WO2002076177A2 - Conception et synthese de ligands optimises pour ppar - Google Patents

Conception et synthese de ligands optimises pour ppar Download PDF

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WO2002076177A2
WO2002076177A2 PCT/US2002/009287 US0209287W WO02076177A2 WO 2002076177 A2 WO2002076177 A2 WO 2002076177A2 US 0209287 W US0209287 W US 0209287W WO 02076177 A2 WO02076177 A2 WO 02076177A2
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substituted
group
dione
ppar
compound
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PCT/US2002/009287
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WO2002076177A3 (fr
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Harrihar Ajodhya Pershadsingh
Mitchell Allen Avery
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Bethesda Pharmaceuticals, Inc.
University Of Mississippi
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Priority to AU2002303156A priority Critical patent/AU2002303156A1/en
Publication of WO2002076177A2 publication Critical patent/WO2002076177A2/fr
Publication of WO2002076177A3 publication Critical patent/WO2002076177A3/fr

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    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
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    • 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
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
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    • 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
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    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to the field of rational drug design. Specifically the invention relates to compounds that interact with peroxisome proliferator activated receptors (PPARs) and methods for their design and synthesis.
  • PPARs peroxisome proliferator activated receptors
  • PPARs Peroxisome proliferator-activated receptors
  • PPARgamma and PPARdelta Three subtypes of PPARs have been cloned from the mouse and human: i.e., PPARalpha, PPARgamma and PPARdelta.
  • PPARgamma and PPARalpha are differentially expressed in organs and tissues (Willson et al. J. Med. Chem. 43:527-50 (2000)
  • Nuclear receptors like PPAR possess DNA binding domains (DBDs) that recognized specific DNA sequences (called response elements) located in the regulatory regions of their target genes Mangelsdorf et al Cell 83:835-839 (1995)).
  • DBDs DNA binding domains
  • PPARgamma consists of three forms, PPARgammal which is broadly expressed in most tissues, PPARgamma2, is more restricted to adipose (white fat and brown fat) tissue, and PPARgamma3.
  • PPARgamma3 is confined to adipose tissue, macrophages and colonic epithelium in rodent and human tissues (Mangelsdorf, and Evans Cell (1995) 83:841-850; Spiegelman. Diabetes (1998) 47:507-514; Willson et al., J. Med.
  • PPARgamma is functionally involved in intermediary metabolism of cells and tissues that express this nuclear receptor. [0005] PPARgamma and PPARalpha and PPARdelta are differentially expressed in different organs and tissues.
  • Activation of PPARgamma and or PPARalpha and/or PPARdelta modulates the expression of genes involved in: 1) glucose and lipid metabolism, 2) the regulation of cell growth, differentiation and regulation of the mitotic cycle, 3) the inflammatory response in cells of the immune system, 4) suppression of components of the immune system that become activated in pathological situations, and 5) regulation of apoptosis (programmed cell death) in a variety of cell types. Impairment in these processes lead to pathophysiolgical conditions involving metabolic (endocrine) dysfunction, proliferative diseases, inflammatory diseases and degenerative diseases. (Pershadsingh, Expert Opin. Investig. Drugs 8(11): 1859-1872 (1999)).
  • Nutrient retinoids and retinoic acid such as 13-all-trans-retinoic acid are converted to 9-cis-, 11-cis-, or 13-cis-retinoic acid by ubiquitous intracellular isomerases (Warrell Jr et al, New Engl. J. Med. 329(3): 177- 189 (1993)).
  • the full spectrum of genes that can be regulated by PPARalpha or PPARgamma or PPARdelta or their respective heterodimers remain to be defined.
  • PPAR agonists have been shown to inhibit the expression of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), IL-1, IL-2, IL-6 in cells of the immune system including, T lymphocytes, B lymphocytes, monocytes, monocyte/macrophages, and splenocytes.
  • cytokines such as tumor necrosis factor-alpha (TNF-alpha), IL-1, IL-2, IL-6
  • TNF-alpha tumor necrosis factor-alpha
  • B lymphocytes IL-1
  • monocytes monocytes
  • monocyte/macrophages monocyte/macrophages
  • splenocytes splenocytes.
  • PPARgamma agonists tend to suppress inflammation mediated by Thl lymphocytes (Marx et al., J. Immunol. 164:6503 (2000); Padilla et al., Ann N. Y. Acad. Sci. 905:97
  • PPARgamma activators are not useful for the treatment of acute inflammation in db/db diabetic mice (Thieringer et al., J. Immunol. (2000) 164:1046).
  • Thiazolidinedione-treated db/db mice challenged with lipopolysaccharide, a potent pro-inflammatory agent displayed no suppression of cytokine production. Rather, their blood levels of TNF-alpha and IL-6 were elevated beyond the levels observed in control mice.
  • PPAR agonists have also been shown to inhibit proliferation and promote differentiation of a variety of normal and neoplastic cell types.
  • Spiegelman et al. PCT/US97/22879, published June 18, 1998, disclose methods for inhibiting proliferation of PPARgamma-responsive hyperproliferative cells by using PPARgamma agonists; numerous PPARgamma agonists are disclosed by Spiegelman et al., as well as methods for diagnosing PPARgamma-responsive cells.
  • the method relates to superior efficacy of PPAR activators or co-activators of various subtypes in: 1) promoting apoptosis of neoplastic cells, 2) systemic anti-inflammatory effect by suppressing Thl -mediated inflammatory cytokines and promoting Thl to Th2 phenotypic transition resulting in of immunosuppression, leading to prevention, amelioration or reversal of degenerative diseases.
  • diseases susceptible to the immunosuppressive effects of activators of PPARgamma, or PPARalpha, or PPARdelta, or co-activators of any of these subtypes are: inflammatory skin diseases (e.g. psoriasis, atopic dermatitis, eczema, acne vulgaris, and other dermatitides), neurodegenerative diseases (e.g. multiple sclerosis, Alzheimer's disease, Parkinson's disease), cardiovascular diseases (e.g.
  • the immune system includes T lymphocytes, B lymphocytes, monocytes, macrophages, monocyte/macrophages, macrophage-like cells (e.g.
  • astrocytes in the brain retinal pigmented epithelial cells in the retina
  • cells of myeloid origin in any tissue in particular the bone marrow (stem cells, pre- promyelocytes, promyelocytes, myelocytes, granulocytes, plasma cells, mast cells, basophils, polymorphonuclear cells, eosinophils).
  • PPARgamma and PPARalpha and PPARdelta are differentially expressed in organs and tissues (Willson et al., J. Med. Chem. (2000) 43 (4):527-50). This heterogeneous distribution is particularly evident in the complex structure of the eye (Braissant et al., Endocrinology (1996) 137:354-366; Pershadsingh et al., Proceedings of the Society for Neurosciences. Miami Beach, USA,1999).
  • PPARgamma and/or PPARalpha activity and/or PPARdelta due to the varied tissue distribution of expression of the various PPAR subtypes and the varied amounts of their respective proteins in various cells.
  • some PPAR subtypes are expressed in some cells while in a normal state, but not expressed or expressed to a lesser or greater degree by the abnormal cells, or visa versa.
  • PPARgamma and PPARalpha are differentially expressed in diseased versus normal cells.
  • PPARgamma is expressed in normal human keratinocytes but not in normal human dermal fibroblasts (Ellis et al., Arch. Dermatol. (2000) 136:609-616). PPARgamma has been shown to be expressed in a greater amount in level was increased in the subcellular cytosolic fraction of Alzheimer's disease brains, compared to control brains (Kitamura et al., Biochem. Biophys. Res. Commun. 1999; 254:582-586).
  • PPARgamma or PPARalpha or PPARdelta depends on the degree to which the receptor protein is phosphorylated and/or on the conformation of the receptor. It has been proposed that phosphorylation could alter interactions with protein cofactors of PPARgamma which act as corepressors or coactivators. Nuclear receptors function as "ligand-gated” platforms for the assembly of these cofactors into large protein complexes on specific DNA sequences (Spiegelman Diabetes (1998) 47:507-514). Some of these coactivator proteins (CBP/p300, SRC1, pCAF) have histone acetyltransferase activity that functions to "open" the configuration of chromatin, allowing more efficient transcription.
  • CBP/p300, SRC1, pCAF histone acetyltransferase activity that functions to "open" the configuration of chromatin, allowing more efficient transcription.
  • tissue expressing PPARgamma and or PPARalpha and/or PPARdelta may respond to a particular ligand, and a pathological state will be attenuated, arrested, accentuated or worsened by said ligand can vary for example in the case in which a single ligand activates both PPARgamma and PPARalpha to similar degrees, i.e. a co-activator of both PPARgamma and PPARalpha (or similarly, both PPARgamma and PPARdelta or PPARalpha and PPARdelta).
  • PPARalpha and PPARgamma activators have been shown, independently, to suppress expression of these inflammatory regulators, inhibit proliferation and promote apoptosis of pathological cellular phenotypes.
  • the therapeutic compositions are administered in the treatment of degenerative disease such as multiple sclerosis (a neurodegenerative) or retinopathies and retinitis (retinal degenerative diseases), in which prevention of apoptosis is the operative mechanism.
  • activation of PPARalpha and PPARgamma by suppressing transcription of inflammatory cytokines prevents apoptosis of the target cell and promotes survival of the non- pathological cellular phenotype.
  • the target cell sustaining the pathological insult is the myelin sheath (oligodendrocyte) in the central nervous system.
  • the pathological cellular phenotypes are amnestic T lymphocytes lacking immune recognition of oligodendrocytes, and inappropriately activated microglia, resulting in inappropriately activation and production of harmful inflammatory cytokines (Zhang et al., Mult. Scler.
  • PPARgamma activation can inhibit neuronal apoptosis and promote neuronal protection through the upregulation of neuronal apoptosis inhibitory protein (Magun et al., Diabetes (1998) 47ll 948-52). Indeed, PPARgamma activation protects cerebellar granule cells from cytokine-induced apoptotic cell death (Heneka et al, J. Neuroimmunol (1999) 100:156-68). Moreover, PPARalpha has been shown to suppress inflammatory cytokines and nuclear factors in monocyte/macrophages.
  • PPARalpha/PPARgamma activation could promote Thl/Th2 differentiation as a final common pathway to inhibit apoptosis of the non-pathological phenotype and promotion of neuronal protection (Giorgini et al., Horm. Metab. Res. (1999) 31:1-4; Clark et al., J. Immunol. (2000) 164:1364-71). [0014] PPARgamma interactions with co-activators and co-repressors tend to be ligand-specific.
  • the natural PPARgamma ligand, 15-deoxy-delta- 12,14-prostaglandin J2 can induce the receptor-ligand complex to interact with the cofactors: SRC-1, TIF2, AB-1, p300, TRAP220/DRIP205, whereas, under the same conditions the anti-diabetic thiazolidinedione, troglitazone, a synthetic PPARgamma ligand does not. Therefore, ligand binding may alter PPARgamma structure in a ligand-type specific way, resulting in distinct PPARgamma-coactivator interactions (Kodera et al., J. Biol. Chem. (2000) 275(43):33201-33204. By analogy, a similar mechanism would provide ligand-specific control of gene expression in the case of PPARalpha activation or PPARdelta activation.
  • This invention involves the discovery of new chemical entities that have utility for treating a variety of clinical disorders including those that are influenced by the activity of peroxisome proliferator activated receptors (PPAR) including PPARalpha, PPARdelta, and or PPARgamma (the term "subtypes" is used herein to refer to the various types of PPARs including PPARalpha, PPARdelta, and PPARgamma).
  • PPAR peroxisome proliferator activated receptors
  • subtypes is used herein to refer to the various types of PPARs including PPARalpha, PPARdelta, and PPARgamma.
  • the invention also involves the surprising finding that the compounds are potent activators of peroxisome proliferator activated receptors. Compounds and methods on how to design, make and use the compounds are described herein.
  • the invention also describes tautomers, stereoisomers and derivatives of the subject compounds, and pharmaceutically acceptable salts and solvates thereof, and their uses in the treatment of metabolic, inflammatory, autoimmune, proliferative and degenerative diseases.
  • This invention describes novel compounds that activate PPARs and that are useful for the treatment of clinical disorders that are influenced by the activity of various PPAR subtypes.
  • Methods of this invention include how to make and use the compounds for the treatment of a T lymphocyte-related or autoimmune, inflammatory, proliferative, dystrophic, degenerative diseases, such as those involving ischemia, angiogenesis, atherosclerosis, increased cell proliferation, immune mediated inflammation, neovascularization, and or apoptosis, by administering to a human or animal in need of treatment an effective amount of a PPARgamma activator, or a PPARalpha activator, or a co-activator of both PPARgamma and PPARalpha, or a PPARdelta activator to attenuate, reverse, prevent, ameliorate, or stop the disorder.
  • a PPARgamma activator or a PPARalpha activator, or a co-activator of both PPARgamma and PPARalpha, or a PPARdelta activator
  • the invention provides compounds containing a halogen- substituted pyridine group that can form a covalent linkage with a cysteine residue in a particular nuclear receptor.
  • the substituted pyridine group is located at the tail- end of the molecule.
  • this invention discloses compounds with molecular characteristics that enhance their binding affinity to the ligand-binding domain (LBD) of PPAR nuclear receptors, wherein the compound has structural features and constraints that enhance (optimize) receptor binding in order to maximize transactivation or deactivation.
  • Preferred ligands contain a polar headgroup that promotes high affinity binding to activating site of the of the PPAR LBD, leading to efficient PPAR transactivation, i.e., the binding of agonist ligands to the receptor resulting in changes in the expression level of mRNAs encoded by PPAR target genes.
  • Receptor deactivation or antagonism may occur when it is covalently bound, but the headgroup fails to effectively engage the activating site of the LBD, resulting in failure of the ligand to transactivate the nuclear receptor.
  • compositions comprising compounds disclosed herein, as wells as salts solvates, esters, tautomers or stereoisomers are provided.
  • the composition further includes a pharmaceutically acceptable excipient.
  • a method for treating a peroxisome proliferator activated receptor (PPAR) mediated disease, or risk factor wherein the method includes administering to a human or an animal in need thereof, a therapeutically effective amount of a compound according to any one of the compounds described herein.
