to reflux. The reaction was refluxed overnight. The reaction mixture was allowed to cool to RT. No precipitate formed. The pH of reaction mixture was ca. 5. Acetic acid (20 drops) was added, and the reaction was evaporated in vacuo. The material was adsorbed onto silica gel and chromatographed eluting with 30-40% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 3.18g (86%) of die title compound as a light yellow solid. MS (ESI-) for C18Hi5NO4S m/z 340.1 (M-H)-.
[00246] Step 3: Preparation of 5-[4-(2-hydroxy-2-phenyl€thoxy)b€nzyl]-1,3-thiazolidine- 2,4-dione.
[00247] To a mixture of 5-[4-(2-hydroxy-2-phenylethoxy)benzylidene]-1,3-thiazolidine-2,4- dione (1.50 g, 4.39 mmol) in THF (20 mL) was added H2O (20 mL), IM NaOH (3 mL), cobalt (II) chloride hexahydrate (0.60 mg, 0.003 mmol) and dimethylglyoxime (15 mg, 0.13 mmol). A solution of sodium tetrahydroborate (240 mg, 6.33 mmol) in 0.2M NaOH (3.6 mL) was added. The reaction mixture immediately turned dark but very soon assumed a clear yellow appearance. Acetic acid was added dropwise until the solution turned dark (3 drops). After ca. one hour, the reaction lightened. Additional NaBH4, CoCl2 and HOAc were added to produce a deep blue-purple color. When that color faded, more NaBH4 was added. When HPLC analysis indicated that the reaction was complete, it was partitioned between H2O and EtOAc, and the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting foamy solid was chromatographed, eluting with 50% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 1.15 g (76%) of the title compound as a white solid. MS (ESI-) for Ci8H17NO4S m/z
342.1 (M-H)-.
[00248] Step 4: Preparation of 5-[4-(2-oxo-2-phenyIethoxy)benzyl]-1,3-thiazolidine-2,4- dione.
[00249] To a stirring solution of 5-[4-(2-hydroxy-2-phenylethoxy)benzyl]-1,3-thiazolidine-
2,4-dione (1.00 g, 2.91 mmol) in DCM (35 mL) was added DMSO (2 mL) and the solution was cooled to 0 °C. Phosphorus pentoxide (0.83 g, 2.91 mmol) was added followed by triethylamine (1.8 mL, 13.1 mmol). The reaction was allowed to slowly warm to RT. After 2 hours, the reaction mixture was partitioned between DCM and water and the organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow oil was chromatographed on silica gel eluting with 25-35% EtOAc/hexanes.
Fractions containing product were combined and evaporated in vacuo to give 0.40 g (40%) of the title compound as a white solid. Trituration with ether afforded 245 mg of clean product.
MS (ESI-) for C18Hi5NO4S m/z 340.1 (M-H)-.
[00250] Example 2: Preparation of 5-{4-[2-(4-fluorophenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione.
Figure imgf000057_0001
[00251] Step 1: Preparation of 4-[2-(fluorophenyl)-2-hydroxyethoxy]benzaldehyde
[00252] To a stirring solution of 2-(4-fluorophenyl)oxirane (5.60 g, 40.0 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (7.40 g, 61.0 mmol), IM NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the reaction was heated at 78 °C overnight. After cooling to RT, the reaction was extracted with EtOAc (2 x 150 mL) and the combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed on silica gel eluting with 30-40%
EtOAc/hexanes. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 2.38 g of the regioisomer of the product as a white solid. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 1.54g (22%) of the title compound as a colorless viscous oil.
[00253] Step 2: Preparation of 5-{4-[2-(4-fluorophenyl)-2-hydroxyethoxy]benzylidene}- 1,3-thiazolidine-2, 4-dione [00254] To a stirring solution of the aldehyde (2.36 g, 10.8 mmol) in absolute EtOH (75 mL) was added 2,4-thiazolidinedione (1.06 g, 9.07 mmol) and piperidine (0.45 mL, 4.50 mmol), and the resulting solution was heated to reflux. After refluxing overnight, the reaction was allowed to cool to RT, and then evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed, eluting with 30-40% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to give 0.88 g (27%) of the title compound as a yellow solid. MS (ESI-) for Ci8Hi4FNO4S m/z 358.1 (M-H)-.
[00255] Step 3: Preparation of 5-{4-[2-(4-fluorophenyl)- 2-hydroxyethoxy]benzyl}-1,3- thiazolidine-2,4-dione
[00256] To a stirring mixture of 5-{4-[2-(4-fluorophenyl)-2-hydroxyethoxy]benzylidene}- 1,3-thiazolidine-2,4-dione (0.87 g, 2.40 mmol) in THF/H2O (1:1, 20 mL) was added IM NaOH (2 mL), cobalt (II) chloride hexahydrate (0.30 g, 0.001 mmol), dimethylglyoxime (8,4 mg, 0.073 mmol), and finally sodium tetrahydroborate (0.13 g, 3.53 mmol). The reaction turned a deep blue/purple color. After a short time, the dark color began to fade and HOAc was added dropwise to regenerate the darker color. When the color faded and addition of HOAc failed to regenerate it, NaBH4 was added to regenerate the darker color. The reaction was left to stir at RT overnight. The reaction was partitioned between water and EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed, eluting with 35% EtOAc/hexanes. Fractions containing compound were combined and evaporated in vacuo to give 0.77 g (88%) of a light yellow solid. The yellow solid was dissolved in THF (8 mL) and H2O (8 mL), and the resulting solution was treated with CoCl2 (a small crystal), and 2,2'-dipyridyl (5 mg). Finally, NaBH4 was added in small portions until the deep blue color persisted. The reaction mixture was partitioned between EtOAc and H2O, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting slightly tinted oil was chromatographed on a small silica gel column eluting with 25-35% EtOAc/hexanes. Fractions containing product were combined and evaporated in vacuo to afford 527 mg (60%) of the title compound as a white solid. MS (ESI-) for C18H16FNO4S m/z 360.1 (M-H)-.
[00257] Step 4: Preparation of 5-{4-[2-(4-fluorophenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione
[00258] To a stirring solution of 5-{4-[2-(4-fluorophenyl)-2-hydroxyethoxy]benzyl }-1,3- thiazolidine-2,4-dione (0.52 g, 1.40 mmol) in DCM (15 mL) was added DMSO (0.5 mL) and the solution was cooled to 0 °C. Phosphorus pentoxide (0.41 g, 1.44 mmol) was added followed by triethylamine (0.90 mL, 6.48 mmol). The reaction was allowed to slowly warm to RT and then stirred for 5 hours. The reaction mixture was partitioned between DCM and H2O, and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting white solid was chromatographed on a small silica gel column eluting with 10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.25 g (48%) of the title compound as a white solid. MS (ESI+) for Ci8H14FNO4S m/z 359.9 (M+H)+. MS (ESI-) for C]8H14FNO4S m/z 358.0 (M-H)'.
[00259] Example 3: Preparation of 5-{4-[2-(2-fluorophenyl)- 2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione.
Figure imgf000059_0001
[00260] Step 1: Preparation of 2-(2-fluorophenyl)oxirane
[00261] To a solution of o-fluorostyrene (5.0 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 mL) and H2O (78 mL) at 0 °C was added N-bromosuccinimide (8.02 g, 45.0 mol) in three portions. The reaction was allowed to warm to RT and stirred overnight. Sodium carbonate (8.68 g, 81.9 mmol) was added in portions and then IM NaOH (ca. 10 mL) was added and the reaction was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 5.31 g (94%) of the title compound as a slightly tinted oil which was used without further purification. MS (ESI+) for C8H7FO m/z 138.1 (M+H)+.
[00262] Step 2: Preparation of 4-[2-(2-fluorophenyl)-2-hydroxyethoxy]benzaldehyde
[00263] To a stirring solution of 2-(2-fluorophenyl)oxirane (5.30 g, 38.4 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (7.0 g, 58.0 mmol), IM NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78 °C overnight. The reaction was allowed to cool to RT and then extracted with EtOAc (2 x 150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was adsorbed onto silica gel and chromatographed, eluting with 30-40% EtOAc/hexanes to give 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.1Og (1 1%) of the title compound as a colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.67g (7%) of the regioisomer as a colorless oil.
[00264] Step 3: Preparation of 5-{4-[2-(2-fluorophenyl)- 2-hydroxyethoxy]benzylidene}- 1,3-thiazolidine-2, 4-dione.
[00265] To a stirring solution of the aldehyde (2.36 g, 10.8 mmol) in absolute EtOH (40 mL) was added 2,4-thiazolidinedione (0.495 g, 4.23 mmol) and piperidine (0.21 mL, 2.10 mmol), and the resulting solution was heated to reflux. After refluxing overnight, the reaction mixture was cooled to RT and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with dilute aqueous HOAc, brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow solid was washed with DCM and acetone and the filtrate was evaporated in vacuo. This material was adsorbed onto silica gel and chromatographed using 10-25% EtOAc/DCM. Fractions containing compound were combined and evaporated in vacuo to give 0.5 Ig of the title compound as a yellow solid. MS (ESI-) for C18H14FNO4S m/z 358.0 (M-H)-.
[00266] Step 4: Preparation of 5-{4-[2-(2-fluorophenvl)- 2-hydroxyethoxy]benzyl}- 1,3- thiazolidine-2,4-dione.