  • the compound is a PPARgamma activator, PPARalpha activator, or PPARdelta activator.
  • PPAR peroxisome proliferator activated receptor
  • a method for designing a compound which is an L-shaped ligand molecule capable of binding to at least one of PPAR- ⁇ , ⁇ , and ⁇ includes: identifying at least one ligand binding domain (LBD) in a selected PPAR; selecting at least a first chemical group capable of binding to the LBD of the PPAR; selecting a second chemical group capable of interacting with at least one amino acid in the LBD to have an effect on transcription mediated by the PPAR; and determining a formula of an L-shaped ligand molecule wherein the L-shaped ligand molecule comprises a first leg section and a second leg section, the first leg section comprising the first chemical group that binds the LBD of the PPAR, and the second leg section comprising the second chemical group which interacts with an amino acid on the PPAR, and further wherein the first and second leg sections of the L-shaped ligand molecule are connected at an elbow atom common to both legs such
  • the method can also include synthesizing the L-shaped ligand molecule and determining its ability to bind to at least one of PPAR- ⁇ , ⁇ , and ⁇ .
  • the LBD of the PPAR may comprise a cysteine residue.
  • the first chemical group may comprise a thiol which is capable of forming a disulfide linkage with the cysteine residue in the LBD.
  • the first leg section of the L-shaped ligand molecule may comprise a lipophilic terminal group that promotes binding to an active site of a PPAR isoform.
  • the first chemical group may comprise a halogen-substituted pyridine group which which is capable of forming a covalent linkage with the cysteine residue in the LBD.
  • Interaction of the amino acid of the LBD with a second chemical group on the L-shaped ligand molecule may be via hydrogen bonding.
  • the compound may be an activating ligand that binds the PPAR, and a second chemical group on the L-shaped ligand molecule may interact with a Tyr473 residue on the PPAR.
  • the L-shaped ligand molecule may be an inactivating ligand that binds the PPAR, wherein the second chemical group on the L-shaped ligand molecule does not interact with a Tyr473 residue on the PPAR.
  • an L-shaped ligand molecule may be designed for optimal binding to a PPAR LBD by determining at least one geometric constraint on the ligand.
  • the L-shaped ligand molecule is an agonist of the PPAR or an antagonist of the PPAR.
  • a computer-assisted method for designing a compound which is an L-shaped ligand molecule specific for at least one of PPAR- ⁇ , ⁇ , and ⁇ , using a programmable computer including a processor, an input device, and an output device is provided.
  • the method comprises in one embodiment:
  • the L-shaped ligand molecule comprises a first leg section comprising the first chemical group which binds the LBD of the PPAR, and a second leg section comprising the second chemical group which interacts with an amino acid on a PPAR, and further wherein the first and second leg sections of the ligand molecule are comiected at an elbow atom common to both leg sections, such that the first and second leg sections are capable of orienting in a conformation with an angle of about 80 to 110 degrees with respect to each other.
  • the L-shaped ligand molecule may be designed for optimal binding to a PPAR LBD by determining at least one geometric constraint on the compound.
  • Another method for designing an L-shaped ligand molecule capable of binding to at least one of PPAR- ⁇ , ⁇ , ⁇ comprises identifying an L-shaped molecule comprising a first leg section Li and a second leg section L 2 wherein the longitudinal axes of Li and L 2 are connected by a shared elbow atom c, wherein:
  • Li and L 2 are capable of assuming approximately linear extended conformations wherein Li and L 2 are independently each about 9-13 A in length;
  • leg sections Li and L 2 are connected at the elbow atom c such that the first and second leg sections are capable of orienting in a conformation which creates an angle of about 80 to 110 degrees between the first and second legs;
  • a terminus of Li contains an acidic moiety of pK a between 4 and 6, and has acceptor atoms capable of hydrogen-bonding;
  • a terminus of L 2 contains a moiety selected from the group consisting of a basic moiety, an acidic moiety, functional groups of varying polarity, and a neutral hydrocarbon moiety.
  • the angle between leg sections Li and L is about 90 degrees.
  • L-shaped ligand molecules identified by the method described herein are optionally synthesized, and optionally tested for an ability to bind at least one of PPAR- ⁇ , ⁇ , and ⁇ or PPAR isoforms.
  • L ⁇ and L 2 independently are about 11-12 A.
  • Li is about 11.1 A and L 2 is about 11.4A.
  • an L-shaped ligand molecule is designed that is capable of assuming a configuration wherein a torsional dihedral angle is generated by atoms a-b-c- d of the molecule, wherein atoms a and b are adjacent connected atoms in leg section Li, atom b is connected to elbow atom c, and atom c is connected to atom d in leg section L 2 , further wherein: a dihedral angle between a plane containing the atoms a, b and c and a plane containing the atoms b, c and d is between 45 and 85 degrees; and a distance from an Li head group acid proton to an apex of the dihedral angle is at least about 3.5A.
  • Figure 1 illustrates an overlay of compound 20 (DOCKed with PPAR- ⁇ , protein omitted) with compound 56.
  • Figure 2 illustrates acidic head group (Z in Case I) replacements for the thiazolidine-2,4-dione in PPAR Ligand Design.
  • Figure 3 illustrates examples of various combinations of R and Z groups that are possible for Case 1.
  • Figure 4 is a schematic representation of how a large ligand substituent in proximity to Ile-341 creates a significantly unfavorable thermodynamic interaction.
  • Figure 5 shows the structure of exemplary binding ligands.
  • Figure 6 shows the structure of exemplary ligands of PPAR.
  • alkyl includes a branched or unbranched hydrocarbon chain, for example, including about 1 to about 8 carbons, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tertrbutyl, octa-decyl and 2- methylpentyl.
  • Alkyl can be optionally substituted with one or more functional groups which are attached commonly to such chains, such as hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio, aryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form substituted alkyl groups such as trifluoro methyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, cyanobutyl and the like.
  • the term "cycloalkyl” includes a cyclic alkyl.
  • heteroalkyl includes a branched or unbranched hydrocarbon chain having one or more heteroatoms in between carbon atoms.
  • heterocycle includes a hydrocarbon chain forming one or more rings and having one or more heteroatoms in the ring.
  • Alkylheterocycles include alkyl groups attached to heterocycles.
  • Alkylheteroaryls include alkyl groups attached to heteroaryls.
  • Heteroalkyl and heterocyclic groups may be substituted for example as described for alkyl groups.
  • aryl includes a chain of carbon atoms which form at least one aromatic ring having for example between about 6-14 carbon atoms, such as phenyl, naphthyl, and the like.
  • the aryl optionally may be substituted with one or more functional groups which are attached commonly to such chains, such as hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like.
  • Aryl and substituted aryl groups include biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenyl, imidazolylmethylphenyl, and the like.
  • heteroaryl includes a ring system including one or more aromatic rings and containing one or more heteroatoms, N, O, or S, in the aromatic ring. Heteroaryl groups can be unsubstituted or may be substituted for example as described for alkyl groups.
  • acyl refers to moiety of the formula ⁇ C(O)R', wherein R' is for example alkyl, aryl, heteroaryl, heterocyclic; such as formyl, aceiyl, propionyl, or butyryl.
  • This invention relates to the synthesis and uses of new compounds to treat diseases of multiple organ systems, including those contained in the cardiovascular system, pulmonary system, integumentary system, skeletal system, bone marrow, • immune system, central and peripheral nervous system, endocrine and exocrine glands, urogenital system, and gastrointestinal system, and other tissues that express peroxisome proliferator-activated nuclear receptors (PPARs), including PPARalpha, gamma and delta, a family of nuclear transcription factors.
  • PPAR ⁇ includes the ⁇ i, ⁇ 2 or ⁇ 3 isotypes or a combination of all three isotypes.
  • PPARs are nuclear receptors which naturally bind to fatty acids and which have been implicated in adipocyte differentiation (Perlmann & Evans, Cell, 90:391-397 (1997)).
  • This invention further relates to modulating the activity of nuclear transcription factors or other factors that are involved in the promotion of diseases involving derangements in: lipid and carbohydrate metabolism, inflammation, proliferation, differentiation, pathological activation of lymphocytes, apoptosis, nitric oxide formation, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPases (TIMPs) by pharmaceutically acceptable forms including salts and solvates of the compounds described herein.
  • MMPs matrix metalloproteinases
  • TRIPs tissue inhibitors of MMPases
  • Another aspect of this invention relates to methods and uses of PPARgamma activators, or PPARalpha activators, or PPARdelta activators or co-activators of any combination of the PPAR subtypes, for treating inflammatory immune-mediated diseases by suppressing acute and chronic inflammatory production of inflammatory cytokines, and by promoting phenotypic transition of lymphocytes from the Thl to the Th2 phenotype.
  • this invention relates to the subject compounds in the treatment of the diseases listed in Tables I through Table X, administered as either as a single agent, or in combination with a natural or synthetic compounds.
  • Such compounds include agonists for PPARalpha, PPARdelta, PPARgamma, retinoid X receptor (RXR), vitamin D receptor (VDR), glucocorticoid receptor (GR), Liver X receptor (LXR) or LXR/RXR (e.g.
  • an oxysterol 22(R)-hydroxycholesterol, 25-hydroxycholesterol, 7a- hydroxycholesterol, 24-hydroxycholesterol, 27-hydroxycholesterol, 40- hydroxycholesterol, 20,22-dihydroxycholesterol, and 20(S)-hydroxycholesterol, or a synthetic, synthetic nonsteroidal LXR-selective agonist (represented by T0314407 and T0901317, Schultz et al, Genes £>ev.l4(22):2831-8 (2000)), Famseoid X receptor (FXR) or FXR/RXR (e.g.
  • the compounds of this invention can also be, administered as either a single agent, or in combination with a natural or synthetic compounds that include inhibitors for 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase (e.g. atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin), and cholesterol ester transfer protein (CETP) (e.g. a substituted-l,2,3,4-tetrahydroquinoline).
  • HMG-CoA 3-hydroxy- 3-methylglutaryl coenzyme A reductase
  • CETP cholesterol ester transfer protein
  • the compounds of this invention can also be administered as either a single agent, or in combination with a natural or synthetic compounds that can include a pharmacological agent that increases the expression or upregulates the ATP-binding cassette protein 1 (ABC1), calcineurin inhibitor (e.g. cyclosporine A, tacrolimus, sirolimus), an anti-hypertensive angiotensin converting enzyme (ACE) inhibitor (e.g.
  • a pharmacological agent that increases the expression or upregulates the ATP-binding cassette protein 1 (ABC1)
  • calcineurin inhibitor e.g. cyclosporine A, tacrolimus, sirolimus
  • ACE anti-hypertensive angiotensin converting enzyme
  • an anti-hypertensive angiotensin receptor blocker e.g. losartan, valsartan, irbesartan, candesartan
  • telmisartan eprosartan
  • Another aspect of this invention relates to methods for screening libraries of compounds to determine which are the best candidates among the subject compounds for use in the practice of this invention.
  • the present invention generally relates to the treatment of T lymphocyte-related diseases that involve activation of nuclear factor of activated T lymphocyte NEAT, NF-kappaB or AP-1, inappropriate activation of nuclear transcription factors that regulate the transcription of genes encoding inflammatory cytokines, inappropriate transcription of genes encoding said inflammatory cytokines, and increased secretion and activity of said inflammatory cytokines.
  • cytokines relating to this invention include, but are not limited to interferon-gamma(INFgarnma), tumor necrosis factor-alpha (TNF-alpha), and a variety of the inflammatory and immunomodulatory interleukins (Chinetti et al. J. Biol. Chem.
  • This invention further relates to the prevention or treatment of disorders of inflammatory and immunomodulatory responses of the immune system involving: T helper (TH), T suppressor (Ts), Thl and Th2 lymphocytes, natural killer (NK.) and other T cell subsets; the T cell receptor (TCR) and cellular signal transduction pathways initiated by TCR activation; the major histocompatibility complex (MHC) and cellular transduction pathways initiated by MHC activation.
  • T helper TH
  • Ts T suppressor
  • Thl and Th2 lymphocytes e. Leukoc. Biol. 1999; 66:733-739
  • Rocchi and Auwerx Ann. Med. 1999; 31:342-351
  • This invention further relates to the prevention or treatment of disorders of inflammatory and immunomodulatory responses of the immune system involving: T helper (TH), T suppressor (Ts), Thl and Th2 lymphocytes, natural killer (NK.) and other T cell subsets; the T cell receptor (TCR) and cellular signal transduction
  • Inflammatory cytokine produced by T lymphocytes include but not limited to: IL-1 alpha, IL-lbeta, IL-2, IL-4, IL-6, IL-8, IL-9, IL-11, IL-12, IL-15, IL-16, IL-18, TNF-alpha or INFgamma.
  • Lymphoid-specific and other ubiquitous transcription factors include but are not limited to NFAT, NF-JL2 A, activated protein-1 (AP-1), nuclear factor-kappaB (NF-kappaB), Octl, CD28; signal transducers and activator of transcription (STATs) which regulate DNA gene promoter sequences; oncogenes (e.g.
  • the present invention is directed to compounds including positional and optical isomers of the subject compounds having one or any combination of the following properties: anti-inflammatory activity, e.g. by blocking production of inflammatory cytokines; prevention of programmed cell death (apoptosis), e.g. in degenerative diseases; induction of programmed cell death (apoptosis), e.g. in neoplastic cells or malignancies; anti-proliferative activity by blocking mitosis or otherwise interrupting the cell cycle; anti-proliferative activity by promoting differentiation; anti- thrombotic or blood clot dissolving activity, e.g.
  • thrombin or GP Ilb/IIIa inhibitory effect on nitric oxide synthase (iNOS); inhibitory effect on matrix meidlloproteinases (MMPase) e.g gelatinases, collagenases, stromelysins, matrilysins, and/or their respective pro-enzymes; inhibition of the nuclear receptor, nuclear factor- kappaB (NF-kappaB); inhibition of the nuclear receptor, activated protein-1 (AP-1); and inhibition of the of the nuclear receptor, nuclear factor of activated T lymphocytes (NFAT).
  • iNOS nitric oxide synthase
  • MMPase matrix meidlloproteinases
  • NF-kappaB nuclear factor- kappaB
  • AP-1 activated protein-1
  • NFAT nuclear factor of activated T lymphocytes
  • the present invention generally relates to the treatment of diseases involving inappropriate apoptosis or inappropriate activation of the apoptotic programmed cell death pathway.
  • Apoptotic regulators which malfunction resulting in pathological diseases or conditions include: fas/fasL, Apo-l/CD95, FADD, TRADD, Apo2L/TRAIL, the TNF receptor, caspases (in particular caspase-3), inducible nitric oxide (iNOS) gene transcription and nitric oxide production.
  • Several of these components are regulated primarily or secondarily by PPARgamma and/or PPARalpha activation. (Delerive, et al., J. Endocrinol 169(3):453-9 (2001))
  • Activation of both PPARalpha and PPARgamma have effects on metabolic risk factors that lead to chronic systemic inflammation that can result in diabetes, atherosclerosis, congestive heart failure, ulcerative colitis, rheumatoid arthritis, osteoporosis, Alzheimer's disease, multiple sclerosis, and other autoimmune and degenerative diseases (Pershadsingh, Expert Opin. Investig. Drugs 8:1859-1872 (1999); Neve et al., Biochem. Pharmacol. 60:1245-1250 (2000); McGeer et al., J. Neural. Transm. Suppl. 59:53-7 (2000); Bar-Or et al., J.
  • Pharmacological co-activation of both subtypes provides for a synergistic therapeutic effect.
  • An essential aspect of this invention is a unique and novel approach to the treatment of such diseases that involves the unexpected outcome, that simultaneous pharmacological activation of both PPARalpha and PPARgamma leads to superior efficacy, compared to the effects derived from the algebraic sum of the effects of activation of PPARalpha or PPARgamma, independently.
  • Synergy may be achieved either with a ligand that co-activates both PPARalph?. and PPARgamma subtypes, or therapeutic compositions consisting of a PPARalpha agonist and a PPARgamma agonist resulting in attenuating, arresting, reversing or preventing the target disease.
  • This aspect of the invention is illustrated in the unique approach to the treatment of atherosclerosis or psoriasis, that have dermato logical or vascular manifestations of a chronic disease with inflammatory, proliferative and degenerative (apoptotic) components.
  • the pathogenesis of both atherosclerosis and psoriasis involve inappropriate proliferation (vascular smooth muscle cells in atherosclerosis and epidermal keratinocytes in psoriasis) and expression of inflammatory cytokines, mediated by activation of the inflammatory transcription factors, NF-kappaB, AP-1 and NFAT (Neve et al., Biochem. Pharmacol, 60:1245-1250 (2000) and Ellis et al., Arch.
  • PPARgamma inhibits proliferation of vascular smooth muscle (VSM)cells, and iNOS production and matrix metalloproteinase (MMP) activity in the vessel wall
  • VSM vascular smooth muscle
  • MMP matrix metalloproteinase
  • PPARalpha decreases the activity of cell adhesion moles and affects lipoprotein metabolism, resulting in a profound anti-dyslipidemic systemic effect
  • pharmacological co-activation of PPARalpha and PPARgamma can provide synergistic therapy in the treatment of atherosclerosis or psoriasis.
  • PPARalpha inhibits expression of inflammatory genes, such as interleukin-6, cyclooxygenase-2, endothelin-1, and the expression of monocyte-recruiting proteins such as vascular cell adhesion molecule (VCAM)-1, and recruitment of monocytes and foam cells in atherosclerotic lesions.
  • inflammatory genes such as interleukin-6, cyclooxygenase-2, endothelin-1
  • monocyte-recruiting proteins such as vascular cell adhesion molecule (VCAM)-1
  • PPARgamma activation in macrophages and foam cells inhibits the expression of genes encoding iNOS, MMP-9, scavenger receptor A, VCAM-1.
  • treatment modalities involving the simultaneous activation of PPARalpha and PPARgamma can provide a synergistic therapeutic effect and leading to superior improvement, resolution or prevention of systemic cardiovascular inflammation, including atherosclerosis, vascular restenosis, congestive heart failure and myocardial fibrosis (Takano et al, Circ. Res. 87:596-602(2000); Lee et al., Circ. Res., 87:516-21 (2000); Fruchart et al., Curr. Opin. Lipidol 10:245-57(1999)).
  • the compound may be a PPAR ligand with properties selected from the group consisting of: 1) a PPARgamma agonist, 2) a PPARgamma partial agonist (i.e. as SPARM (slective PPAR modulator), 3) a PPARgamma antagonist, 4) a PPARalpha agonist, 5) a PPARalpha partial agonist, 6) a PPARalpha antagonist, 7) a PPARdelta agonist, 8) a PPARdelta partial agonist, 9) a PPARdelta antagonist, 10) a PPARgamma/PPARalpha dual agonist), 11) a PPARgamma/PPARdelta dual agonist, 12) a PPARalpha/PPARdelta dual agonist, 13) a PPARgamma partial agonist that also activates PPARalpha, 14) a PPARgamma partial agonist that also activates PPARdelta, and
  • the compounds disclosed herein may be designed by certain design methods as disclosed herein.
  • This invention relates to compounds that can act as ligands that bind and covalently modify nuclear receptors, with consequent activation or deactivation the particular nuclear receptor.
  • the present invention relates to ligands capable of forming a covalent bond between the ligand and a cysteine residue in the nuclear receptor.
  • Another aspect of this invention relates to geometric constraints on the ligand designed to provide for enhanced binding to nuclear receptors, in particular the peroxisome proliferator-activated receptors (PPARs).
  • PPARs peroxisome proliferator-activated receptors
  • Another aspect of the present invention relates to methods of associating a particular disease or condition with a particular nuclear receptor.
  • Another aspect of the present invention is the prevention or treatment of a disease associated with a nuclear receptor through ligand-induced activation or deactivation of a particular receptor.
  • the methods described in this invention relates to improvements in recruiting co-activators and/or co-repressors in order to optimize the activation or inactivation of the various PPAR isoforms in the treatment or prevention of a particular disease involving, for example: 1) promoting apoptosis of neoplastic cells, 2) inhibiting apoptosis in degenerative diseases such as multiple sclerosis and other autoimmune diseases, 3) inhibiting systemic inflammation by suppressing Thl -mediated inflammatory cytokines and promoting Thl to Th2 phenotypic transition, leading to treatment or prevention diseases such as atherosclerosis, syndrome X and congestive heart failure.
  • nuclear receptors to which the present invention applies are: the constitutive androstane (xenobiotic) receptor (CAR), the retinoid X receptor (RXR), the pregnane X receptor, the Farnesiod X receptor, the liver X receptor, and the steroid X receptor.
  • CAR constitutive androstane (xenobiotic) receptor
  • RXR retinoid X receptor
  • pregnane X receptor the pregnane X receptor
  • Farnesiod X receptor the Farnesiod X receptor
  • the liver X receptor the steroid X receptor.
  • steroid X receptor nuclear receptors contain cysteine residues in their ligand binding domains (LBDs), and in both the apo-LBD and the ligand-bound complex of these receptors contain the AF-2 helix motif which is essential for specific ligand binding and adopt a conformation similar to that of the PPARs, in particular PPARgamma.
  • this invention discloses compounds that bind to nuclear receptors by forming a disulfide linkage between a thiol group in the ligand and a cysteine residue in the receptor.
  • the invention discloses compounds containing a halogen-substituted pyridine group that can form a covalent linkage with a cysteine residue in a particular nuclear receptor.
  • the substituted pyridine group is located at the tail-end of the molecule.
  • this invention discloses compounds with molecular characteristics that enhances their binding affinity to the ligand-binding domain (LBD) of PPAR nuclear receptors, wherein the compound has structural features and constraints that enhance (optimize) receptor binding in order to maximize transactivation or deactivation.
  • Preferred ligands contain a lipophihc headgroup that promotes high affinity binding to activating site of the of the PPAR LBD, leading to efficient PPAR transactivation, i.e. the binding of agonist ligands to the receptor resulting in changes in the expression level of mRNAs encoded by PPAR target genes.
  • Receptor deactivation may occur when is covalently bound, but the headgroup fails to effectively engage the activating site of the LBD, resulting in failure of the ligand to transactivate the nuclear receptor.
  • the structure of the PPARgamma LBD has been determined by X-ray crystallography (Nolte et al., Nature 395:137-43(1998)).
  • the PPARgamma LBD is a bundle of 13 alpha-helices and a small four-stranded beta-sheet (Willson et al. J. Med. Chem. 43:527-50(2000)), with an overall fold similar to other nuclear receptor structures from helix 3 to the C-terminus.
  • the crystal structure of the apo-PPARgamma LBD revealed a large ( ⁇ 1300 A 3 ) Y-shaped ligand-binding site located within the bottom half of the LBD.
  • the PPARgamma thiazolidinedione (TZD) agonist, rosiglitazone binds in a U-shaped conformation, while occupying only 40% of the ligand-binding site.
  • the TZD headgroup makes several specific hydrogen-bonding interactions with His449, Tyr473, His323, Ser289, and Gln286 (Willson et al., JMed Chem. 2000;43:527-50).
  • Tyr473 lies on the C-terminal AF-2 helix, which is critical for transcriptional activation. This interaction of the ligand with the AF-2 helix locks the receptor in an activated state.
  • an inactivating ligand is one which binds with high affinity to the PPAR LBD without hydrogen-bonding interactions with Tyr 473, and failure to transactivate the transcriptional machinery.
  • the present invention discloses methods for activating or deactivating a nuclear receptor by covalently linking a ligand to the LBD.
  • One method disclosed herein is the strategic incorporation a thiol group in the ligand such that it is capable of forming a disulfide bridge with the sulfhydryl group of a cysteine residue in the nuclear receptor LBD.
  • a second method disclosed herein is the strategic inco ⁇ oration of a halogenated pyridyl group at the tail-end terminus of the ligand such the pyridine ring is capable of forming a covalent bond with the sulfhydryl group of a cysteine residue in the nuclear receptor LBD.
  • the present invention discloses methods that provide for optimal binding to the PPAR LBD, and relates to specific geometric constraints on the ligand. These constraints consist of angular torsion, i.e. a bend, in the ligand at an optimal distance from the head group.
  • the PPAR LBD contains an overall fold similar to other nuclear receptor structures from helix 3 to the C-terminus.
  • the conformation of the PPAR LBD is such that a ligand must clear the helix-3 fold in order to fit within the LBD. Geometrically, this requires a twist or torsional bend in the ligand molecule, and can be accomplished by inserting a chemical group capable of inducing required angular flexion in the molecule.
  • the torsional angle is measured by examining computer models of rosiglitozone in PPARgamma, a selective thiazolidinedione derivative that has a low EC50 for PPARgamma transactivation ( ⁇ 1 nM, as measured by FRET analysis) (see U.S. Pat. No: 6,127,394). Based on structural considerations, the intra-ligand torsion angle is optimally 45 to 85 degrees with a torsion angle of 60 to 70 degrees preferred.
  • the lower limit of the distance (di) between the headgroup of the ligand and the apex of the torsion angle is optionally 3.5 Angstroms, with 4.0 Angstroms preferred.
  • ligands include chemical substituents that can effect formation of a covalent bond with a cysteine in the ligand binding domain.
  • the present invention relates to methods of associating a particular disease or condition with a particular nuclear receptor, for example, the nuclear receptor PPARgamma.
  • associating is meant that a particular disease or condition can be treated by administration of a compound of this invention that activates or deactivates the particular nuclear receptor.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • the present invention provides for a method of treating a nuclear receptor-mediated disease or condition by administration of a compound of this invention that activates or deactivates the particular nuclear receptor by covalently modifying the nuclear receptor through formation of a covalent bond between the sulfhydryl group or the substituted pyridine of the ligand and a cysteine residue in the nuclear receptor.
  • Preferred compounds of this invention are capable of binding to the LBD of a particular nuclear receptor and forming a covalent bond with a cysteine residue therein.
  • a library of compounds having formulae described herein can be prepared.
  • the binding affinity of a compound of this invention to a particular receptor can be determined using well-described binding assays.
  • the ability of a compound of this invention to activate a particular receptor can also be determined using well-described transcriptional activation assays.
  • a method for designing a compound that is an L-shaped ligand molecule capable of binding to at least one of PPAR- ⁇ , ⁇ , and ⁇ includes: identifying at least one ligand binding domain (LBD) in a selected PPAR; selecting at least a first chemical group capable of binding to the LBD of the PPAR; selecting a second chemical group capable of interacting with at least one amino acid in the LBD to have an effect on transcription mediated by the PPAR; and determining a formula of an L-shaped ligand molecule wherein the L-shaped ligand molecule comprises a first leg section and a second leg section, the first leg section comprising the first chemical group that binds the LBD of the PPAR, and the second leg section comprising the second chemical group which interacts with an amino acid on the PPAR, and further wherein the first and second leg sections of the L-shaped ligand molecule are connected at an elbow atom common to both legs such
  • the method can also include synthesizing the L-shaped ligand molecule and determining its ability to bind to at least one of PPAR- ⁇ , ⁇ , and ⁇ .
  • the LBD of the PPAR may comprise a cysteine residue.
  • the first chemical group may comprise a thiol which is capable of forming a disulfide linkage with the cysteine residue in the LBD.
  • the first leg section of the L-shaped ligand molecule may comprise a lipophihc terminal group that promotes binding to an active site of a PPAR isoform.
  • the first chemical group may comprise a halogen-substituted pyridine group which which is capable of forming a covalent linkage with the cysteine residue in the LBD.
  • Interaction of the amino acid of the LBD with a second chemical group on the L-shaped ligand molecule may be via hydrogen bonding.
  • the compound may be an activating ligand that binds the PPAR, and a second chemical group on the L-shaped ligand molecule may interact with a Tyr473 residue on the PPAR.
  • the L-shaped ligand molecule may be an inactivating ligand that binds the PPAR, wherein the second chemical group on the L-shaped ligand molecule does not interact with a Tyr473 residue on the PPAR.