[00267] To a stirring mixture of 5-{4-[2-(2-fluorophenyl)-2-hydroxyethoxy]benzylidene}- 1,3-thiazolidine-2,4-dione (0.52 g, 1.40 mmol) inTHF/H2O (1:1, 16 mL) was added IM NaOH (2 mL), cobalt (H) chloride hexahydrate (0.2 mg, 0.0009 mmol), 2,2'-bipyridine (50.8 mg, 0.33 mmol), and finally sodium tetrahydroborate (0.11 g, 2.90 mmol). The reaction turned a deep blue/purple color. After a short time, the dark color began to fade and HOAc was added dropwise to regenerate the darker color. When the color faded and addition of HOAc failed to regenerate it, NaBH4 was added to regenerate the darker color. Added small portions OfNaBH4 and HOAc dropwise until deep blue color persisted. After repeating this several times, HPLC indicated that the reaction was complete despite the fact that the deep blue color has given way to a light brown solution. The reaction was partitioned between water and EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed, eluting with 35% EtOAc/hexanes. Fractions containing compound were combined and evaporated in vacuo to give 0.32 g of the title compound as a white solid. MS (ESI-) for Ci8Hi6FNO4S m/z 360.1 (M-H)-. [00268] Step 5: Preparation of 5-{4-[2-(2-fluorophenyl)- 2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione.
[00269] To a stirring solution of 5-{4-[2-(2-fluorophenyI)-2-hydroxyethoxy]benzyl}-1,3- thiazolidine-2,4-dione (0.29 g, 0.80 mmol) in DCM (15 mL) was added DMSO (0.5 mL) and the solution was cooled to 0 °C. Phosphorus pentoxide (0.23 g, 0.80 mmol) was added, followed by triethylamine (0.50 mL, 3.6 mmol). The reaction was allowed to slowly warm to
RT. After 3 hours, water was added and the phases were separated. The pH of the aqueous phase was adjusted to ca. 7 and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried (Na2SOzO, filtered and evaporated in vacuo.
The resulting white solid was chromatographed on a small silica gel column eluting with 10%
EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give
0.19 g (66%) of the title compound as a white solid. MS (ESI-) for Ci8Hi4FNO4S m/z 358.0
(M-H)-.
[00270] Example 4: Preparation of 5-{4-[2-(3-fluorophenyl)- 2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione
Figure imgf000061_0001
[00271] Step 1: Preparation of 2-(3-fluorophenyl)oxirane
[00272] To a solution of m-fluorostyrene (5.00 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 mL) and H2O (78 mL) at 0 °C was added N-bromosuccinimide (8.02 g, 45.0 mmol) in three portions. The reaction was allowed to warm to RT. After 4 hours, 2N NaOH (60 mL) was added and the reaction was left to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 6.30 g of the title compound as a slightly tinted oil which was used without further purification.
[00273] Step 2: Preparation of 4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzaldehyde
[00274] To a stirring solution of 2-(3-fluorophenyl)oxirane (5.60 g, 40.5 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (7.40 g, 61.0 mmol), IM NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78 °C overnight. The reaction mixture was allowed to cool to RT and then extracted with EtOAc (2 x 150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed eluting with 30- 40% EtOAc/hexanes to give 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.78 g (17%) of the title compound as a white solid. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.90 g (9%) of the regioisomer as a nearly colorless oil.
[00275] Step 3: Preparation of 5-{4-[2-(3-fluorophenyl)- 2-hydroxyethoxy]benzylidene}- 1,3-thiazolidine-2, 4-dione
[00276] To a stirring solution of the aldehyde (2.36 g, 10.8 mmol) in absolute EtOH (40 mL) was added 2,4-thiazolidinedione (0.90 g, 7.69 mmol) and piperidine (0.76 mL, 7.7 mmol), and the resulting solution was heated to reflux. After 6 hours, the reaction mixture was allowed to cool to RT. The mixture was evaporated in vacuo and the residue was dissolved in EtOAc. This solution was washed with a dilute aqueous HOAc, brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting yellow solid was dissolved in MeOH/DCM adsorbed onto silica gel and chromatographed eluting with 30% EtOAc/DCM. Fractions containing compound were combined and evaporated in vacuo to afford 2.17 g (86%) of the title compound as a yellow solid. MS (ESI-) for Ci8H14FNO4S m/z 358.1 (M-H)'.
[00277] Step 4: Preparation of 5-{4-[2-(3-fluorophenyl)- 2-hydroxyethoxy]benzyl}-1,3- thiazolidine-2,4-dione
[00278] 5-{4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione (1.00 g, 2.78 mmol) was suspended in THF (15 mL) and H2O (10 mL). To this solution was added a small crystal of cobalt chloride followed by 2,2'-bipyridine (98 mg, 0.63 mmol). NaBH4 was added in portions until blue color persisted. The color gradually faded and was regenerated repeatedly by small additions of borohydride and HOAc. When HPLC analysis indicated that the reaction was complete, the reaction mixture was partitioned between EtOAc and H2O. HOAc was added until the pH of the aqueous phase was ca. 6. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.72 g (72%) of the title compound as a white solid. This material was rechromatographed on a small silica column eluting with 10- 20% EtOAc/DCM. MS (ESI-) for C18Hi6FNO4S m/z 360.1 (M-H)-.
[00279] Step 5: Preparation of 5-{4-[2-(3-fluorophenyI)- 2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione [00280] To a stirring solution of 5-{4-[2-(3-fluorophenyl)-2-hydroxyethoxy]benzyl}-1,3- thiazolidine-2,4-dione (0.62 g, 1.70 mmol) in DCM (15 mL) was added DMSO (0.5 mL) and the solution was cooled to 0 °C. Added phosphorus pentoxide (0.49 g, 1.72 mmol) followed by triethylamine (1.1 mL, 7.72 mmol). The reaction mixture was allowed to slowly warm to RT. After 2 hours, HPLC shows that the reaction was complete. Added water and separated phases. The pH of the aqueous phase was adjusted to ca. 7 with 2M NaOH and the aqueous phase was then extracted with EtOAc. The combined extracts were washed with brine, dried (NBaSO4), filtered and evaporated in vacuo. The resulting white solid was chromatographed on a small silica gel column eluting with 10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.25g (40%) of the title compound as a white solid. MS (ESI-) for Ci8H]4FNO4S m/z 358.0 (M-H)-.
[00281] Example 5: Preparation of 5-{4-[2-(3-methoxyphenyl) -2-oxoethoxy]benzyl}-1,3 -thiazolidine-2,4-dione.
O
Figure imgf000063_0001
[00282] Step 1: 2-(3-methoxyphenyl)oxirane
[00283] To a solution of 3-vinylanisole (5.0 g, 37.0 mmol) and acetic acid (2.1 mL, 37.0 mmol) in dioxane (33 mL) and H2O (78 mL) at 0 °C was added N-bromosuccinimide (7.30 g, 41.0 mmol) in three portions. The reaction was allowed to warm to R.T. and then 2M NaOH (50 mL) was added. The reaction was left to stir at RT overnight. The reaction mixture was then partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 5.60 g (100%) of the title compound as a slightly tinted oil.
[00284] Step 2: 4-[2-hydroxy-2-(3-methoxypheαyl)ethoxy]benzaldehyde
[00285] To a stirring solution of 2-(3-methoxyphenyl)oxirane (5.60 g, 37.0 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (6.80 g, 5.60 mmol), IM NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78 °C overnight. The reaction mixture was allowed to cool to RT and extracted with EtOAc (2 x 150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed, eluting with 30- 40% EtOAc/hexanes. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.86 g (18%) of the title compound as a clear colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.90 g (9%) the regioisomer as a nearly colorless oil.
[00286] Step 3: 5-{4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzylidene}-1,3- thiazolidine-2,4-dione
[00287] To a stirring solution of 4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzaldehyde
(1.76 g, 6.46 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.83 g, 7.11 mmol) and piperidine (0.70 mL, 7,11 mmol), and the resulting solution was heated to reflux.
The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with water (pH adjusted to ca. 5-6 with
HOAc), brine, dried (Na2SO4), filtered and adsorbed onto silica gel. After chromatography with 20-30% EtOAc/DCM, the fractions containing compound were combined and evaporated in vacuo to give 1.38 g (58%) of the title compound as a yellow solid. MS (ESI-) for Ci9Hi7NO5S m/z 370.1 (M-H)-.
[00288] Step 4: 5-{4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzyl} -1,3-thiazolidine-
2,4-dione
[00289] 5-{4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzylidene }- 1 ,3-thiazolidine-2,4- dione (1.15 g, 3.10 mmol) was dissolved in THF (15 mL). Added H2O (15 mL) and sufficient THF to give a clear solution. A small crystal of cobalt chloride was added, followed by 2,2'-bipyridine (109 mg, 0.70 mmol). NaBH4 was added in portions until the blue color persisted. The color gradually faded, but was regenerated repeatedly by small additions of borohydride and HOAc. When HPLC indicated that the reaction was complete the reaction mixture was partitioned between EtOAc and H2O. HOAc was added until the pH of the aqueous phase was ca. 6, and then the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO-O, filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 20%
EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give
0.82 g (74%) of the title compound as a white solid. MS (ESI-) for C]9H19NO5S m/z 372.0
(M-H)-.