  • an L-shaped ligand molecule may be designed for optimal binding to a PPAR LBD by determining at least one geometric constraint on the ligand.
  • the L-shaped ligand molecule is an agonist of the PPAR or an antagonist of the PPAR.
  • a computer-assisted method for designing an L- shaped ligand molecule specific for at least one of PPAR- ⁇ , ⁇ , and ⁇ , using a programmable computer including a processor, an input device, and an output device is provided.
  • the method comprises in one embodiment:
  • the L-shaped ligand molecule comprises a first leg section comprising the first chemical group which binds the LBD of the PPAR, and a second leg section comprising the second chemical group which interacts with an amino acid on a PPAR, and further wherein the first and second leg sections of the ligand molecule are connected at an elbow atom common to both leg sections, such that the first and second leg sections are capable of orienting in a conformation with an angle of about 80 to 110 degrees with respect to each other.
  • the L-shaped ligand molecule may be designed for optimal binding to a PPAR LBD by determining at least one geometric constraint on the molecule.
  • Another method for designing an L-shaped ligand molecule capable of binding to at least one of PPAR- ⁇ , ⁇ , ⁇ comprises identifying an L-shaped molecule comprising a first leg section Li and a second leg section L 2 wherein the longitudinal axes of Li and L 2 are connected by a shared elbow atom c, wherein:
  • Li and L 2 are capable of assuming approximately linear extended conformations wherein Li and L 2 are independently each about 9-13 A in length;
  • leg sections Li and L 2 are connected at the elbow atom c such that the first and second leg sections are capable of orienting in a conformation which creates an angle of about 80 to 110 degrees between the first and second legs;
  • a terminus of Li contains an acidic moiety of pK a between 4 and 6, and has acceptor atoms capable of hydrogen-bonding;
  • a terminus of L 2 contains a moiety selected from the group consisting of a basic moiety, an acidic moiety, functional groups of varying polarity, and a neutral hydrocarbon moiety.
  • the angle between leg sections Li and L 2 is about 90 degrees.
  • the L-shaped ligand molecules identified by the method described herein are optionally synthesized, and optionally tested for an ability to bind at least one of PPAR- ⁇ , ⁇ , and ⁇ or PPAR isoforms.
  • L ⁇ and L 2 independently are about 11-12 A.
  • Li is about 11.1 A and L 2 is about 11.4A.
  • an L-shaped ligand molecule is designed that is capable of assuming a configuration wherein a torsional dihedral angle is generated by atoms a-b-c- d of the molecule, wherein atoms a and b are adjacent connected atoms in leg section Li, atom b is connected to elbow atom c, and atom c is connected to atom d in leg section L 2 , further wherein: a dihedral angle between a plane containing the atoms a, b and c and a plane containing the atoms b, c and d is between 45 and 85 degrees; and a distance from an Li head group acid proton to an apex of the dihedral angle is at least about 3.5 A.
  • the invention relates to L-shaped molecules designed by the method discussed in the preceeding section that are ligands for PPAR- ⁇ , ⁇ , or ⁇ or any combination of isoforms wherein each leg, Li and L 2 (as shown, for example, in Schemes la and 2a), of the L-shaped molecule is of approximately the same length, about 9-13 A, preferably 11-12 A, and optimally Li is 11.1 A and L 2 is 11.4 A respectively.
  • Li and L 2 comprise chemical moieties that are in approximately linear extended conformations, and Li and L 2 are connected at an elbow atom c such that Li and L 2 can adopt an L shape.
  • the first non-H atom at which one side chain Li deviates significantly from a straight line and traverses in an approximately 90° angle e.g., 80-110° down L 2 is c, and the angle between chains is called pi, describing the elbow of this L (Scheme la).
  • This angle pi is a geometric angle using the long axes of the Lj and L 2 legs ofL.
  • the terminus of Li in one embodiment contains an acidic moiety of pK a approximately 4-6, and has acceptor atoms capable of hydrogen-bonding (e.g. S, N or O atoms).
  • the terminus of L 2 can for example contain either a basic moiety (pK a - 7-12), an acidic moiety (pK a - 4 - 6), functional groups of varying polarity (variable pK a ), or a neutral hydrocarbon moiety (aryl, alkyl, alkenyl, alkynyl).
  • L shaped compounds wherein the L 2 length is shortened by - 3 A can have poor activity as a result of the terminal ring making severe stereoelectronic interaction with Ile-341 in the PPAR- ⁇ receptor ( Figure 4).
  • a larger ligand substituent in proximity to Ile-341 would clearly create a significantly unfavorable thermodynamic interaction.
  • the compounds are L shaped, wherein the L 2 length is shortened by 6-10 A. These will have good activity as a result of the fact that the interaction with Ile-341 cannot occur (Scheme 2a).
  • the terminal group for Li is the acid proton of a 2,5-thiazolidinedione which, together with the other heteroatoms of the TZD ring, makes contacts with His-449, His-323; Tyr-473; Ser-289; and Gln-286 forming a network of hydrogen bonds.
  • the terminal group for Li is any acid group capable of donating and accepting H-bonds to this complex of His-449, His-323 and Tyr-473.
  • the terminal group for L 2 is a pyridyl N of a 1,4-substituted pyridine.
  • the terminal group for L 2 is a pyridyl N of a 1,3-substituted pyridine.
  • the terminal group for L 2 is a pyridyl N of a 1 ,2-substituted pyridine.
  • the terminal group for L 2 is any mono or bicyclic aromatic heterocycle.
  • the terminal group for L is any mono or bicyclic heterocycle, subject to size restrictions in the PPAR isoforms L 2 terminal pocket.
  • L 2 is contained within an N-methyl amide.
  • L 2 is contained within a cis-double bond (Scheme 3a).
  • the elbow atom c connecting Li and L 2 is contained within a cis-disubstituted cyclopropyl ring (Scheme 3a).
  • the elbow atom c connecting Li and L 2 is contained within a ortho-disubstituted benzenoid or heterocycle (Scheme 4a).
  • the elbow atom c connecting Li and L 2 is contained within a meta-disubstituted benzenoid or heterocycle.
  • the elbow atom c connecting Li and L is contained within a para-disubstituted benzenoid or heterocycle such as ortho- disubstituted benzenoid (6) or heterocycle (furanoid, 7) as shown below .
  • both Li and L 2 are identical, as shown below in Scheme 5 a:
  • Li and L 2 are closely similar, using an intermediate for Li 10 as L 2 11, i.e. compound 9 in Scheme 6a.
  • Synthesis of Li (11) for compound 8 is accomplished by reduction of compound 10. Coupling of 10 and 11 gives compound 9, a dehydro-analogue of compound 8.
  • the L 2 TZD ring is replaced with a heterocyclic ring (Ar) such as a 2, 3 or 4 pyridyl ring. (Scheme 7a).
  • the terminal group for L 2 is a sulfhydryl SH, with either one or two methylene atoms separating the SH from the amide carbonyl, for example compound 3 in Scheme 2a.
  • the SH of compound 3 may form a covalent disulfide bridge to PPAR ⁇ .
  • the terminal SH is converted to a prodrug for oral bioavailability (oral administration), and to promote formulation stability.
  • examples include thioesters, thiocarbonates, thiourethanes, thioethers, and others.
  • the aforementioned elbow moiety whose centroid is for example, approximately equidistant from the termini of either Li or
  • L 2 is chosen from the group of scaffolds shown in Scheme 9a .
  • Each Li and L 2 group may be connected to the scaffolds via free NH or OH groups.
  • the groups X, Y, Z, Q can be optionally selected from N, CH, CR, C-
  • X, Y and Z are selected optionally from CH, CR, CAr, COH, C-halogen, NH, N, NR, S, O and so on.
  • Y and Z are selected optionally from CH2, CHR, CR ⁇ , CHAr, CHOH, CH-halogen, NH, S, O, and may contain unsatuations in differing locations.
  • X is H, halogen, -CH 3 , -OCH 3 , -NH 2 , or -NO 2 ;
  • Y is H, halogen, -CH 3 , -OCH 3 , -NH 2 , or -NO 2 ; n is C ⁇ - 6 alkyl;
  • Ri is H, Ci. 6 alkyl, o phenyl optionally substituted with 1 or 2 groups selected fromC ⁇ - 3 alkoxy, and halogen.
  • Preferred compounds of this invention are capable of binding to the ligand binding domain of a nuclear receptor and forming a covalent bond with a cysteine residue of the receptor; preferably Ri is -CH 3 ; and
  • R 2 is a hydrophobic organic group with molecular weight less than 500
  • X and Y are independently CI, F or Br, most preferably, X is
  • R 2 is C ⁇ - 3 alkenyl-adamantyl
  • R 3 is H, mono-substituted or unsubstituted phenyl, or C ⁇ _ 3 alkyl, oxygen, or a direct link; most preferably R 3 is oxygen.
  • Preferred compounds are capable of binding to the LBD of a nuclear receptor and forming a covalent bond with a cysteine residue of the receptor.
  • Preferred compounds with a suitable apparent pKi (for inhibition or deactivation) or pKa (for activation), where pKi > 5, preferably > 7 for deactivation; and pKa > 5, preferably > 7 for activation.
  • the present invention provides a method for the treatment of a nuclear receptor-mediated disease or condition by administration of a compound that activates or deactivates the particular receptor that is associated with said disease or condition, using the methods described in this invention.
  • the ligand requires a head group with capability of forming H-bond interaction with His449, His323, and Tyr473 in the AF-2 helix.
  • the head group should be 2.5A from a central aromatic ring (distance between 1 and 2), which occupies a narrow pocket between Cys285 and Met364.
  • the aromatic ring resides over the helix-3.
  • the oxygen atom (3) and the amide functionality (4) provide a vital geometry to the tail (lipoate group) through the carbon linkers with a torsion angle of 64.3 degrees, as shown above.
  • the distances and the angles are determined by molecular modeling by methods familiar to those skilled in the art.
  • the PPAR structure and ligands can be downloaded from the Proteinn Data Bank on the World Wide Web. H.M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H. Weissig, I.N. Shindyalov, P.E. Bourne:The Protein Data Bank, Nucleic Acids Research, 28 pp. 235-242 (2000).
  • the PPAR structure and ligands can be visualized using commercially available software such as Swiss-Pdb Viewer (GlaxoSmithKline, Geneva, Switzerland) or RasMol (Biomolecular Structures Group, Glaxo Wellcome Research & Development Stevenage, Hertfordshire, UK) (e.g., WinRas/WinTop) on for example a PC platform.
  • Structure 1 in Figure 6 represents a case where a benzene ring could provide the desired bend, i.e. the required torsional constraint in the molecule by virtue of the substitution (meta) pattern.
  • the benzene ring is shown between the carbons numbered 3 and 5.
  • Structure 2 in Figure 6 represents a similar case, but the benzene ring is now located between the carbons numbered 5 and 7.
  • the required torsional constraint or bend in the molecule is conferred by virtue of the substitution (meta) pattern.
  • position of the bend in the molecule can be altered by strategic placement a benzene ring.
  • the benzene ring is optionally substituted in any unoccupied position; wherein the substituent group is selected from the group consisting of one or more of the following: hydrogen, hydroxy, methyl, halogen, methoxy, ethoxy, alkyl, aryl, and arylalkyl.
  • Exemplary compounds capable of interacting with PPAR receptors include the following:
  • Case 1 represents compounds of the formula:
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, R ⁇ NH, R ⁇ R 7 N,
  • R 1 - R 13 independently H, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, alkylheterocyclic .
  • W O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)O-, -SO 2 -, -
  • G O, NH, NR 1 , S, -S-S-, R ox S ox racemic -S(lone pair)O-, -SO 2 -, -
  • ONR 1 ; NR'O-, E or Z -CH CH-; -C ⁇ €-; CH 2 ; -ON-;
  • ⁇ O, NH, NR 1 , S, -S-S-, R ox Sox racemic -S(lone pair)O-, -SO 2 -, -
  • ONR 1 ; NR'O-, E or Z -CH CH-; -C ⁇ €-; CH 2 ; -ON-;
  • J O, NH, NR 1 (e.g. N-Me), S, -S-S-, R or S or racemic -S(lone pair)O-, -
  • X H, halogen, OR 1 , O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)O-, -SO 2 -, -SONH-, -NHSO-, -NR ⁇ O-, -SONR 1 -, -SO 2 NH-, -
  • a 2- or 4-pyridinol is indicated, which automatically includes the keto-tautomers, the 2- and 4- pyridones.
  • the side chain (Y p ) can be attached via the pyridone N, or at one of the remaining positions.
  • the ring can be benzenoid, pyridinoid, pyrimidinoid, and so on where benzenoid is preferred.
  • Z CO 2 R 1 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; all diastereomers of 3,4- disubstituted-pyrrolidine-2,5-dione; R or S or racemic 4-substituted- azetidine-2-one; R or S or racemic 3-substituted-azetidine-2-one; all diastereomers of 3,4-disubstituted-azetidine-2-one; 3-substituted- azetidine-2,4-dione; l-substituted-l,3-diazetidine-2,4-dione; 1-substituted- l,3-diazetidine-2-one; all diastereomers of l,4-disubstituted-l,3- diazetidine-2-one
  • Case 2 represents compounds of the formula:
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, ⁇ NH, R ⁇ R 7 N, R 8 S, R 8 SO, R 8 SO 2 , R 8 SO 2 NH, R 8 SO 2 NR 9 , R 10 CO, RioOCO, R ⁇ 0 NHCO, RioRnNCO, R t2 O, R ⁇ SCO, R ⁇ 4 NCONHR ⁇ 5 , R 8 NSO 2 NH, R 8 NSO 2 NR 9 , RioNCO, R 10 OCONR ⁇ 6 , R, 0 NHCO, RioRnNCO, R 13 SCONR ⁇ 7 .
  • A O, S.
  • R 1 - R 13 independently H, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, alkylheterocyclic.
  • the side chain (Y p ) can be attached via the pyrrolone N, or at one of the remaining positions.
  • the ring can contain multiple heteroatoms such as would be the case for: thiazoles, isothiazoles, oxazoles, isoxazoles, histidines, pyrrazoles, triazoles, tetrazoles, and so on, where thiazole or isothiazole is preferred.
  • Z CO 2 R !
  • Case 3 represents compounds of the formula:
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, ReNH, R ⁇ R 7 N,
  • R 1 - R 13 independently H, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, alkylheterocyclic.
  • W O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)O-, -SO 2 -, -
  • the side chain (Y p ) can be attached, for example, via the indanoyl or benzoimidazolyl N, or at one of the remaining positions.
  • the ring system can at its simplest be represented by benzofused 5-membered heterocycles, such as indoles, benzoimidazoles, benzopyrrazoles, benzoisoxazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzoisothiazole, and so on.
  • Z CO 2 R !
  • Case 4 represents compounds of the formula:
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, R ⁇ NH, eR-zN,
  • R 1 - R 13 independently H, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, alkylheterocyclic.
  • W O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)O-, -SO 2 -, -
  • the side chain (Y p ) can be attached, for example, via the quinolinone N, or at one of the remaining positions.
  • the ring system can at its simplest be represented by naphthalene-based heterocycles, such as quinolines, phthalazines, quinazines, and so on.
  • Z CO 2 R 1 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; all diastereomers of 3,4- disubstituted-pyrrolidine-2,5-dione; R or S or racemic 4-substituted- azetidine-2-one; R or S or racemic 3-substituted-azetidine-2-one; all diastereomers of 3,4-disubstituted-azetidine-2-one; 3-substituted- azetidine-2,4-dione; l-substituted-l,3-diazetidine-2,4-dione; 1-substituted- l,3-diazetidine-2-one; all diastereomers of l,4-disubstituted-l,3- diazetidine-2-one
  • Case 5 represents compounds of the formula
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, R ⁇ NH, eR 7 N,
  • R 1 - R 13 independently H, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, alkylheterocyclic.
  • W O, NH, NR 1 , S, -S-S-, R ox S ox racemic -S(lone pair)O-, -SO 2 -, -
  • X H, halogen, OR 1 , O, NH, NR 1 , S, -S-S-, R or S or racemic -S ⁇ one pair)O-, -S0 2 -, -SONH-, -NHSO-, -NR !
  • Q,L,M, V, ⁇ , and U are any combination of CH, S, O, N, N-oxide.
  • L and M are both O
  • a furo-[2,3-b]furan is indicated in which the side-chains can be attached to provide the 2,3-; 2,4-; 2,5-; or 3,4-disubstituted furo-[2,3-b]furans.
  • M and U are both O
  • a furo- [3,2-b]furan is indicated in which the side chains can be attached to provide the 2,3-; 2,5-; 2,6-disubstituted furo-[3,2-b]furans.
  • the resultant heterocycle is a 6H- furo[2,3-b] ⁇ yrrole, where substitution can occur at the 2,3-; 2,4-; 2,5-; and 2,6-positions.
  • Z CO 2 R'; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; all diastereomers of 3,4- disubstituted-pyrrolidine-2,5-dione; R or S or racemic 4-substituted- azetidine-2-one; R ox Sox racemic 3-substituted-azetidine-2-one; all diastereomers of 3,4-disubstituted-azetidine-2-one; 3-substituted- azetidine-2,4-dione; 1 -substituted- 1 ,3-diazetidine-2,4-dione; 1 -substituted- l,3-diazetidine-2-one; all diastereomers of l,4-disubstituted-l,3- diazet
  • Case 6 represents compounds of the formula:
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, R ⁇ NH, 6 R 7 N,
  • R 1 - R 13 independently H, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, alkylheterocyclic.
  • W O, NH, NR 1 , S, -S-S-, R ox S ox racemic -S(lone pair)O-, -SO2-, -
  • X H, halogen, OR 1 , O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)O-, -SO 2 -, -SONH-, -NHSO-, -NR !
  • the side chain (Y p ) can be attached via the pyridone N, or at one of the remaining positions.
  • the ring can be benzenoid, pyridinoid, pyrimidinoid, and so on where benzenoid is preferred.
  • Z CO 2 R' ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; all diastereomers of 3,4- disubstituted-pyrrolidine-2,5-dione; R or S or racemic 4-substituted- azetidine-2-one; R or S or racemic 3-substituted-azetidine-2-one; all diastereomers of 3,4-disubstituted-azetidine-2-one; 3-substituted- azetidine-2,4-dione; 1 -substituted- 1 ,3-diazetidine-2,4-dione; 1 -substituted- l,3
  • ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • Preferred in this arrangement is the cis-cyclopropyl compound.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ form a second bond while concurrently, ⁇ and ⁇ form a third bond such that the entire unit enclosed by t is a triple bond (alkyne).
  • Preferred in this arrangement is the Z- double bond.
  • Another exampie is exemplified when the Z-double bond is substituted by ⁇ and ⁇ such that together they form a ring. This ring can be benzenoid, heterocyclic, heteroaryl, and so on.
  • Case 7 represents compounds of the formula:
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, ReNH, R ⁇ R N,
  • R 10 NCO, RioOCONRig, RioNHCO, RioRnNCO, R ⁇ 3 SCONR ⁇ 7 .
  • R 1 — R 13 independently H, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, alkylheterocyclic.
  • W O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)O-, -SO 2 -, -
  • X H, halogen, OR 1 , O, NH, NR 1 , S, -S-S-, R ox S ox racemic -S(lone pair)O-, -SO2-, -SONH-, -NHSO-, -NR ⁇ O-, -SONR 1 -, -SO 2 NH-, -
  • the side chain (Y p ) can be attached via the pyrrolone N, or at one of the remaining positions.
  • the ring can contain multiple heteroatoms such as would be the case for: histidinoid, pyrrazoloid, triazoloid, tetrazoloid, and so on, where thiazoloid or isothiazoloid is preferred.
  • Z CO 2 R 1 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; all diastereomers of 3,4- disubstituted-pyrrolidine-2,5-dione; R or S or racemic 4-substituted- azetidine-2-one; R ox S ox racemic 3-substituted-azetidine-2-one; all diastereomers of 3,4-disubstituted-azetidine-2-one; 3-substituted- azetidine-2,4-dione; 1 -substituted- 1 ,3 -diazetidine-2,4-dione; 1 -substituted- l,3-diazetidine-2-one; all diastereomers of l,4-disubstituted-l,3-
  • ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • Preferred in this arrangement is the cis-cyclopropyl compound.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ form a second bond while concurrently, ⁇ and ⁇ form a third bond such that the entire unit enclosed by t is a triple bond (alkyne).
  • Preferred in this arrangement is the Z- double bond.
  • Another example is exemplified when the Z-double bond is substituted by ⁇ and ⁇ such that together they form a ring. This ring can be benzenoid, heterocyclic, heteroaryl, and so on.
  • Case 8 represents compounds of the formula:
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, R ⁇ sNH, R ⁇ R 7 N,
  • R 1 - R 13 independently H, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, alkylheterocyclic .
  • W O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)O-, -SO 2 -, -
  • X H, halogen, OR 1 , O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone? pair)0-, -SO 2 -, -SONH-, -NHSO-, -NR !
  • the side chain (Y p ) can be attached, for example, via the indanoyl or benzoimidazolyl N, or at one of the remaining positions.
  • the ring system can at its simplest be represented by benzofused 5-membered heterocycles, such as indoles, benzoimidazoles, benzopyrrazoles, benzoisoxazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzoisothiazole, and so on.
  • Z CO 2 R 1 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; all diastereomers of 3,4- disubstituted-pyrrolidine-2,5-dione; R or S or racemic 4-substituted- azetidine-2-one; R or S or racemic 3-substituted-azetidine-2-one; all diastereomers of 3,4-disubstituted-azetidine-2-one; 3-substituted- azetidine-2,4-dione; l-substituted-l,3-diazetidine-2,4-dione; 1-substituted- l,3-diazetidine-2-one; all diastereomers of l,4-disubstituted-l,3- diazetidine-2-one
  • one of p or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • Preferred in this arrangement is the cis-cyclopropyl compound.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • Case 9 represents compounds of the formula:
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, ReNH, R ⁇ R 7 N,
  • R - R independently H, optionally substituted alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, alkylheterocyclic.
  • W O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)0-, -S0 2 -, -
  • X H, halogen, OR 1 , 0, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)O-, -SO 2 -, -SONH-, -NHSO-, -NR !
  • the side chain (Y p ) can be attached, for example, via the quinolinone N, or at one of the remaining positions.
  • the ring system can at its simplest be represented by naphthalene-based heterocycles, such as quinolines, phthalazines, quinazines, and so on.
  • Z CO 2 R 1 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; all diastereomers of 3,4- disubstituted-pyrrolidine-2,5-dione; R or S or racemic 4-substituted- azetidine-2-one; R or S or racemic 3-substituted-azetidine-2-one; all diastereomers of 3,4-disubstituted-azetidine-2-one; 3-substituted- azetidine-2,4-dione; 1 -substituted- 1 ,3-diazetidine-2,4-dione; 1 -substituted- l,3-diazetidine-2-one; all diastereomers of l,4-disubstituted-l,3- diazetidine
  • one of p or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • Preferred in this arrangement is the cis-cyclopropyl compound.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ form a third bond such that the entire unit enclosed by t is a triple bond (alkyne).
  • Preferred in this arrangement is the Z- double bond.
  • Another example is exemplified when the Z-double bond is substituted by ⁇ and ⁇ such that together they form a ring. This ring can be benzenoid, heterocyclic, heteroaryl, and so on.
  • Case 10 represents compounds of the formula:
  • R cycloalkyl, heterocycloalkyl, alkyl, aryl, heteroaryl, R 6 NH, 6 R 7 N,
  • ⁇ O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone ⁇ air)O-, -SO 2 -, -
  • J O, NH, NR 1 (e.g. N-Me), S, -S-S-, R or S or racemic -S(lone pair)O-, -
  • X H, halogen, OR 1 , O, NH, NR 1 , S, -S-S-, R or S or racemic -S(lone pair)O-, -SO 2 -, -SONH-, -NHSO-, -NR ⁇ O-, -SONR 1 -, -SO 2 NH-, -
  • Z CO 2 R*; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; all diastereomers of 3,4- disubstituted-pyrrolidine-2,5-dione; R or S or racemic 4-substituted- azetidine-2-one; R or S or racemic 3-substituted-azetidine-2-one; all diastereomers of 3,4-disubstituted-azetidine-2-one; 3-substituted- azetidine-2,4-dione; 1 -substituted- 1 ,3-diazetidine-2,4-dione; 1-substituted- l,3-diazetidine-2-one; all diastereomers of l,4-disubstituted-l,3- diazetidine-2-one
  • ⁇ or ⁇ is either CH 2 , 0, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • Preferred in this arrangement is the cis-cyclopropyl compound.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ form a second bond while concurrently, ⁇ and ⁇ form a third bond such that the entire unit enclosed by t is a triple bond (alkyne).
  • Preferred in this arrangement is the Z- double bond.
  • Another example is exemplified when the Z-double bond is substituted by ⁇ and ⁇ such that together they form a ring. This ring can be benzenoid, heterocyclic, heteroaryl, and so on.
  • A O or S.
  • H lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • G, E or J independently O, N, S, -SO 2 -,-NHSO 2 -; -SO 2 NH-; C,
  • X H, halogen, OR 10 , NRioRn, SR, -SO 2 R, -SO 2 NRioR ⁇ , or
  • Y O, N, S, -SO 2 -,-NHSO 2 -; -SO 2 NH-; C, OO, CH, or CH 2 with Y attached either meta ox para to the Z containing side chain.
  • U can be CH, CX, CY, N, or N-oxide; where the point of attachment of Y and X are preferably via carbon atoms in the central ring.
  • Z CO 2 R 9 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine-
  • Ri is a 2, 3, or 4-pyridyl ring
  • R is a lone pair of electrons (Ipe), H, substituted or unsubsituted alkyl or aryl group;
  • R 2 -(CH 2 ) 6 to -(CH 2 ) 2 -;
  • t H, CH 3 , ethyl, or propyl;
  • R 5 -(CH 2 )- to -(CH 2 ) 4 -;
  • R ⁇ lone pair of electrons (Ipe) or H, substituted or unsubsituted alkyl or aryl group;
  • A O or S;
  • J O, N, or S;
  • Y O, N, S, or CH;
  • X H, F, Cl, Br, or I;
  • U N, or CH;
  • R 9 H, substituted or unsubstituted alkyl group, or nontoxic metal salt
  • Z COOR 9 or 5-substituted l,3-thiazolidine-2,4-dione
  • Ri is a 4-pyridyl ring
  • R is a Ipe, H, substituted or unsubsituted alkyl group;
  • G CH;
  • b,f 0;
  • a, c,d,g and e 1;
  • R 2 -(CH 2 ) 6 to -(CH 2 ) -;
  • R 5 -(CH 2 )2- to -(CH 2 ) 4 -;
  • Ro Ipe or H, substituted or unsubstituted alkyl group
  • A O or S
  • Y O or S;
  • X H, F, C1;
  • U CH;
  • R 8 CH 2 ;
  • Ri is a 4-pyridyl ring
  • R 2 -(CH 2 ) 3 -
  • R 4 CH 3
  • R 5 -(CH 2 ) 2 -
  • R 6 lpe
  • Z 5-substituted l,3-thiazolidine-2,4-dione.
  • R, Ri - Rn independently any combination of naught, H, lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • W, G, E or J independently O, N, S, -SO 2 -,-NHSO 2 -; -SO 2 NH-; C,
  • X H, halogen, ORio, NR 10 Rn, SR, -SO 2 R, -SO 2 NRioRn, -NR ⁇ 0 SO 2 Rn, with X attached either meta ox para to the Z containing side chain.
  • Y O, N, S, -SO 2 -,-NHSO 2 -; -SO 2 NH-; C, OO, CH, CH 2 with Y attached either meta ox para to the Z containing side chain.
  • U, L, M, Q can independently be CH, CX, CY, S, N, N-oxide.
  • Z CO 2 R 9 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine-
  • Ri is a N-methylated 2, 3, or 4-piperidenyl ring.
  • R is a Ipe, H, substituted or unsubsituted alkyl or aryl group.