[00290] Step 5: Preparation of 5-{4-[2-(3-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione
[00291] To a stirring solution of 5-{4-[2-hydroxy-2-(3-methoxyphenyl)ethoxy]benzyl}-1,3- thiazolidine-2,4-dione (0.62 g, 1.7 mmol) in DCM (15 mL) was added DMSO (0.5 mL) and the solution was cooled to 0 °C. Added phosphorus pentoxide (0.52 g, 1.8 mmol) followed by triethylamine (1.2 mL, 8.3 mmol). The reaction was allowed to slowly warm to RT. After 2 hours water was added and the phases were separated. The pH of the aqueous phase was adjusted to ca. 7 with 2M NaOH. The aqueous phase was extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting white solid was chromatographed on a small silica gel column eluting with 10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.33 g (54%) of the title compound as a white solid. MS (ESI+) for C19Hi7NO5S m/z 372.0 (M+H)+. MS (ESI-) for C9H17NO5S m/z 370.1 (M-H)-.
[00292] Example 6: Preparation of 5-{4-[2-(2-methoxyphenyl) -2-oxoethoxy]benzyl}- 1,3-thiazolidine-2,4-dione.
Figure imgf000065_0001
[00293] Step 1: Preparation of 2-(2-methoxyphenyl)oxirane
[00294] To a solution of 2-vinyl anisole (5.0 g, 0.037 mol) and acetic acid (2.1 mL, 37 mmol) in dioxane (33 mL) and H2O (78 mL) at 0 °C was added N-bromosuccinimide (7.30 g, 40.1 mmol) in three portions. The reaction was allowed to warm to R.T. and after 1 hour, 2M NaOH (50 mL) was added. The reaction was left to stir at RT overnight. The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO^, filtered and evaporated in vacuo to give 7.56 g slightly tinted oil. This was dissolved in dioxane, 2N NaOH was added and the reaction was stirred at RT overnight. Repeated aqueous work-up gave 5.60 g of the title compound as a nearly colorless oil.
[00295] Step 2: Preparation of 4-[2-hydroxy-2-(2- methoxyphenyl)ethoxy]benzaldehyde
[00296] To a stirring solution of 2-(2-methoxyphenyl)oxirane (5.60 g, 37.3 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (6.80 g, 56.0 mmol), IM NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78 °C overnight. The reaction was allowed to cool to RT and it was then extracted with EtOAc (2 x 150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light oil was adsorbed onto silica gel and
chromatographed eluting with 30-40% EtOAc/hexanes to give 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.71 g (17%) the regioisomer as a brown oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 2.05 g (20%) of the title compound as a yellow solid.
[00297] Step 3: Preparation of (5Z)-5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy] benzylidene}-1,3-thiazolidine-2,4-dione
[00298] To a stirring solution of 4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzaldehyde
(1.71 g, 6.28 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.8 Ig, 6.91 mmol) and piperidine (0.68 mL, 6.9 mmol), and the resulting solution was heated to reflux.
The reaction was refluxed overnight and then evaporated in vacuo. The residue was dissolved in EtOAc and this solution was washed with aqueous HOAc (pH 5-6), brine, dried
(Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed on silica gel eluting with 20-40% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.87 g (80%) of the title compound as a light yellow solid. MS (ESI-) for Ci9H17NO5S m/z 370.1 (M-H)-.
[00299] Step 4: 5-(4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzyl} -1,3-thiazolidine-
2,4-dione
[00300] (5Z)-5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzylidene}-1,3-thiazolidine-
2,4-dione (1.00 g, 2.69 mmol) was dissolved in THF (20 mL). Water (20 mL) was added and then sufficient additional THF was added to give a clear solution. A small crystal of cobalt chloride was added followed by 2,2'-bipyridine (95 mg, 0.61 mmol). The reaction mixture was cooled to 0 °C. NaBH4 was added in portions until the blue color persisted. The color gradually faded and was regenerated repeatedly by small additions of borohydride and
HOAc. When HPLC indicated that the reaction was complete the reaction mixture was partitioned between EtOAc and H2O. HOAc was added until the pH of the aqueous phase was ca.6, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.63 g (63%) of the title compound as a white solid. MS (ESI-) for Ci9Hi9NO5S m/z 372.1 (M-H)-.
[00301] Step 5: Preparation of 5-{4-[2-(2-methoxyphenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione
[00302] To a stirring solution of phosphorus pentoxide (0.30 g, 1.10 mmol) in DCM (8 mL) at 0 °C was added a solution of 5-{4-[2-hydroxy-2-(2-methoxyphenyl)ethoxy]benzyl }-1,3- thiazolidine-2,4-dione (0.20 g, 0.54 mmol) in DCM (8 mL) followed by dimethyl sulfoxide (0.20 mL, 2.80 mmol). After stirring for 15 minutes, N,N-diiisopropylethylamine (0.28 mL, 1.60 mmol) was added. After 45 minutes, the reaction mixture was cast into cold saturated NaHCO3 and extracted with EtOAc (x2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 175 mg (88%) of the title compound as a light yellow solid. MS (ESI-) for C19HnNO5S m/z 370.1 (M-H)-.
[00303] Example 7: Preparation of 5-{4-[2-(3-chlorophenyl)-2-oxoettioxy]benzyl}-1,3- thiazolidine-2,4-dione.
Figure imgf000067_0001
[00304] Step 1: 2-(3-chlorophenyl)oxirane
[00305] To a solution of m-chlorostyrene (5.70 g, 41.0 mmol) and acetic acid (2.33 mL, 40.9 mmol) in dioxane (33 mL) and H2O (78 mL) at 0 °C was added N-bromosuccinimide (8.02 g,
45.0 mmol) in three portions. The reaction was allowed to warm to R.T. After 4 hours, 2N
NaOH (60 mL) was added and the reaction was allowed to stir at RT overnight.
The reaction mixture was partitioned between water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried
(Na2SO-O, filtered and evaporated in vacuo to give 6.20 g of a slightly tinted oil which was used without further purification.
[00306] Step 2: 4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzaldehyde
[00307] To a stirring solution of 2-(3-chlorophenyl)oxirane (6.20 g, 40.0 mmol) in toluene
(65 mL) was added 4-hydroxybenzaldehyde (7.30 g, 60.0 mmol), IM NaOH (65 mL) and
PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78 °C for three hours. The reaction was allowed to cool to RT and then extracted with EtOAc (2 x 150 mL).
The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was adsorbed onto silica gel and chromatographed eluting with 25-40% EtOAc/hexanes. There are 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.08 g (10%) of the desired product as a colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.95 g (8%) of the regioisomer as a colorless oil, 44B. Some starting epoxide (2.85 g) was also recovered.
[00308] Step 3: 5-{4-[2-(3-cMorophenyl)-2-hydroxyethoxy]benzylidene}-1,3- thiazolidine-2,4-dione
[00309] To a stirring solution of 4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzaldehyde (1.08 g, 3.90 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.50 g, 4.29 mmol) and piperidine (0.42 mL, 4.3 mmol), and the resulting solution was heated to reflux and then stirred overnight at room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in EtOAc. This solution was washed with aqueous
HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed eluting with 10-20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.31 g (89%) of the product as a light yellow solid. MS (ESI+) for Ci8H14ClNO4S m/z 375.0 (M+H)+. MS (ESI-) for CI8HI4CINO4S m/z 374.1 (M-H)-.
[00310] Step 4: 5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzyl}-1,3-thiazolidine-2,4- dione
[00311] 5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzylidene}-1,3-thiazolidine-2,4-dione
(0.74 g, 2.00 mmol) was dissolved in THF (20 mL). Water (20 mL) was added and then more THF was added until all solids dissolved. A small crystal of cobalt chloride was added, followed by 2,2'-bipyridine (69 mg, 0.44 mmol). The reaction mixture was cooled to 0 °C.
NaBH4 was added in portions until the blue color persisted. The color gradually faded and was regenerated repeatedly by small additions of borohydride and HOAc. When HPLC indicated that the reaction was complete, the reaction mixture was partitioned between
EtOAc and H2O. HOAc was added until the pH of the aqueous phase was ca. 6, and then the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-10% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 0.44 g (59%) of a sticky yellow solid. MS
(ESI-) for Ci8H16ClNO4S m/z 376.1 (M-H)-.
[00312] Step 5: Preparation of 5-{4-[2-(3-chlorophenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione
[00313] To a stirring solution of phosphorus pentoxide (0.38 g, 1.30 mmol) in DCM (8 mL) at 0 °C was added a solution of 5-{4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzyl}-1,3- thiazolidine-2,4-dione (0.25 g, 0.66 mmol) in DCM (8 mL) followed by dimethyl sulfoxide
(0.23 mL, 3.30 mL). After stirring for 15 minutes N,N-diiisopropylethylamine (0.34 mL,
2.00 mmol) was added. After 45 minutes the reaction was poured into cold saturated
NaHCO3 and the mixture was extracted with EtOAc (x2). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was chromatographed on a small silica gel column eluting with 0-15% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 117 mg (47%) of a white solid. MS (ESI-) for Ci8Hi4ClNO4S m/z 374.1 (M-H)-.
[00314] Example 8: Preparation of 5-{4-[2-(2-chlorophenyl)-2-oxoethoxy]benzyl}-1,3- thiazolidine-2,4-dione.
[00315] The title compound can be prepared as described in Example 7 using appropriate starting materials, such as 2-(2-chlorophenyl)oxirane.
[00316] Example 9: Preparation of 5-{4-[2-(4-methoxyphenyl) -2-oxoethoxy]benzyl}-
1,3-thiazolidine-2,4-dione.
The title compound was prepared as described in Examples 5 and 6 using appropriate starting materials, such as 2-(4-methoxyphenyl)oxirane. MS (ESI-) for Ci9Hi7NO5S 370.2 m/z (M-
1).