  • R 2 -(CH 2 ) 6 to -(CH 2 )2-
  • R-i H, CH 3 , ethyl, propyl
  • R 5 -(CH 2 ) - to -(CH 2 ) 4 -
  • R ⁇ Ipe or H, substituted or unsubsituted alkyl or aryl group.
  • U, L, M, Q independently CH or C, ⁇ , ⁇ H, O, S
  • R 9 H, substituted or unsubstituted alkyl group, or nontoxic metal salt.
  • Ri is a 4- ⁇ -methyl piperidenyl ring.
  • R is a Ipe, H, substituted or unsubstituted alkyl group.
  • R 2 -(CH 2 ) 6 to -(CH 2 ) 3 -
  • R 5 -(CH 2 )- to -(CH 2 ) 4 -
  • Re Ipe or H, substituted or unsubsituted alkyl group.
  • U, L, M, Q independently CH or C, N, NH, or O
  • Ri is a 4-pyridyl ring.
  • R 2 -(CH 2 ) 4 -
  • R 4 CH 3
  • R 5 -(CH 2 ) 2 -
  • L C
  • Z 5-substituted l,3-thiazolidine-2,4-dione and R 8 and Y are attached 2,5 to one another on the ring.
  • the compound is:
  • R, Ri - Rn independently any combination of naught, H, lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • W, G, E or J independently O, N, S, -SO 2 -,-NHSO 2 -; -SO 2 NH-; C,
  • X H, halogen, ORio, NRioRn, SR, -SO 2 R, -SO 2 NR 10 R n , -NR ⁇ 0 SO 2 Rn, with X attached either meta ox para to the Z containing side chain.
  • Y O, N, S, -SO 2 -,-NHSO 2 -; -SO 2 NH-; C, OO, CH, CH 2 with Y attached either meta ox para to the Z containing side chain.
  • U, L, or M can independently be CH, N, NH, S, O, OO; where the point of attachment of Y and X are preferably via carbon atoms in the benzo ring.
  • Z C0 2 R 9 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine- 2,4-dione; 5-substituted-imidazolidine-2,4-dione; 5-substituted-isoindole- 1 ,3-dione; 3-substituted-pyrrole-2,4-dione; 3-Hydroxy-4-substituted- pyrrole-2,5-dione; 4-hydroxy-5-substituted-l ,2-dihydropyrazol-3-one; 5- substituted-l,2-dihydro-pyrazol-3-one; 4-substituted-pyrazolidine-3,5- dione; 3-substituted-lH-[l ,2,4]triazole; 4-substituted-2
  • R is a Ipe, H, substituted or unsubsituted alkyl or aryl group.
  • R 2 -(CH 2 ) ⁇ o to -(CH 2 ) 4 -
  • R4 H, CH 3j ethyl, propyl
  • R 5 -(CH 2 ) - to -(CH 2 ) 4 -
  • Re Ipe or H, substituted or unsubsituted alkyl or aryl group.
  • R H, substituted or unsubstituted alkyl group, or nontoxic metal salt.
  • Z COOR 9 or 5-substituted l,3-thiazolidine-2,4-dione. [0133] In one particular embodiment of Formula 3: Ri is a SAc group
  • R is a Ipe, H, substituted or unsubsituted alkyl group
  • R 5 -(CH 2 ) - to -(CH 2 ) 4 -
  • Re Ipe or H, substituted or unsubsituted alkyl group.
  • Ri is a SAc group
  • a, c,d,g 1
  • R 2 -(CH 2 ) 6 -
  • R 4 CH 3
  • J N
  • X H
  • R, Ri - Rn independently any combination of naught, H, lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • W, G, E or J independently O, N, S, -S0 2 -,-NHS0 2 -; -S0 2 NH-; C,
  • X H, halogen, ORio, NR, 0 Rn, SR, -S0 2 R, -S0 2 NRioRn, -NR ⁇ 0 SO 2 R ⁇ , with X attached either meta ox para to the Z containing side chain.
  • Y O, N, S, -S0 2 -,-NHS0 2 -; -S0 2 NH-; C, OO, CH, CH 2 with Y attached either meta ox para to the Z containing side chain.
  • U, L, Q, M can independently be CH, CX, CY, N, or N-oxide; where the point of attachment of Y and X are preferably via carbon atoms in the central ring.
  • Z C ⁇ 2 R 9 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine- 2,4-dione; 5-substituted-imidazolidine-2,4-dione; 5-substituted-isoindole- 1 ,3-dione; 3-substituted-pyrrole-2,4-dione; 3-Hydroxy-4-substituted- pyrrole-2,5-dione; 4-hydroxy-5 -substituted- 1 ,2-dihydropyrazol-3-one; 5- substituted-l,2-dihydro-pyrazol-3-one; 4-substituted-pyrazolidine-3,5- dione; 3-substituted-l H-[ 1 ,2,4]triazole; 4-substituted
  • Ri is a 2, 3, or 4-C1 benzene ring
  • R is a Ipe, H, substituted or unsubsituted alkyl or aryl group
  • R 2 -(CH 2 ) 6 to -(CH 2 ) 2 -
  • Ri H, CH 3 , ethyl, propyl
  • R 5 -(CH 2 )- to -(CH 2 ) 4 -
  • R - Ipe or H substituted or unsubsituted alkyl or aryl group.
  • Y O, N, S, or CH
  • U, L, Q, M can be CH, CX, CY, N, N-oxide
  • R 9 H, substituted or unsubstituted alkyl group, or nontoxic metal salt
  • Z COOR 9 or 5-substituted l,3-thiazolidine-2,4-dione.
  • Ri is a 4-pyridyl ring
  • R 5 -(CH 2 ) 2 - to -(CH 2 ) 4 -
  • Re Ipe or H, substituted or unsubsituted alkyl group.
  • Ri is a 4-C1 benzene ring.
  • R 2 -(CH 2 ) 3 -
  • R CH 3
  • R 5 -(CH 2 )-
  • L, Q, M are CH
  • R 8 CH 2
  • Z 5-substituted l,3-thiazolidine-2,4-dione where R 8 and R 5 are on the 2,6 positions of a quinoline ring.
  • the compound is:
  • R, Ri - Rn independently any combination of naught, H, lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • W, G, E or J independently O, N, S, -SO 2 -,-NHSO 2 -; -SO 2 NH-; C,
  • X H, halogen, ORio, NR 10 Rn, SR, -SO 2 R, -SO 2 NR ⁇ 0 Rn, -NR 10 SO 2 Rn.
  • Y O, N, S, ⁇ SO 2 -,-NHSO 2 -; -SO 2 NH-; C, OO, CH, CH 2 .
  • U, L, Q, h, i or M can be independently CH, N, NH, S, O, OO.
  • Z C0 2 R ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine- 2,4-dione; 5-substituted-imidazolidine-2,4-dione; 5-substituted-isoindole- 1 ,3-dione; 3-substituted-pyrrole-2,4-dione; 3-Hydroxy-4-substituted- pyrrole-2,5-dione; 4-hydroxy-5 -substituted- 1 ,2-dihydropyrazol-3-one; 5- substituted- 1 ,2-dihydro-pyrazol-3 -one; 4-substituted-pyrazolidine-3 , 5 - dione; 3-substituted-lH-[l,2,4]triazole; 4-substit
  • Ri is a SH, SAc, S-aminoacid, or Salkyl.
  • R 5 -(CH 2 ) - to -(CH 2 ) 4 -
  • Re Ipe or H, substituted or unsubsituted alkyl or aryl group.
  • R 9 H, substituted or unsubstituted alkyl group, or nontoxic metal salt
  • R is a Ipe, H, substituted or unsubsituted alkyl group.
  • R 2 -(CH 2 ) 8 to-(CH 2 ) 6 -
  • R 4 CH 3
  • R 5 -(CH 2 )-to-(CH 2 ) 4 -
  • Re Ipe or H, substituted or unsubsituted alkyl group.
  • R4 CH 3
  • the compound is:
  • R, Ri -Rn independently any combination of naught, H, lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • W, G, E or J independently O, N, S, -S0 2 -,-NHS0 2 -; -S0 2 NH-; C,
  • X H, halogen, ORio, NRioRn, SR, -S0 2 R, -S0 2 NRioRn, -NR 10 SO 2 Rn, with X attached either met ⁇ ox para to the Z containing side chain.
  • Y O, N, S, -S0 2 -,-NHS0 2 -; -S0 2 NH-; C, OO, CH, CH 2 with Y attached either meta ox para to the Z containing side chain.
  • U can be.CH, CX, CY, N, N-oxide; where the point of attachment of Y and X are preferably via carbon atoms in the central ring.
  • Z C0 2 R 9 ; R ox S ox racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine- 2,4-dione; 5-substituted-imidazolidine-2,4-dione; 5-substituted-isoindole- 1 ,3-dione; 3-substituted-pyrrole-2,4-dione; 3-Hydroxy-4-substituted- pyrrole-2,5-dione; 4-hydroxy-5-substituted-l ,2-dihydropyrazol-3-one; 5- substituted-l,2-dihydro-pyrazol-3-one; 4-substituted-pyrazolidine-3,5- dione; 3-substituted-lH-[l ,2,4]triazole; 4-substi
  • ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • Ri is a 2, 3, or 4-pyridyl ring.
  • R 2 -(CH 2 ) 6 to-(CH 2 )2-
  • R 5 -(CH 2 )-to-(CH 2 )-
  • R 6 Ipe or H, substituted or unsubsituted alkyl or aryl group.
  • E, G, J, Y, W independently O, N, S, OO, CH, CH 2
  • N,CH ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, double bond, epoxide, aziridine, or episulf ⁇ de.
  • R 9 H, substituted or unsubstituted alkyl group, or nontoxic metal salt.
  • Ri is a 3 -pyridyl ring.
  • R 2 -(CH 2 ) 6 to-(CH 2 ) 4 -
  • R 5 -(CH 2 ) 2 - to -(CH 2 ) 4 -
  • Re is a Ipe, H, substituted or unsubsituted alkyl group.
  • Y O, N, or S
  • X H,F,orCl.
  • U CH ⁇ or ⁇ is either CH 2 , and together with the other, form a cis or trans cyclopropane or double bond. When both ⁇ or ⁇ and ⁇ or ⁇ are double bonds, a triple bond results.
  • R 9 a variously substituted alkyl group.
  • Z COOR 9 or 5-substituted l,3-thiazolidine-2,4-dione.
  • Ri is a 3 -pyridyl ring.
  • R 2 -(CH 2 ) 3 -
  • R 5 -(CH 2 ) 2 -
  • F U CH ⁇ or ⁇ is a CH 2 , and together with the other, form a cis or trans cyclopropane.
  • R 9 ethyl.
  • R, R] - R independently any combination of naught, H, lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • W, G, E or J independently O, N, S, -S0 2 -,-NHS0 2 -; -S0 2 NH-; C,
  • X H, halogen, ORio, NRioRn, SR, -S0 2 R, -S0 2 NRioRn, -NR ⁇ 0 SO 2 Rn.
  • Y O, N, S, -S0 2 -,-NHS0 2 -; -S0 2 NH-; C, OO, CH, CH 2 .
  • U, V, M, Q independently can be C, CH, CX, S, N, NH, O.
  • Z CO 2 R 1 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine-
  • ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ form a second bond while concurrently, ⁇ and ⁇ form a third bond such that the entire unit enclosed by t is a triple bond (alkyne).
  • Ri is a 2, 3, or 4-N-methylpiperidinyl ring
  • R 2 -(CH 2 ) 6 to -(CH 2 ) 2 -
  • R 3 H, Ipe, substituted or unsubsituted alkyl or aryl group
  • R 5 -(CH 2 ) 4 - to -(CH 2 )-
  • Re is a Ipe, H, substituted or unsubsituted alkyl or aryl group
  • R 7 H, Ipe, substituted or unsubsituted alkyl or aryl group
  • ⁇ , G, J, Y, W independently O, ⁇ , S, OO, CH, or CH 2
  • U ⁇ or CH ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, double bond, epoxide, aziridine, or episulfide when both ⁇ or ⁇ and ⁇ or ⁇ are double bonds, a triple bond results,
  • R 9 H, substituted or unsubstituted alkyl group, or nontoxic metal salt
  • Z COOR or 5-substituted l,3-thiazolidine-2,4-dione, 5-substituted-2H- tetrazole.
  • Ri is a 4-N-methylpiperidinyl ring.
  • R is H
  • R 2 -(CH 2 ) 4 to -(CH 2 ) 2 -
  • R 5 -(CH 2 ) 2 - to -(CH 2 ) 4 -
  • X H, F, CI.
  • U CH ⁇ or ⁇ is either CH 2 , and together with the other, form a cis or trans cyclopropane or double bond.
  • Ri is a 4-N-methylpiperidinyl ring.
  • R is H
  • R 2 -(CH 2 ) 3 -
  • R 5 -(CH 2 ) 2 -
  • R 6 H
  • R, Ri - Rn independently any combination of naught, H, lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • W, G, E or J independently O, N, S, -S0 2 -,-NHS0 2 -; -S0 2 NH ⁇ ; C,
  • X H, halogen, ORio, NRioRn, SR, -SO 2 R, -SO 2 NRioRn, -NR ⁇ 0 SO 2 Rn.
  • U, L, M independently can be C, CH, CX, S, N, NH, or O.
  • Z C0 2 R' ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine- 2,4-dione; 5-substituted-imidazolidine-2,4-dione; 5-substituted-isoindole- 1 ,3-dione; 3-substituted-pyrrole-2,4-dione; 3-Hydroxy-4-substituted- pyrrole-2,5-dione; 4-hydroxy-5-substituted-l ,2-dihydropyrazol-3-one; 5- substituted- 1 ,2-dihydro-pyrazol-3 -one; 4-substituted-pyrazolidine-3 , 5 - dione; 3-substituted-lH-[l ,2,4]triazole; 4-substi
  • ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ form a second bond while concurrently, ⁇ and ⁇ form a third bond such that the entire unit enclosed by t is a triple bond (alkyne).
  • Ri is an optionally substituted alkyl group.
  • R 2 -(CH 2 ) 8 to -(CH 2 ) 2 -
  • R 3 H, Ipe, substituted or unsubsituted alkyl or aryl group.