[00317] Physical Data for Representative Compounds
1H-NMR Data (40OmHz)
Figure imgf000069_0001
δH
1H-NMR (DMSO-rf6) δ: 12.00 (s, 1H), 7.50 (s, 1H), 7.42-7.32 (m, 3H), 7.13 (d, J= 8.5 Hz,
2H), 6.87 (d, J = 8.5 Hz, 2H), 5.77 (d, J = 5.0 Hz, 1H), 4.92 (d, J = 6.2 Hz, 1H), 4.86 (dd, J = 8.9, 4.3 Hz, 1H), 4.00 (m, 2H), 3.29 (dd, J = 14.3, 4.3 Hz, 1H), 3.05(dd, J = 14.2, 9.0 Hz, 1H).
Figure imgf000069_0002
1H-NMR (DMSO-^6) δ: 12.52 (s, 1H), 7.75 (s, 1H), 7.54 (m, 3H), 7.44-7.33 (m, 3H), 7.11
(d, J= 8.91 Hz, 2H), 5.84 (d, J = 4.77 Hz, 1H), 4.97 (m, 1H), 4.12 (m, 2H).
Figure imgf000070_0001
1H-NMR (CDCl3) 5: 8.32 (brs, 1H), 7.50 (d, J = 8.50 Hz, 2H), 7.26 (m, 2H), 7.17 (m, 2H),
6.88 (m, 2H), 5.15 (dd, J = 8.71, 3.11 Hz, 1H), 4.51 (dd, J = 9.23, 4.04 Hz, 1H), 4.09 (dd, 7 = 9.64, 3.21 Hz, 1H), 3.45 (dd, J = 14.1, 3.94 Hz, 1H), 3.13 (dd, J = 14.2, 9.23 Hz, 1H), 2.87 (brs, 1H).
Figure imgf000070_0002
1H-NMR (CDCl3) δ: 8.35 (brs, 1H), 7.23 (t, J = 8.09, 1H), 7.07 (d, J = 8.71 Hz, 2H), 6.94
(m, 2H), 6.81 (m, 3H), 5.03 (dd, J = 8.60, 2.80 Hz, 1H), 4.42 (dd, J = 9.33, 3.94 Hz, 1H), 4.02 (m, 1H), 3.93 (t, 7 = 9.23 Hz, 1H), 3.76 (s, 3H), 3.36 (dd, 7= 14.20, 3.84 Hz, 1H), 3.04 (dd, 7= 14.10, 9.33 Hz, 1H), 2.75 (brs, 1H).
Figure imgf000070_0003
1H-NMR (CDCl3) δ: 8.42 (brs, 1H), 7.23 (t, 7 = 7.98 Hz, 1H), 7.07 (d, 7 = 8.71 Hz, 2H), 6.94
(m, 2H), 6.82-6.78 (m, 3H), 5.03 (dd, 7 = 8.71, 2.90 Hz, 1H), 4.41 (dd, 7 = 9.33, 3.94 Hz, 1H), 4.02 (m, 1H), 3.93 (t, J = 9.12 Hz, 1H), 3.76 (s, 3H), 3.36 (dd, 7= 14.10, 3.94 Hz, 1H), 3.03 (dd, 7= 14.31, 9.33 Hz, 1H), 2.77 (brs, 1H).
Figure imgf000070_0004
1H-NMR (DMSO-d6) 8: 12.03 (brs, 1H), 7.62 (d, 7 = 7.67 Hz, 1H), 7.49 (m, 2H), 7.27 (dd, 7
= 8.19, 2.38 Hz, 1H), 7.16 (d, 7 = 8.50 Hz, 2H), 6.91 (d, 7 = 8.50 Hz, 2H), 5.55 (s, 2H), 4.88 (dd, 7= 9.12, 4.35 Hz, 1H), 3.84 (s, 3H), 3.33-3.29 (m, 1H), 3.05 (dd, J= 14.31, 9.12 Hz, 1H).
Figure imgf000071_0001
1H-NMR (DMSO-d6) δ: 12.02 (brs, 1H), 8.05 (t, J = 1.66 Hz, 1H), 7.96 (d, J = 7.88 Hz, 1H), 7.77 (m, 1H), 7.61 (t, J = 7.88 Hz, 1H), 7.16 (d, J = 8.71 Hz, 2H), 6.93 (d, J = 8.71 Hz, 2H), 5.57 (s, 2H), 4.88 (dd, J = 9.12, 4.35 Hz, 1H), 3.31 (m, 1H), 3.06 (dd, J = 14.20, 9.23 Hz, 1H).
Figure imgf000071_0002
1H-NMR (DMSO-d6) δ: 12.02 (brs, 1H), 7.83 (m, 2H), 7.59 (m, 2H), 7.16 (d, J = 8.71 Hz, 2H), 6.93 (d, J = 8.71, 2H), 5.56 (s, 2H), 4.88 (dd, J = 9.12, 4.35 Hz, 1H), 3.33-3.29 (m, 1H), 3.06 (dd, J = 14.10, 9.12 Hz, 1H).
Figure imgf000071_0003
O
1H-NMR (DMSO-d6) δ: 12.02 (s, 1H), 8.03 (d, J = 8.71 Hz, 2H), 7.65 (d, J = 8.50 Hz, 2H),
7.15 (d, J = 8.50 Hz, 2H), 6.92 (d, J = 8.71 Hz, 2H), 5.54 (s, 2H), 4.88 (dd, J = 9.12, 4.35 Hz, 1H), 3.33-3.29 (m, 1H), 3.05 (dd, J = 14.10, 9.12 Hz, 1H).
Figure imgf000071_0004
1H-NMR (CDCl3) δ: 8.08 (m, 3H), 7.34 (d, J = 8.09 Hz, 2H), 7.17 (d, J = 8.71 Hz, 2H), 6.90 (d, J = 8.71 Hz, 2H), 5.23 (s, 2H), 4.51 (dd, J = 9.43, 3.84 Hz, 1H), 3.46 (dd, J = 14.10, 3.94 Hz, 1H), 3.13 (dd, 14.20, 9.43 Hz, 1H), 1.60 (brs, 1H).
Figure imgf000072_0001
1H-NMR (OMSO d6) δ: 12.20 (s, 1H), 8.30 (m, 2H), 8.07 (d, J = 7.88 Hz, 1H), 7.82 (t, J =
7.88 Hz, 1H), 7.16 (d, J = 8.71 Hz, 2H), 6.95 (d, J = 8.71 Hz, 2H), 5.64 (s, 2H), 4.88 (dd, / = 9.33, 4.35 Hz, 1H), 3.34-3.29 (m, 1H), 3.06 (dd, J = 14.10.9.12 Hz, 1H).
Figure imgf000072_0002
1H-NMR (CDCl3) δ: 8.42 (brs, 1H), 7.38 (m, 5H), 7.15 (d, J = 8.50 Hz, 2H), 6.88 (d, J = 8.50
Hz, 2H), 5.14 (dd, J = 8.81, 3.01Hz, 1H), 4.50 (dd, J = 9.33, 3.94 Hz, 1H), 4.11 (m, 1H), 4.01 (t, J = 9.23 Hz, 1H), 3.45 (dd, J = 14.20, 3.84 Hz, 1H), 3.12 (dd, J = 14.20, 9.43 Hz, 1H), 2.84 (brs, 1H).
Figure imgf000072_0003
1H-NMR (CDCl3) δ: 8.35 (brs, 1H), 7.23 (t, J = 8.09, 1H), 7.07 (d, J = 8.71 Hz, 2H), 6.94
(m, 2H), 6.81 (m, 3H), 5.03 (dd, J = 8.60, 2.80 Hz, 1H), 4.42 (dd, J = 9.33, 3.94 Hz, 1H), 4.02 (m, 1H), 3.93 (t, J = 9.23 Hz, 1H), 3.76 (s, 3H), 3.36 (dd, J = 14.20, 3.84 Hz, 1H), 3.04 (dd, J= 14.10, 9.33 Hz, 1H), 2.75 (brs, 1H).
Figure imgf000072_0004
1H-NMR (CDCl3) δ: 8.42 (brs, 1H), 7.23 (t, J = 7.98 Hz, 1H), 7.07 (d, J = 8.71 Hz, 2H), 6.94
(m, 2H), 6.82-6.78 (m, 3H), 5.03 (dd, J = 8.71, 2.90 Hz, 1H), 4.41 (dd, J = 9.33, 3.94 Hz, 1H), 4.02 (m, 1H), 3.93 (t, J = 9.12 Hz, 1H), 3.76 (s, 3H), 3.36 (dd, J = 14.10, 3.94 Hz, 1H), 3.03 (dd, J = 14.31, 9.33 Hz, 1H), 2.77 (brs, 1H).
Figure imgf000073_0001
1H-NMR (DMSO-40 δ: 12.03 (brs, 1H), 8.02 (m, 2H), 7.69 (t, J = 7.36 Hz, 1H), 7.57 (t, / = 7.67 Hz, 2H), 7.15 (d, J = 8.50 Hz, 2H), 6.91 (d, J = 8.50 Hz, 2H), 5.56 (s, 2H), 4.88 (dd, J = 9.23, 4.25 Hz, 1H), 3.31 (m, 2H), 3.05 (dd, J = 14.02, 9.23 Hz, 1H).
Figure imgf000073_0002
1H-NMR (CDCl3): δ = 8.57(brs, 1H), 7.28(m, 1H), 7.16(m, 1H), 6.99(m, 2H), 6.87(m, 3H), 6.12(dd, J=7.8, 3.6Hz, 1H), 4.49(dd, J=9.3, 3.9Hz, 1H), 4.25(m, 1H), 4.13(dd, J=10.5, 3.6Hz, 1H), 3.83(s, 3H), 3.45(dd, J=14.2, 3.8Hz, 1H), 3.10(dd, J=14.0, 9.6Hz, 1H), 2.14(8, 3H).