  • i H, Ipe, substituted or unsubsituted alkyl or aryl group.
  • R 5 -(CH 2 ) 4 - to -(CH 2 )-
  • Re is a Ipe, H, substituted or unsubsituted alkyl or aryl group.
  • R 7 H, Ipe, substituted or unsubsituted alkyl or aryl group.
  • E, G, J, Y, W independently O, N, S, OO, CH, CH 2
  • U, L, M can be C, CH, CX, S, N, NH, O.
  • ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, double bond, epoxide, aziridine, or episulfide.
  • R 9 H, substituted or unsubstituted alkyl group, or nontoxic metal salt.
  • Ri is a 4-N-methylpiperidinyl ring
  • R is H
  • R 2 -(CH 2 ) 8 to -(CH 2 ) 2 -
  • R 5 -(CH 2 ) 2 - to -(CH 2 ) 4 -
  • Re is a Ipe, H, substituted or unsubsituted alkyl group.
  • Y O or S
  • X H, F, or Cl
  • U CH ⁇ or ⁇ is either CH 2 , and together with the other, form a cis or trans cyclopropane or double bond.
  • Ri is a thioglycinate HC1 salt.
  • R is Ipe
  • R 2 -(CH 2 ) 7 -
  • R 5 -(CH 2 )-
  • X H
  • Formula 9 represents compounds of the formula:
  • R, Ri - Rn independently any combination of naught, H, lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • W, G, E or J independently O, N, S, -S0 2 -,-NHS0 2 -; -S0 2 NH-; C,
  • X H, halogen, ORio, NRioRn, SR, -SO 2 R, -SO 2 NRioRn, or -
  • Y O, N, S, -SO 2 -,-NHSO 2 -; -SO 2 NH-; C, OO, CH, CH 2 .
  • U, L, M and Q can independently be C, CH, CX, S, N, NH, O.
  • Z CO 2 R 1 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine-
  • t 1
  • one of ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ne embodiment of Formula 9 Ri is a 2, 3, or 4-pyridyl group.
  • R 3 H, Ipe, substituted or unsubsituted alkyl or aryl group.
  • R 4 H, Ipe, substituted or unsubsituted alkyl or aryl group.
  • R 5 -(CH 2 ) 4 - to -(CH 2 )-
  • Re is a Ipe, H, substituted or unsubsituted alkyl or aryl group.
  • R 7 H, Ipe, substituted or unsubsituted alkyl or aryl group.
  • ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, double bond, epoxide, aziridine, or episulfide. When both p or ⁇ and ⁇ or ⁇ are double bonds, a triple bond results.
  • R 9 H, substituted or unsubstituted alkyl group, or nontoxic metal salt.
  • Z COOR 9 or 5-substituted l,3-thiazolidine-2,4-dione, 5-substituted-2H- tetrazole; 3-substituted-pyrrole-2,5-dione.
  • Ri is a 4-N-methylpiperidinyl ring.
  • R 2 -(CH 2 ) 8 to -(CH 2 ) 2 -
  • R 5 -(CH 2 ) 2 - to -(CH 2 ) 4 -
  • R 6 is a Ipe, H, substituted or unsubsituted alkyl group.
  • Y O or S
  • X H, F, C1.
  • U, L, M and Q can independently be C, CH, CX, N.
  • p or ⁇ is either CH 2 , and together with the other, form a cis or trans cyclopropane or double bond.
  • R 9 a variously substituted alkyl group.
  • Z COOR 9 or 5-substituted l,3-thiazolidine-2,4-dione.
  • Ri is a thioglycinate HC1 salt.
  • R is Ipe
  • R 2 -(CH 2 ) 7 -
  • R 5 -(CH 2 )-
  • R, Ri - R 11 independently any combination of naught, H, lone pair of electrons, optionally substituted heteroatomic group, or alkyl, cycloalkyl, alkylcycloalkyl, arylalkyl, aryl, heteroaryl, heterocyclic, alkylheteroaryl, or alkylheterocyclic group; or optionally substituted ester, amide, carbonate, or carbamate.
  • W, G, E or J independently O, N, S, -S0 2 -,-NHS0 2 -; -S0 2 NH-; C,
  • X H, halogen, ORio, NRioR , SR, -SO 2 R, -SO 2 NRioRn, or -
  • Y O, N, S, -SO 2 -,-NHS0 -; -SO 2 NH-; C, OO, CH, or CH 2 .
  • U, L, Q, h, i or M can independently be CH, N, NH, S, O, or OO.
  • Z CO R 9 ; R or S or racemic 5-substituted-thiazolidine-2,4-dione; R or S or racemic 3-substituted-pyrrolidine-2,5-dione; 5-substituted-oxazolidine-
  • one of ⁇ or ⁇ is either CH2, O, N, or S and together with the other, form a cis or trans cyclopropane, epoxide, aziridine, or episulfide.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ are either cis or trans to one another, and can be any combination of H, alkyl, alkoxyl, halogen, thioalkoxyl, acyloxyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, and optionally substituted derivatives therein.
  • ⁇ and ⁇ form a second bond while concurrently, ⁇ and ⁇ form a third bond such that the entire unit enclosed by t is a triple bond (alkyne).
  • R 2 -(CH 2 ) ⁇ 0 to -(CH 2 ) 4 -
  • R t H, CH 3, ethyl, propyl
  • R 5 -(CH 2 ) - to -(CH 2 ) 4 -
  • Re is a Ipe, H, substituted or unsubsituted alkyl or aryl group.
  • U, L, M, Q, h, i independently N, NH, C, CH, S, O ⁇ or ⁇ is either CH 2 , O, N, or S and together with the other, form a cis or trans cyclopropane, double bond, epoxide, aziridine, or episulfide.
  • R 8 - CH CH- or CH 2
  • R H, substituted or unsubstituted alkyl group, or nontoxic metal salt.
  • Z COOR 9 ; or 5-substituted l,3-thiazolidine-2,4-dione, 3-substituted- pyrrole-2 ,4-dione
  • Ri is a 4-piperidinyl group with an amino-acid amide bond to the ring N.
  • R 2 -(CH 2 ) 8 to -(CH 2 ) 6 -
  • R 5 -(CH 2 ) - to -(CH 2 ) -
  • R 6 is a Ipe, H, substituted or unsubsituted alkyl group.
  • A O or S
  • U, L, M, Q, h, and i independently CH, C, N, O, S ⁇ or ⁇ is either CH 2 , and together with the other, form a cis or trans cyclopropane, or cis or trans double bond.
  • Z 5-substituted l,3-thiazolidine-2,4-dione, 3-substituted-pyrrole-2,4- dione more particular embodiment of Formula 10 :
  • Ri is a 4-piperidylglycinamide HCL salt group.
  • R 2 -(CH 2 ) 4 -
  • R 5 -(CH 2 ) -
  • X H
  • Z 3-substituted-pyrrole-2,4-dione.
  • the compound is:
  • heterocycloalkyl R groups are represented by piperidinyl or piperazinyl moieties, or any other optionally substituted heterocyclic ring system such as those containing O, N and/or S, SO SONH, SO2NH, or SO 2 .
  • the acids 1- 11 and 6h-l lh are available commercially or can be prepared by known methods.
  • a precursor for Scheme 3, 5-(Cyclopentyl)pentanoic acid 5, is prepared by employing a modified procedure to the one reported (Nagumao,et al. Tetrahedron 49 (46), 1993, 10501-10510) starting from cyclopentanone 12 as shown in Scheme 2.
  • Self- condensation of cyclopentanone 12 in the presence of ethyl ene glycol and boron trifluoride-etherate furnishes the hydroxy ethyl ester 13.
  • Transesterification with methanol and potassium carbonate converts 13 into the methyl ester 14.
  • Catalytic hydrogenation reduces the double bond to give methyl 5-(cyclopentyl)pentanoate 15. Ester hydrolysis of 15 occurrs readily using sodium hydroxide to give the desired acid 5.
  • the phenol 23 is coupled with the t-BOC alcohol 22 via its mesylate to furnish the t-BOC protected amine 24.
  • the t-BOC protecting group is removed by acid treatment to furnish the desired amine 21.
  • the final acid coupling occurs readily to afford the target amide 25. Hydrolysis of 25 smoothly furnishes the acid 26.
  • the aldehyde 33 thus formed is then condensed with thiazolidinedione (Bernhard, et al. J. Med. Chem. 35, 1992, 1853-1864; Clark, et al. J. Med. Chem. 34, 1991, 319-325), to provide the adduct 34, which is reduced using sodium dithionite to give the desired TZD compound 35.
  • Deprotection of the t-BOC group gives the amine 36, which is coupled with desired acids (e.g. 1-11, 6h-l lh), which in Scheme 6 was phenylvaleric acid 6.
  • the acid 38 is first coupled with the amino alcohol 39 via the mixed anhydride prepared in situ using isobutyl chloroformate and triethylamine.
  • the resulting alcohol 40 is then converted to the bromide 41 using bromine and triphenylphosphine.
  • With the bromo compound 41 in hand coupling to the phenols 34-39 corresponding to the different structural classes via the phenoxides provides the desired targets.
  • the triflate 47 is then coupled with the iodocompound 51 (Piber, et al. Org. Lett. 1999, 1323-1326), which is prepared from its alcohol 50 by treating with iodine and triphenylphosphine, to give the t-BOC compound 48.
  • the t-BOC group is removed in the presence of acid to give the free amine 49 which is coupled with the acids 1-11, 6h- 1 lh to arrive at the targets as shown in Scheme 9.
  • Cinnamates such as 55-58 are excellent stereoelectronic mimetics for the corresponding thiazolidine-2,4-diones (e.g. 56 vs. 20).
  • An overlay of 20 with 56 ( Figure 1) shows near perfect alignment of the acidic protons, the aryl rings, and the terminal cyclopentyl rings. These same space-filling and hydrogen bonding capabilities are confirmed in docking studies with PPAR- ⁇ .
  • a prodrug of the carboxyl group is a logical necessity for optimization of oral or topical bioavailability, such as, but not limited to, the simple ethyl ester 55.
  • Synthesis of 55 and 56 follow from previous schemes, and are shown in Schemes 10 and 11.
  • the first step is to prepare the cinnamyl amine (54, Scheme 10) followed by coupling to a carboxylic acid.
  • the cyclopentyl (55, 56) and phenyl (57, 58) R groups were arbitrarily selected as examples of the method.
  • the 2H-tetrazole ring is a good isoelectronic replacement for a carboxylic acid or TZD group.
  • the tetrazole variant 81 is readily prepared from the corresponding nitrile 78 upon treatment with azide ion, followed by t-BOC deprotection and coupling to the pyridyl acid 80.
  • the compounds can be used in a variety of therapeutic applications.
  • This invention relates to the prevention and treatment of diseases involving tissues that express PPARgamma and/or PPARalpha, and/or PPARdelta and to new methods for treating inflammatory, proliferative, degenerative diseases, and diseases involving angiogenesis and neovascularization, deriving from organs and tissues of all embryological origins.
  • diseases involving tissues that express PPARgamma and/or PPARalpha, and/or PPARdelta and to new methods for treating inflammatory, proliferative, degenerative diseases, and diseases involving angiogenesis and neovascularization, deriving from organs and tissues of all embryological origins.
  • These include vitreoretinopathies and uveitis, hereditary and non- hereditary degenerative neural (e.g. multiple sclerosis) and retinal diseases (e.g. retinitis pigmentosa), diseases resulting from hypoxia or vascular ischemia (e.g. ischemic heart disease), diseases involving angiogenesis
  • neoplastic diseases e.g. of the retina and skin
  • age-related degenerative diseases e.g. of the retina and skin
  • degenerative or dystrophic diseases or involving premature apoptosis e.g. retinal dystrophies and retinopathies resulting from glaucoma
  • chronic systemic diseases e.g. diabetes, congestive heart failure, asthma, chronic obstructive pulmonary disease, cardiomyopathy, hypertension, atherosclerosis, myocardial fibrosis, osteoporosis, inflammatory bowel diseases.
  • This invention relates to the treatment of diseases tissues and organs regardless of etiological agent.
  • the treatment of corneal injury or ulceration caused by unrelated etiological agents 1) foreign body (e.g. contact lens), infectious agent (e.g. Candida albicans, chlamydia trachomatis, cytomegalovirus or human immunodeficiency virus), physical agent (e.g. UV radiation), chemical agent (e.g. acids, caustic solvents) chronic systemic disease (e.g. autoimmune or collagen vascular diseases).
  • infectious agent e.g. Candida albicans, chlamydia trachomatis, cytomegalovirus or human immunodeficiency virus
  • physical agent e.g. UV radiation
  • chemical agent e.g. acids, caustic solvents
  • chronic systemic disease e.g. autoimmune or collagen vascular diseases.
  • the compounds can be used to treat the group of metabolic diseases associated with insulin resistance, that consists of: obesity, type 2 diabetes mellitus, gestational diabetes, impaired glucose tolerance, Cushing's syndrome (e.g. secondary to chronic glucocorticoid therapy), polycystic ovarian syndrome.
  • the compounds can be used to treat the metabolic disease, osteoporosis.
  • the compounds can be used to treat inflammatory, proliferative or degenerative skin disease, such as psoriasis, keratitis, hidradenitis, ichthyosis, acne vulgaris, rosacea, verrucae and other HPN infections, atopic dermatitis, allergic dermatitis, chemical (irritant) dermatitis, seborrheic dermatitis, solar dermatitis, acute and chronic eczema, seborrheic keratosis, senile keratosis, actinic keratosis, photo-induced keratosis, skin aging, thinning skin, dry skin, wrinkle formation, photo-induced skin aging, keloids, lichen planus, acute or chronic pruritus.
  • inflammatory, proliferative or degenerative skin disease such as psoriasis, keratitis, hidradenitis, ichthyosis, acne vulgaris, rosace
  • the compounds can be used to treat occlusive vascular disease, such as atherosclerosis, thrombosis, thromboembolism, restenosis after an invasive procedure (e.g. angioplasty and vascular grafting).
  • occlusive vascular disease such as atherosclerosis, thrombosis, thromboembolism, restenosis after an invasive procedure (e.g. angioplasty and vascular grafting).