Figure imgf000073_0003
1H-NMR (CDCI3): δ = 8.31 (brs, 1H), 7.29(m, 1H), 7.17(m, 1H), 6.99(m, 2H), 6.88(m, 3H), 6.12(dd, J=7.8, 3.4Hz, 1H), 4.50(dd, J=9.4, 3.8Hz, 1H), 4.25(m, 1H), 4.13(dd, J=10.4, 3.7Hz, 1H), 3.83(s, 3H), 3.45(dd, J=14.2, 3.8Hz, 1H), 3.11(dd, J=14.1, 9.3Hz, 1H), 2.14(s, 3H).
Figure imgf000073_0004
1H-NMR (CDCl3): δ = 8.65(m, 1H), 7.29(m, 1H), 7.13(m, 1H), 6.97(m, 2H), 6.86(m, 3H),
6.13(m, 1H), 4.49(dd, J=9.1, 3.9Hz, 1H), 4.24(m, 1H), 4.14(m, 1H), 3.82(s, 3H), 3.40(m, 1H), 3.12(dd, J=14.2, 9.0Hz, 1H), 2.69(m, 4H).
Figure imgf000074_0001
1H-NMR (CDCl3): δ = 8.78(brs, 1H), 7.29(m, 1H), 7.13(m, 1H), 6.97(m, 2H), 6.85(m, 3H),
6.12(m, 1H), 4.47(dd, J=8.8, 3.8Hz, 1H), 4.20(m, 2H), 3.81(s, 3H), 3.36(m, 1H), 3.13(m, 1H), 2.68(m, 4H).
Figure imgf000074_0002
1H-NMR (CDCl3): δ = 8.74(brs, 1H), 7.42(s, 1H), 7.3 l(m, 2H), 7.15(d, J-8.7Hz, 2H), 6.85(d, J=8.7Hz, 2H), 6.10((dd, J=7.4, 4.0Hz, 1H), 4.50(dd, J=9.3, 3.9Hz, 1H), 4.24(M, 1H), 4.13(dd, J=10.4, 4.2Hz, 1H), 3.45(dd, J=14.1, 3.7Hz, 1H), 3.10(dd, J=14.0, 9.4Hz, 1H), 2.15(s, 3H).
Figure imgf000074_0003
1H-NMR (CDCl3): δ = 8.67(brs, 1H), 7.42(s, 1H), 7.30(m, 2H), 7.15(d, J=7.2Hz, 2H), 6.85(d, J=8.5Hz, 2H), 6.10(dd, J=7.4, 4.0Hz, 1H), 4.50(dd, J=9.3, 3.9Hz, 1H), 4.24(m, 1H), 4.13(dd, J=10.4, 4.2Hz, 1H), 3.45(dd, J=14.2, 3.8Hz, 1H), 3.1 l(dd, J=14.2, 9.4Hz, 1H), 2.15(s, 3H).
Figure imgf000074_0004
1H-NMR (CDCl3): δ = 8.94,(d, J=4.8Hz, 1H), 7.40(s, 1H), 7.30(m, 3H), 7.14(d, J=8.5Hz, 2H), 6.84(d, J=8.5Hz, 2H), 6.1 l(m, 1H), 4.49(dd, J=9.0, 3.8Hz, 1H), 4.23(m, 1H), 4.13(m, 1H), 3.40(dd, J=14.1, 3.5Hz, 1H), 3.13(dd, J=14.1, 9.1Hz, 1H), 2.71(m, 4H).
Figure imgf000075_0001
1H-NMR (CDCl3): δ = 8.88(d, J=6.4Hz, 1H), 7.40(s, 1H), 7.30(m, 3H), 7.14(d, J=8.5Hz, H), 6.84(d, J=7.7Hz, 2H), 6.1 l(m, 1H), 4.49(dd, 1=9.1, 3.9Hz, 1H), 4.24(m, 1H), 4.14(m, 1H), 3.40(dd, J=14.3, 3.7Hz, 1H), 3.13(dd, J=14.2, 9.0Hz, 1H), 2.70(m, 4H).
Mass Spectra
Figure imgf000075_0002
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
377.84 ES- 376.1 (M-I)
OH
Q 373.42 ES- 372.1 (M-I)
I JL NH
OH
411.39 ES- 410.2 (M-I)
O
-JO OH
411.39 ES- 410.2 (M-I)
OH O
373.42 ES- 372.1 (M-I)
O
N^^o^^
OH
373.42 ES- 372.1 (M-I) p
Y^o I L/NH
OH
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
[00318] Example 10: Assays
[00319] Assays for Measuring Reduced PPARγ Receptor Activation
[00320] Whereas activation of the PPARγ receptor is generally believed to be a selection criteria to select for molecules that may have anti-diabetic and insulin sensitizing pharmacology, 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 PPARγ. The optimal compounds have at least a 10- fold reduced potency as compared to pioglitazone and less than 50% of the full activation produced by rosiglitazone in assays conducted in vitro for transactivation of the PPARγ receptor. The assays are conducted by first evaluation of the direct interactions of the molecules with the ligand binding domain of PPARγ. This can be performed with a commercial interaction kit that measures the direct interaction by florescence using rosiglitazone as a positive control. Further assays can be conducted in a manner similar to that described by Lehmann et al. [Lehmann JM, Moore LB, Smith-Oliver TA: An
Antidiabetic Thiazolidinedione is a High Affinity Ligand for Peroxisome Proliferator- activated Receptor (PPAR) J. Biol. Chem.(1995) 270: 12953] but will use luciferase as a reporter as in Vosper et al. [Vosper, H., Khoudoli, GA, Palmer, CN (2003) The peroxisome proliferators activated receptor d is required for the differentiation of THP-I moncytic cells by phorbol ester. Nuclear Receptor 1 :9]. Compound stocks will be dissolved in DMSO and added to the cell cultures at final concentrations of 0.1 to 100 μM and the relative activation will be calculated as induction of the reporter gene (luciferase) as corrected for by the expression of the control plasmid (coding for galactosidase). Pioglitazone and rosiglitazone will be used as reference compound . [00321] In addition to showing the reduced activation of the PPARγ receptor in vitro, the compounds will not produce significant activation of the receptor in animals. Compounds dosed to full effect for insulin sensitizing actions in vivo (see below) will be not increase activation of PPARγ in the liver as measured by the expression of a P2, a biomarker for ectopic adipogenesis in the liver [Matsusue K, Haluzik M, LambertG, Yim S-H, Oksana Gavrilova O, Ward JM, Brewer B,Reitman ML, Gonzalez FJ. (2003) Liver-specific disruption of PPAR in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J. Clin. Invest.; Ill: 737] in contrast to pioglitazone and rosiglitazone, which do increase a P2 expression under these conditions.
[00322] The insulin sensitizing and antidiabetic pharmacology are measured in the KKA Y mice as previously reported [Hofmann, C, Lornez, K., and Colca, J.R. (1991). Glucose transport deficiency corrected by treatment with the oral anti-hyperglycemic agent
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, 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.
[00323] Measuring PPARγ Receptor Activation
[00324] The ability of several exemplary compounds of the present invention to bind to PPARγ was measured using a commercial binding assay (Invitrogen Corporation, Carlsbad, CA) that measures the test compounds abililty to bind with PPAR-LBD/Fluormone PPAR Green complex. These assays were performed on three occasions with each assay using four separate wells (quadruplicate) at each concentration of tested compound. The data are mean and SEM of the values obtained from the three experiments. Rosiglitazone was used as the positive control in each experiment. Compounds were added at the concentrations shown, which range from 0.1-100 micromolar.
[00325] Glucose, Insulin, and Triglyceride in Diabetic KKAy Mice Treated with Exemplary Compounds of the Present Invention.
[00326] The insulin sensitizing and antidiabetic pharmacology are measured in the KKAy mice as previously reported [Hofmann, C, Lornez, K., and Colca, J.R. (1991). Glucose transport deficiency corrected by treatment with the oral anti-hyperglycemic agent
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.
[00327] Compounds were formulated by suspension and orally dosed to KKAy mice at 93 mg/kg for 4 days. The compounds were first dissolved in DMSO and then placed into aqueous suspension containing 7-10% DMSO, 1% sodium methylcarboxycellulose, and 0.01 % Tween 20. On the fifth day, the mice were fasted and blood samples were obtained approximately 18 hours after the last dose. The parameters were measured by standard assay methods. Data are mean and SEM N=6-12 mice.
Table B Assay Results
Figure imgf000084_0001
[00328] Compounds from examples 1, 2, 3, 4 and 5 exhibited a plasma insulin level of less than about 5 ng/ml and example 6 exhibited a plasma insulin level between about 15 and 20 ng/ml; examples 1, 2, 3, 4, and 5 exhibited a plasma triglyceride level of between about 100 and 200 mg/dl and example 6 exhibited a plasma triglyceride level between about 300 and 400 mg/dl; examples 1, 2, 3, 4, and 5 exhibited a plasma gluclose level of between about 350 and 425 mg/dl and example 6 exhibited a plasma gluclose level between about 450 and 525 mg/dl.
[00329] The PPARγ-sparing compounds of this invention will be more effective for the treatment of diseases caused by metabolic inflammation such as diabetes and metabolic syndrome by limiting the side effects attributable to direct and partial activation of nuclear transcription factors.
[00330] Because the compounds of the present invention exhibit reduced PPARγ activation, it is anticipated that these compounds are suitable for use in combination with other compounds having antidiabetic activity, such as metformin, DDP-4 inhibitors, or other antidibaetic agents that function by differing mechanisms to augment the actions or secretions of GLPl or insulin. Specifically because of the reduced PPARγ interaction, these compounds will also be useful for treating dyslipidemia associated with metabolic inflammatory diseases combining particularly well with lipid lowering statins such as atorvastatin or the like. It is also anticipated that the combination of a compound of Formula I and other antidiabetic compounds will be more effective in treating diabetes than combinations with PPAR- activating compounds as they will avoid side effects associated with PPARγ activation that may include volume expansion, edema, and bone loss.
OTHER EMBODIMENTS
[00331] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A method for treating hyperstension comprising administering to a patient a pharmaceutical composition comprising a compound of Formula I:
Figure imgf000086_0001
or a pharmaceutically acceptable salt thereof, wherein:
Each of R1 and R4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo;
R2 is -H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2, -O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or
Figure imgf000086_0002
.
Each RA is independently -H or an optionally substituted C1-6 alkyl;
Each RB is independently -H, optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted phenyl,
Or any two of RB, taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring,
Or R2 and R2 taken together form oxo;
R3 is -H or optionally substituted C]-3 aliphatic; and
Ring A is
Figure imgf000086_0003
2. The method of claim 1, wherein Ring A is
Figure imgf000087_0001
3. The method of either of claims 1 or 2, wherein Ring A is phenyl and R1 is attached to the ortho or para position of Ring A.
4. The method of claim 3, wherein R1 is -H or halo; or R1 is -C1-6 aliphatic or
-C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
5. The method of claim 4, wherein R1 is -C1-6 alkoxy optionally substituted with 1-3 halo.
6. The method of claim 5, wherein R1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
7. The method of either of claims 1 or 2, wherein Ring A is phenyl and R1 is attached to the meta or para position of Ring A.
8. The method of claim 7, wherein R1 is attached to the meta position of Ring A.
9. The method of either of claims 7 or 8, wherein R1 is -H or halo; or R1 is -C1-6 aliphatic or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
10. The method of any of claims 7-9, wherein R1 is -Q-β aliphatic optionally substituted with 1-3 halo.
11. The method of claim 10, wherein R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert- butyl, each of which is optionally substituted with 1-3 halo.
12. The method of any of claims 7-9, wherein R1 is -C1-6 alkoxy optionally substituted with 1-3 halo
13. The method of claim 12, wherein R1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
14. The method of any of claims 2, 3, or 7, wherein R1 is -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CF3, -OCHF2, or -OCF3.
15. The method of claim 1 , wherein Ring A is
Figure imgf000088_0001
16. The method of either of claims 1 or 15, wherein Ring A is
Figure imgf000088_0002
or
Figure imgf000088_0003
17. The method of claim 16, wherein Ring A is
Figure imgf000088_0005
18. The method of claim 16, wherein Ring A is
Figure imgf000088_0004
19. The method of any of claims 16-18, wherein R1 is -H or halo; or R1 is -C1-6 aliphatic, or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
20. The method of any of claims 15-19, wherein R1 is -H.
21. The method of any of claims 15-19, wherein R1 is optionally substituted -C1-6 aliphatic.
22. The method of claim 21, wherein R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert- butyl, each of which is optionally substituted with 1-3 halo.
23. The method of claim 17, wherein R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert- butyl, each of which is optionally substituted with 1-3 halo.
24. The method of any of claims 1-23, wherein R4 is -H or halo.
25. The method of claim 1, wherein Ring A and its substituents R1 and R4 form
Figure imgf000089_0001
26. The method of claim 1, wherein Ring A and its substituents R1 and R4 form
Figure imgf000089_0002
27. The method of any of claims 1 -25, wherein R2 is -OH.
28. The method of any of claims 1-25, wherein R2 is -O-acyl, -O-aroyl or -O-heteroaroyl.
29. The method of any of claims 1 -25, wherein R2 and R2 together form oxo.
30. The method of any of claims 1-25, wherein R2 is -H, -OH,
Figure imgf000089_0003
Figure imgf000090_0001
31. The method of any of claims 1 -30, wherein R3 is -H or -CH3.
32. A method for treating hyperstension comprising administering to a patient a pharmaceutical composition comprising a compound of Formula (IA):
Figure imgf000090_0002
or a pharmaceutically acceptable salt thereof, wherein:
Each of R1 and R4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo;
R2 is -H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2, -O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or .
Figure imgf000090_0003
Each RA is independently -H or an optionally substituted C1-6 alkyl;
Each RB is independently -H, optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted phenyl,
Or any two of RB, taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring,
Or R2 and R2 taken together form oxo;
R3 is H; and
Ring A is phenyl.
33. The method of claim 32, wherein R1 is attached to the ortho or para position of Ring A.
34. The method of claim 33, wherein R1 is -H or halo; or R1 is -C1-6 aliphatic or
-C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
35. The method of either of claims 33 or 34, wherein R1 is -C1-6 alkoxy optionally substituted with 1 -3 halo.
36. The method of claim 35, wherein R1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
37. The method of claim 32, wherein R1 is attached to the meta or para position of the phenyl ring.
38. The method of claim 37, wherein R1 is attached to the meta position of the phenyl ring.
39. The method of either of claims 37 or 38, wherein R1 is -H or halo; or R1 is -C1-6 aliphatic or -Ct-6 alkoxy, either of which is optionally substituted with 1-3 halo.
40. The method of any of claims 37-39, wherein R1 is -C1-6 aliphatic optionally substituted with 1-3 halo.
41. The method of claim 40, wherein R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert- butyl, each of which is optionally substituted with 1-3 halo.
42. The method of any of claims 37-39, wherein R1 is -Q-6 alkoxy optionally substituted with 1-3 halo
43. The method of claim 42, wherein R1 is methoxy, ethoxy, propoxy, butoxy, iso- propoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
44. The method of any of claims 32, 33, or 37, wherein R1 is -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CF3, -OCHF2, or -OCF3.
45. The method of any of claims 32-44, wherein R4 is -H, methyl, ethyl, methoxy, ethoxy, iso-propoxy, -CF3, -OCHF2 or -OCF3.
46. The method of any of claims 32-45, wherein R4 is H.
47. The method of claim 32, wherein Ring A and its substituents R1 and R4 form
Figure imgf000092_0001
48. The method of any of claims 32-47, wherein R2 is hydroxy.
49. The method of any of claims 32-47, wherein R2 is -O-acyl, -O-aroyl or
-O-heteroaroyl.
50. The method of any of claims 32-47, wherein R2 is -O-CH(RA)-O-C(O)RB, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6 alkyl, -C3-8cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
51. The method of any of claims 32-47, wherein R2 is -O-CH(RA)OP(O)(ORB)2, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6 alkyl, -C3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
52. The method of any of claims 32-47, wherein R2 is -O-P(O)(ORB)2, and RB is -C1-4 alkyl optionally substituted with 1-3 halo, or two RB groups together with the atoms to which they are attached form an optionally substituted 5-7 membered ring.
53. The method of any of claims 32-47, wherein R2 is -0-SO2NH2.
54. The method of any of claims 32-47, whereiinn R2 is
Figure imgf000093_0001
, and RB is -H or an optionally substituted C 1-4 alkyl.
55. The method of any of claims 32-47, wherein R2 and R2 together form oxo.
56. The method of claim 32, wherein the compound of Formula IA is:
Figure imgf000093_0002
Figure imgf000094_0001
7. The method of claim 32, wherein the compound of Formula IA is :
Figure imgf000094_0002
Figure imgf000095_0001
58. The method of claim 32, wherein the compound of Formula IA is :
Figure imgf000095_0002
Figure imgf000096_0001
hod of claim 32, wherein the compound of Formula IA is
O O
Figure imgf000096_0002
hod of claim 32, wherein the compound of Formula IA is:
Figure imgf000097_0001
O H
Figure imgf000098_0001
Figure imgf000098_0002
The method of claim of claim 32, wherein the compound of Formula IA is:
Figure imgf000098_0003
Figure imgf000099_0001
2. The method of claim 32, wherein the compound of Formula IA is:
H
Figure imgf000099_0002
3. The method of claim 32, wherein the compound of Formula IA is:
Figure imgf000099_0003
Figure imgf000100_0001
4. The method of claim 32, wherein the compound of Formula IA is:
Figure imgf000100_0002
5. The method of claim 32, wherein the compound of Formula IA is:
Figure imgf000101_0001
66. A method for treating hyperstension comprising administering to a patient a pharmaceutical composition comprising a compound of Formula (IB):
Figure imgf000101_0002
or a pharmaceutically acceptable salt thereof, wherein:
Each of R1 and R4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo;
R'2 is -H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2, -0-CH(RA)0C(0)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or
Figure imgf000102_0001
Each RΛ is independently -H or an optionally substituted C1-6 alkyl; Each RB is independently -H, optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted phenyl,
Or any two of RB, taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring,
Or R2 and R2 taken together form oxo;
R3 is H or optionally substituted C1-3 aliphatic; and
Ring A is
Figure imgf000102_0003
67. The method of claim 66, wherein R3 is H.
68. The method of claim 66, wherein R3 is methyl.
69. The method of any of claims 66-68, wherein Ring A is
Figure imgf000102_0002
70. The method of any of claims 66-68, wherein Ring A is
Figure imgf000102_0004
71. The method of any of claims 66-70, wherein R1 is -H or halo; or R1 is -C1-6 alkyl or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
72. The method of any of claims 66, 69, or 70, wherein R1 is -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CF3, -OCHF2, or -OCF3.
73. The method of any of claims 66-72, wherein R1 is H.
74. The method of any of claims 66-72, wherein R1 is ethyl.
75. The method of any of claims 66-74, wherein R4 is -H, methyl, ethyl, methoxy, ethoxy, iso-propoxy, -CF3, -OCHF2 or -OCF3.
76. The method of any of claims 66-75, wherein R4 is -H.
77. The method of claim 66, wherein Ring A and its substituents R1 and R4 form
Figure imgf000103_0001
78. The method of any of claims 66-77, wherein R2 is -O-acyl, -O-aroyl, or -O- heteroaroyl.
79. The method of any of claims 66-77, wherein R2 is -O-CH(RA)-O-C(O)RB, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -Chalky., -Qs-βcycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
80. The method of any of claims 66-77, wherein R2 is -O-CH(RA)OP(O)(ORB)2, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6 alkyl, -C3-gcycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
81. The method of any of claims 66-77, wherein R2 is -O-P(O)(ORB)2, and RB is -C1-4 alkyl optionally substituted with 1-3 halo, or two RB groups together with the atoms to which they are attached form an optionally substituted 5-7 membered ring.
82. The method of any of claims 66-77, wherein R2 is -0-SO2NH2.
83. The method of any of claims 66-77, wherein R2 is
Figure imgf000103_0002
, and RB is -H or an optionally substituted C1-4 alkyl.
84. The method of claim 66, whe i h d of Formula EB is:
Figure imgf000104_0001
85. The method of claim 66, wherein the compound of Formula IB is:
Figure imgf000104_0002
Figure imgf000105_0001
86. The method of claims 1-85, wherein the composition further comprises a diuretic, statin, angiotension II receptor blocker, a renin inhibitor, a beta adrenergic blocker, or combination thereof.
87. A compound of Formula I:
Figure imgf000105_0002
or a pharmaceutically acceptable salt thereof, wherein:
Each of R1 and R4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo;
R'2 is -H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2, -O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or
Figure imgf000106_0001
Each RA is independently -H or an optionally substituted C1-6 alkyl; Each RB is independently -H, optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted phenyl,
Or any two of RB, taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring,
Or R2 and R2 taken together form oxo;
R3 is H or optionally substituted C1-3 aliphatic; and
Ring A is
Figure imgf000106_0002
88. The compound of claim 87, wherein Ring A is
Figure imgf000106_0003
89. The compound of either of claims 87 or 88, wherein Ring A is phenyl and R1 is attached to the ortho or para position of Ring A.
90. The compound of claim 89, wherein R1 is -H or halo; or R1 is -Cue aliphatic or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
91. The compound of claim 90, wherein R1 is -Ci .6 alkoxy optionally substituted with 1-3 halo.
92. The compound of claim 91 , wherein R1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
93. The compound of either of claims 87 or 88, wherein Ring A is phenyl and R1 is attached to the meta or para position of Ring A.
94. The compound of claim 93, wherein R1 is attached to the meta position of Ring A.
95. The compound of either of claims 93 or 94, wherein R1 is -H or halo; or R1 is -C1-6 aliphatic or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
96. The compound of any of claims 93-95, wherein R1 is -C1-6 aliphatic optionally substituted with 1-3 halo.
97. The compound of claim 96, wherein R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert-butyl, each of which is optionally substituted with 1-3 halo.
98. The compound of any of claims 93-95, wherein R1 is -C1-6 alkoxy optionally substituted with 1-3 halo
99. The compound of claim 98, wherein R1 is methoxy, ethoxy, propoxy, butoxy, iso- propoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
100. The compound of any of claims 88, 89, or 93, wherein R1 is -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CF3, -OCHF2, or -OCF3.
101. The compound of claim 87, wherein Ring A is
Figure imgf000107_0001
102. The compound of either of claims 87 or 101 , wherein Ring A is
Figure imgf000107_0003
or
Figure imgf000107_0002
103. The compound of claim 102, wherein Ring A is
Figure imgf000107_0004
104. The compound of claim 102, wherein Ring A is
Figure imgf000108_0001
105. The compound of any of claims 101-104, wherein R1 is -H or halo; or R1 is -C1-6 aliphatic, or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
106. The compound of any of claims 101-105, wherein R1 is -H.
107. The compound of any of claims 101-105, wherein R1 is -C1-6 aliphatic optionally substituted with 1-3 halo.
108. The compound of claim 107, wherein R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert-butyl, each of which is optionally substituted with 1-3 halo.
109. The compound of any of claims 101-105, wherein R1 is -C1-6 alkoxy optionally substituted with 1-3 halo.
110. The compound of claim 109, wherein R1 is methoxy, ethoxy, propoxy, butoxy, iso- propoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
111. The compound of any of claims 87-110, wherein R4 is independently -H or halo.
112. The compound of claim 87, wherein Ring A and its substituents R1 and R4 form
Figure imgf000108_0002
Figure imgf000109_0001
113. The compound of claim 87, wherein Ring A and its substituents R1 and R4 form
Figure imgf000109_0002
114. The compound of any of claims 87-113, wherein R2 is -OH.
115. The compound of any of claims 87-113, wherein R2 is -O-acyl, -0-aroyl or -O- heteroaroyl.
116. The compound of any of claims 87-113, wherein R2 and R'2 together form oxo.
117. The compound of any of claims 87-113, wherein R2 is -H, -OH,
Figure imgf000109_0003
Figure imgf000110_0001
118. The compound of any of claims 87- 117, wherein R3 is -H or -CH3.
119. A compound of Formula (LA):
Figure imgf000110_0002
or a pharmaceutically acceptable salt thereof, wherein:
Each of R1 and R4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo;
R'2 is -H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -O-heteroaroyl, -0(SO2)NH2, -O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or .
Figure imgf000110_0003
Each RA is independently -H or an optionally substituted C 1.6 alkyl; Each RB is independently -H, optionally substituted C1-12 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted phenyl,
Or any two of RB, taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring,
Or R2 and R2 taken together form oxo;
R3 is H; and
Ring A is phenyl.
120. The compound of claim 119, wherein R1 is attached to the ortho or para position of Ring A. 121. The compound of claim 120, wherein R1 is -H or halo; or R1 is -C1-6 aliphatic or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
122. The compound of either of claims 119 or 120, wherein R1 is -C1-6 alkoxy optionally substituted with 1-3 halo.
123. The compound of claim 122, wherein R1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
124. The compound of claim 119, wherein R1 is attached to the meta or para position of Ring A.
125. The compound of claim 124, wherein R1 is attached to the meta position of Ring A.
126. The compound of either of claims 124 or 125, wherein R1 is -H or halo; or R1 is -Ci.6 aliphatic or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
127. The compound of any of claims 124-126, wherein R1 is -C1-6 aliphatic optionally substituted with 1-3 halo.
128. The compound of claim 127, wherein R1 is methyl, ethyl, propyl, butyl, iso-propyl, or tert-butyl, each of which is optionally substituted with 1-3 halo.
129. The compound of any of claims 124-126, wherein R1 is -C1-6 alkoxy optionally substituted with 1-3 halo
130. The compound of claim 129, wherein R1 is methoxy, ethoxy, propoxy, butoxy, isopropoxy, or tert-butoxy, each of which is optionally substituted with 1-3 halo.
131. The compound of any of claims 1 19, 120, or 124, wherein R1 is -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CF3, -OCHF2, or -OCF3.
132. The compound of any of claims 119-131, wherein R4 is -H, methyl, ethyl, methoxy, ethoxy, iso-propoxy, -CF3, -OCHF2 or -OCF3.
133. The compound of any of claims 119-132, wherein R4 is H.
134. The compound of claim 119, wherein Ring A and its substituents R1 and R4 form
Figure imgf000112_0001
135. The compound of any of claims 1 19-134, wherein R2 is -OH.
136. The compound of any of claims 119-134, wherein R2 is -O-acyl, -O-aroyl or -O-heteroaroyl.
137. The compound of any of claims 119-134, wherein R2 is -O-CH(RA)-O-C(O)RB, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6alkyl, -C3,8cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
138. The compound of any of claims 119-134, wherein R2 is -O-CH(RA)OP(O)(ORB)2, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6alkyl, -C3-gcycloalkyU or phenyl, any of which is optionally substituted with 1-3 halo.
139. The compound of any of claims 119-134, wherein R2 is -O-P(O)(ORB)2, and RB is -CM alkyl optionally substituted with 1-3 halo, or two RB groups together with the atoms to which they are attached form an optionally substituted 5-7 membered ring.
140. The compound of any of claims 119-134, wherein R2 is -0-SO2NH2.
X
141. The compound of any of claims 119-134, wherein R2 is
Figure imgf000112_0002
, andRB is -H or an optionally substituted C1-4 alkyl.
142. The compound of any of claims 1 19-134, wherein R2 and R2 taken together form oxo.
143. A compound selected from:
Figure imgf000113_0001
144. A compound selected from:
Figure imgf000114_0001
or
Figure imgf000114_0002
ound selected from:
Figure imgf000115_0001
ound selected from:
Figure imgf000115_0002
Figure imgf000116_0001
ound selected from:
Figure imgf000116_0002
Figure imgf000117_0001
Figure imgf000118_0001
148. A compound selected from:
Figure imgf000118_0002
149. A compound selected from:
Figure imgf000118_0003
Figure imgf000119_0001
150. A compound selected from:
Figure imgf000119_0002
151. A compound selected from:
Figure imgf000120_0001
A compound selected from:
Figure imgf000120_0002
153. A compound of Formula (IB):
Figure imgf000121_0001
or a pharmaceutically acceptable salt thereof, wherein:
Each of R1 and R4 is independently -H, halo, aliphatic, or alkoxy, wherein the aliphatic or alkoxy are optionally substituted with 1-3 of halo;
R2 is -H and R2 is halo, hydroxy, aliphatic, -O-acyl, -O-aroyl, -0-heteroaroyl, -0(SO2)NH2, -O-CH(RA)OC(O)RB, -O-CH(RA)OP(O)(ORB)2, -O-P(O)(ORB)2, or
Figure imgf000121_0002
.
Each RA is independently -H or an optionally substituted C1-6 alkyl; Each RB is independently -H, optionally substituted C1-I2 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted phenyl,
Or any two of RB, taken together with the atoms to which they are attached form an optionally substituted 5 to 7 membered ring,
Or R2 and R'2 taken together form oxo;
R3 is H or optionally substituted C1-3 aliphatic; and
Ring A is
Figure imgf000121_0003
154. The compound of claim 153, wherein R3 is H.
155. The compound of claim 153, wherein R3 is methyl.
156. The compound of any of claims 153-155, wherein Ring A is
Figure imgf000122_0002
157. The compound of any of claims 153-155, wherein Ring A is
Figure imgf000122_0003
158. The compound of any of claims 153-157, wherein R1 is -H or halo; or R1 is -C1-6 alkyl or -C1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
159. The compound of any of claims 153, 156, or 157, wherein R1 is -H, -Cl, -F, -Br, -CH3, -CH2CH3, -CF3, -OCHF2, or -OCF3.
160. The compound of any of claims 153-159, wherein R1 is H.
161. The compound of any of claims 153- 159, wherein R1 is ethyl.
162. The compound of any of claims 153-161, wherein R4 is -H, methyl, ethyl, methoxy, ethoxy, iso-propoxy, -CF3, -OCHF2 or -OCF3.
163. The compound of any of claims 153-162, wherein R4 is -H.
164. The compound of claim 153, wherein Ring A and its substituents R1 and R4 form
Figure imgf000122_0001
165. The compound of any of claims 153-164, wherein R2 is -O-acyl, -O-aroyl, or -O- heteroaroyl.
166. The compound of any of claims 153-164, wherein R2 is -O-CH(RA)-O-C(O)RB, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6 alkyl, -C3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1-3 halo.
167. The compound of any of claims 153-164, wherein R2 is -O-CH(RA)OP(O)(ORB)2, RA is -H, -CH3, -CH2CH3, or -CH(CH3)2, and RB is -H or RB is -C1-6 alkyl, -C3-8 cycloalkyl, or phenyl, any of which is optionally substituted with 1 -3 halo.
168. The compound of any of claims 153- 164, wherein R2 is -O-P(O)(ORB)2, and RB is -Ci.4 alkyl optionally substituted with 1-3 halo, or two RB groups together with the atoms to which they are attached form an optionally substituted 5-7 membered ring.
169. The compound of any of claims 153-164, wherein R2 is -0-SO2NH2.
170. The compound of any of claims 153-164, wherein R2 is
Figure imgf000123_0001
and RB is -H or an optionally substituted C1-4 alkyl.
171. A compound selected from :
Figure imgf000123_0002
Figure imgf000124_0001
or
Figure imgf000124_0002
172. A compound selected from:
Figure imgf000124_0003
173. A method of treating an inflammatory disease, comprising administering
administering to a patient a pharmaceutical composition comprising a compound as described in claims 87-172.
174. The method of claim 173, wherein the composition further comprises a glucocorticoid agonist.
175. The method of claim 174, wherein the glucocorticoid agonist is cortisone, hydrocortisone, predisone, prednisolone, methylprednisolone, betamethasone, and triameclinolone, or any combination thereof.
176. The method of claims 173- 175, wherein the inflammatory disease is rheumatoid arthritis, lupus, myasthenia gravis, muscular dystrophy, vasculitis, Chronic Obstructive Pulmonary Disease, inflammatory bowel disease, multiple sclerosis, acute allergic reactions, and transplant rejections, or any combination thereof.
177. A pharmaceutical composition comprising a compound as described in any of claims 87-172 and a carrier.
178. The pharmaceutical composition of claim 177, further comprising a diuretic, statin, angiotensin II receptor blocker, a renin inhibitor, a beta adrenergic blocker, or any combination thereof.
179. The pharamaceutical composition of claim 177 further comprising a glucocorticoid agonist.
180. The pharmaceutical composition of claim 179, whertein the glucocorticoid agonist is cortisone, hydrocortisone, predisone, prednisolone, methylprednisolone, betamethasone, and triameclinolone, or any combination thereof.
181. A method of treating diabetes comprising administering to a patient a pharmaceutical composition comprising a compound as described in any of claims 87-172.
PCT/US2010/026971 2009-03-12 2010-03-11 Thiazolidinedione analogues WO2010105048A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US15967809P 2009-03-12 2009-03-12
US61/159,678 2009-03-12
US16125809P 2009-03-18 2009-03-18
US61/161,258 2009-03-18

Publications (2)

Publication Number Publication Date
WO2010105048A1 WO2010105048A1 (en) 2010-09-16
WO2010105048A9 true WO2010105048A9 (en) 2011-01-27

Family

ID=42310682

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/026971 WO2010105048A1 (en) 2009-03-12 2010-03-11 Thiazolidinedione analogues

Country Status (1)

Country Link
WO (1) WO2010105048A1 (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8304441B2 (en) 2007-09-14 2012-11-06 Metabolic Solutions Development Company, Llc Thiazolidinedione analogues for the treatment of metabolic diseases
NZ597381A (en) 2007-09-14 2013-03-28 Metabolic Solutions Dev Co Llc Thiazolidinedione analogues for the treatment of diabetes and inflammatory diseases
CN102791269A (en) * 2009-12-15 2012-11-21 新陈代谢解决方案开发公司 PPAR-sparing thiazolidinediones and combinations for the treatment of neurodegenerative diseases
CA2783262A1 (en) * 2009-12-15 2011-07-14 Metabolic Solutions Development Company, Llc Ppar-sparing thiazolidinediones and combinations for the treatment of obesity and other metabolic diseases
WO2011084456A1 (en) * 2009-12-15 2011-07-14 Metabolic Solutions Development Company Ppar-sparing thiazolidinediones and combinations for the treatment of diabetes mellitus and other metabolic diseases
RU2564661C2 (en) 2009-12-15 2015-10-10 МЕТАБОЛИК СОЛЮШНЗ ДЕВЕЛОПМЕНТ КОМПАНИ, ЭлЭлСи Thiazolidinedione salts with reduced affinity to ppar for treatment of metabolic disorders
AU2014202074B2 (en) * 2009-12-15 2016-01-07 Cirius Therapeutics, Inc. PPAR-sparing thiazolidinediones and combinations for the treatment of neurodegenerative diseases
PL2603498T3 (en) * 2010-08-10 2017-06-30 Octeta Therapeutics, Llc Novel synthesis for thiazolidinedione compounds
WO2012109495A1 (en) * 2011-02-09 2012-08-16 Metabolic Solutions Development Company, Llc Cellular targets of thiazolidinediones
WO2012149083A1 (en) * 2011-04-28 2012-11-01 Metabolic Solutions Development Company, Llc Ppar-sparing thiazolidinediones for the treatment of kidney related diseases
EP3623364A1 (en) 2014-02-13 2020-03-18 Ligand Pharmaceuticals, Inc. Prodrug compounds and their uses
GB202210503D0 (en) 2022-07-18 2022-08-31 Univ Court Univ Of Glasgow Materials and methods for treatment of chronic myeloid leukemia (CML)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985004170A1 (en) * 1984-03-21 1985-09-26 Takeda Chemical Industries, Ltd. Thiazolidinedione derivatives, process for their preparation, and medicinal composition containing same
US7465801B2 (en) * 2002-07-16 2008-12-16 Cadila Healthcare Limited Process to prepare pioglitazone via several novel intermediates
NZ571872A (en) * 2006-03-16 2011-05-27 Metabolic Solutions Dev Co Combination therapies of thiazolidinedione analogues and glucocorticoid agonists
NZ597381A (en) * 2007-09-14 2013-03-28 Metabolic Solutions Dev Co Llc Thiazolidinedione analogues for the treatment of diabetes and inflammatory diseases

Also Published As

Publication number Publication date
WO2010105048A1 (en) 2010-09-16

Similar Documents

Publication Publication Date Title
AU2008301905B2 (en) Thiazolidinedione analogues for the treatment of hypertension
CA2646207C (en) Thiazolidinedione analogues for the treatment of metabolic inflammation mediated disease
EP2513070B1 (en) Ppar-sparing thiazolidinedione salts for the treatment of metabolic diseases
WO2010105048A9 (en) Thiazolidinedione analogues
JP2010539171A5 (en)
EP2001469B1 (en) Thiazolidinedione analogues
EP2512475A1 (en) Ppar-sparing thiazolidinediones and combinations for the treatment of obesity and other metabolic diseases
WO2011133611A1 (en) Thiazolidinedione analogues
NZ571872A (en) Combination therapies of thiazolidinedione analogues and glucocorticoid agonists
US8304441B2 (en) Thiazolidinedione analogues for the treatment of metabolic diseases
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: 10717327

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10717327

Country of ref document: EP

Kind code of ref document: A1