  • the compounds can be used to treat cardiovascular disease, such as arteritis, endarteritis, endocarditis, myocarditis, arterial plaque (fibrous cap) rupture, acute coronary syndrome, unstable angina, myocardial infarction, myocardial ischemia, ischemic cardiomyopathies, non-ischemic cardiomyopathies, post-myocardial infarction cardiomyopathy and myocardial fibrosis, drug-induced cardiomyopathy, congestive heart failure.
  • cardiovascular disease such as arteritis, endarteritis, endocarditis, myocarditis, arterial plaque (fibrous cap) rupture, acute coronary syndrome, unstable angina, myocardial infarction, myocardial ischemia, ischemic cardiomyopathies, non-ischemic cardiomyopathies, post-myocardial infarction cardiomyopathy and myocardial fibrosis, drug-induced cardiomyopathy, congestive heart failure.
  • the compounds can be used to treat occlusive vascular disease associated with hyperglycemia, hyperinsulinemia, or obesity.
  • the compounds can be used to treat ophthalmic inflammatory disease such as uveitis, uveoretinitis, panuveitis, retinitis, iridocyclitis, immunological endophthalmitis, choroiditis, vitreitis, keratitis, dry eye syndrome, corneal ulceration, age-related macular degeneration, glaucoma, conjunctivitis, and conjunctival ulceration, and neovascular proliferative disease such as age-related macular degeneration, exudative macular degeneration, atrophic macular degeneration, crystalline retinopathy, retinal toxicosis of systemic medications, idiopathic central serous choroidopathy, macular edema, or primary or secondary retinal detachment.
  • ophthalmic inflammatory disease such as uveitis, uveoretinitis, panuveitis, retinitis, iridocyclitis, immunological endophthal
  • the compounds can be used to treat inflammatory disease such as retinovascular disease or retinopathy, vitreoretinopathy or vasculopathy of vasculo- occlusive or idiopathic etiology, or associated with telangiectasias or aneurysms, or associated with lupus erythematosus, rheumatoid arthritis, multiple sclerosis, myasthenia gravis, uveoretinitis or diabetes mellitus, or associated with intraocular surgery or primary or secondary retinal detachment resulting from a disease or injury.
  • inflammatory disease such as retinovascular disease or retinopathy, vitreoretinopathy or vasculopathy of vasculo- occlusive or idiopathic etiology, or associated with telangiectasias or aneurysms, or associated with lupus erythematosus, rheumatoid arthritis, multiple s
  • the compounds can be used to treat inflammatory autoimmune disease mediated by T lymphocytes, such as chronic rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's disease, Crohn's disease, ulcerative colitis, type 1 diabetes mellitus, autoimmune neuritis.
  • T lymphocytes such as chronic rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's disease, Crohn's disease, ulcerative colitis, type 1 diabetes mellitus, autoimmune neuritis.
  • the compounds can be used to treat inflammatory, degenerative disease such as steatosis, fibrosis, and/or cirrhosis of the liver induced by drugs (e.g. HMG-CoA inhibitos, isoniazid), chronic alcohol consumption, or resulting from poisonous toxins (e.g. mushroom poisoning).
  • drugs e.g. HMG-CoA inhibitos, isoniazid
  • chronic alcohol consumption e.g. mushroom poisoning
  • the compounds can be used to treat inflammatory disease that is a result of rejection of an allograft transplantation and is associated with acute allograft rejection, chronic allograft rejection, graft versus host disease.
  • the compounds can be used to treat inflammatory disease that is a neurodegenerative such as Alzheimer's disease, HIV-related dementia, Parkinson's disease, amyotropic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic pain, allodynia, encephalitis, encephalomyelitis, neuritis, myesthenia gravis, Eaton-Lambert syndrome, congenital and secondary ataxias.
  • a neurodegenerative such as Alzheimer's disease, HIV-related dementia, Parkinson's disease, amyotropic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic pain, allodynia, encephalitis, encephalomyelitis, neuritis, myesthenia gravis, Eaton-Lambert syndrome, congenital and secondary ataxias.
  • the compounds can be used to treat inflammatory disease that are non- carcinogenic and ischemic such as disease associated with angiogenesis and neovascularization (e.g. ischemic heart disease, retinal and choroidal angiogenesis).
  • inflammatory disease that are non- carcinogenic and ischemic such as disease associated with angiogenesis and neovascularization (e.g. ischemic heart disease, retinal and choroidal angiogenesis).
  • the compounds can be used to treat proliferative, inflammatory disease such as angiogenesis and neovascularization that is associated with a carcinogenic (neoplastic) disease.
  • the compounds can be used to treat carcinogenic disease such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, enthotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelimoa, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small
  • the compounds can be used to treat inflammatory disease associated with dysfunction of a T lymphocyte, or T lymphocyte subtype, leading to development of an autoimmune disease.
  • the compounds can be used to treat any disease that involves pathological apoptosis (programmed cell death).
  • a compound of this invention may be effective to slow, reverse, prevent or treat said disease, wherein the disease is an ischemic disease (cardiomyopathies, congestive heart failure), atherosclerosis, or an autoimmune disease (multiple sclerosis, Alzheimer's disease, Parkinson's disease, hepatic fibrosis or cirrhosis, myelodysplasis, arthritis and joint-disease).
  • ischemic disease cardiomyopathies, congestive heart failure
  • atherosclerosis or an autoimmune disease (multiple sclerosis, Alzheimer's disease, Parkinson's disease, hepatic fibrosis or cirrhosis, myelodysplasis, arthritis and joint-disease).
  • the compounds can be used to treat pulmonary disease such as asthma, chronic obstructive pulmonary disease, reactive airway disease, pulmonary fibrosis, or pulmonary hypertension.
  • pulmonary disease such as asthma, chronic obstructive pulmonary disease, reactive airway disease, pulmonary fibrosis, or pulmonary hypertension.
  • the methods of treatment in one aspect of this invention are practiced by administering to a human in need thereof a dose of a compound (or pharmaceutically acceptable salts and solvates thereof in acceptable pharmaceutical excipients) that modifies the activity of PPAR.
  • the methods include treating a human subject prophylactically to alter inflammation, apoptosis, proliferation, angiogenesis, neovascularization, immune dysfunction, and expression of oncogenes and other genes controlling cell metabolism.
  • the present method includes both medical therapeutic and/or prophylactic treatment, as necessary.
  • the methods of treatment provided by this invention are practiced by administering to a human or vertebrate animal in need a dose of a compound, or a pharmaceutically acceptable salt, ester, solvate or tautomer thereof, that activates either PPARgamma, or PPARalpha, or PPARdelta or compounds that activate more than one of these receptors.
  • a compound, or a pharmaceutically acceptable salt, ester, solvate or tautomer thereof that activates either PPARgamma, or PPARalpha, or PPARdelta or compounds that activate more than one of these receptors.
  • novel compounds used to practice this invention are set forth above.
  • the specific diseases and associated disorders that can be treated with the compounds described in this invention are listed in Tables I through X.
  • therapeutic compounds are typically administered to human patients topically to the skin or mucous membranes, by extra-ocular application, intraocularly (by chemical delivery system or invasive device), or systemically (e.g. sublingually, by suppository, by oral ingestion, intradermally, by inhalation, intramuscularly, intra-articularly, intravenously, or other parenteral route).
  • Parenteral administration by a particular route is used in appropriate circumstances apparent to the practitioner.
  • Oral administration is the preferred route for chronic diseases.
  • Topical administration is the preferred route for dermatological diseases.
  • Extra-ocular application is the preferred route for ocular diseases involving the anterior segment of the eye, or chronic diseases
  • the compositions are administered in unit dosage forms suitable for single administration of precise dosage amounts.
  • a therapeutically effective concentration of the compound in one embodiment is placed in a vehicle such as a dermatological one that is known in the art.
  • the amount of the therapeutic compound to be administered and the compound's concentration in the topical formulations depend upon the vehicle, delivery system or device selected, the clinical condition of the patient, the side effects and the stability of the compound in the fo ⁇ nulation.
  • the physician employs the appropriate preparation containing the appropriate concentration of the therapeutic compound and selects the amount of formulation administered, depending upon clinical experience with the patient in question or with similar patients.
  • the therapeutic compound is optionally administered topically by the use of a transdermal therapeutic system (see Barry, Dermatological Formulations, (1983) p. 181 and literature cited therein). While such topical delivery systems have been designed largely for transdermal administration of low molecular weight drugs, by definition they are capable of percutaneous delivery. They may be readily adapted to administration of the therapeutic compounds of the invention by appropriate selection of the rate- controlling microporous membrane.
  • the therapeutic compound is formulated into solutions, suspensions, and ointments appropriate for use in the eye.
  • concentrations are usually as discussed above for topico-local preparations.
  • Ophthalmic formulations see Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, N.Y. (1993) and also Havener, W. H., Ophthalmic Pharmacology, CN. Mosby Co., St. Louis (1983).
  • the therapeutic compound is alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A nonaqueous (e.g., fluorocarbon propellent) suspension could be used. Sonic nebulizers are preferred because they minimize exposing the therapeutic compound to shear, which can result in degradation of the compound.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the therapeutic compound together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • the concentration of the therapeutic compound used depends on the mode of delivery.
  • the concentration of the therapeutic compound is in the range of about 0.01% weight/weight (w/w) to about 10% w/w.
  • the concentration of the therapeutic compound for this mode of delivery is in the range of about 0.025% w/w to about 2.5% w/w.
  • Solid dispersions of the therapeutic compound as well as solubilized preparations can be used.
  • the therapeutic compound in one embodiment is delivered at a concentration high enough to achieve a final concentration in the range of about 0.1 micromol/L to about 10 micromol/L within the target ophthalmic compartment (e.g.
  • the final concentration of the therapeutic compound is in the range of about 0.25 micromol/L to about 5 micromol/L.
  • Solid dispersions of the therapeutic compound as well as solubilized preparations can be used.
  • the precise concentration is subject to modest but not undue experimental manipulation well within the skill of the ordinary medical practitioner in order to optimize the therapeutic response.
  • Suitable vehicles include oil-in-water or water-in-oil emulsions for preparation of ointments using mineral oils, petrolatum, lanolin, glycerin and the like as well as gels such as hydro gel.
  • a preferred embodiment of the present invention involves administration of semi-solid or solid implants containing PPARgamma agonists.
  • Preferred PPARgamma agonists useful for the application of methods described in this invention include the novel compounds described in this invention and in the following submitted patent applications: Pershadsingh HA, Avery MA. 1,2-Dithiolane Derivatives, (US Patent Application No. 09/520,208) and Pershadsingh HA. Novel Dithiolane Derivatives, (US Provisional Patent No. 60/157890).
  • Preferred PPARgamma agonists may include other drugs, which may be in slow release form for topical or systemic delivery. This may be accomplished in a preferred embodiment by using instrumentation and techniques described in U.S. Patent 5,817,075 and U.S. Patent 5,868,728.
  • either solid or fluid unit dosage forms can be prepared.
  • the compound of interest is mixed into formulations with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.
  • Capsules are prepared by mixing the compound of interest with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound of interest with an acceptable vegetable oil, light liquid petrolatum or other inert oil.
  • Fluid unit dosage forms for oral administration such as syrups, elixirs and suspensions can be prepared.
  • the water soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup.
  • An elixir is prepared by using a hydro alcoholic (e.g., ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.
  • Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
  • the therapeutic compound is prepared in an aqueous solution (discussed below) in a concentration of from about 0.1 to about 100 mg/ml. More typically, the concentration is from about 1 to 10 mg/ml or about 20 mg/ml. Concentrations below 1 mg/ml may be necessary in some cases depending on the solubility and potency of the compound selected for use.
  • the formulation which is sterile, is suitable for various topical or parenteral routes including sublingual, by suppository (e.g. per-rectum or vaginal application), oral, intravascular, intradermal, by inhalation, intramuscular, mtra-articular, intravenous, or other parenteral route.
  • compositions may include, depending on the formulation and mode of delivery desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which include vehicles commonly used to form pharmaceutical compositions for animal or human administration.
  • the diluent is selected so as not to unduly affect the biological activity of the combination.
  • examples of such diluents which are especially useful for injectable formulations are water, the various saline, organic or inorganic salt solutions, Ringer's solution, dextrose solution, and Hank's solution.
  • the pharmaceutical composition or formulation may include additives such as other carriers; adjuvants; or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • excipients can be included in the formulation.
  • examples include cosolvents, surfactants, oils, humectants, emollients, preservatives, stabilizers and antioxidants.
  • Any pharmacologically acceptable buffer may be used, e.g., tris or phosphate buffers.
  • Effective amounts of diluents, additives and excipients are those amounts which are effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, etc.
  • the term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired pharmaceutical effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • unit dosage forms of this invention are dictated by and dependent on (a) the unique characteristics of the active material and the particular effect to be achieved and (b) the limitations inherent in the art of compounding such an active material for use in humans and animals.
  • unit dosage forms are tablets, capsules, pills, powder packets, wafers, suppositories, granules, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampoules, vials, aerosols with metered discharges, segregated multiples of any of the foregoing, and other forms as herein described.
  • composition of the invention may include a therapeutic compound which may be formulated with conventional, pharmaceutically acceptable, vehicles for topical, oral or parenteral administration.
  • Formulations may also include small amounts of adjuvants such as buffers and preservatives to maintain isotonicity, physiological and pH stability.
  • adjuvants such as buffers and preservatives to maintain isotonicity, physiological and pH stability.
  • Means of preparation, formulation and administration are known to those of skill. See generally Remington's Pharmaceutical Science 15th ed., Mack Publishing Co., Easton, Pa. (1980).
  • Slow or extended-release delivery systems including any of a number of biopolymers (biological-based systems), systems employing liposomes, colloids, resins, and other polymeric delivery systems or compartmentalized reservoirs, can be utilized with the compositions described herein to provide a continuous or long term source of therapeutic compound.
  • Such slow release systems are applicable to formulations for delivery via topical, intraocular, oral, and parenteral routes. Delivery by Invasive Device
  • delivery intravascularly, intra-articularly, intramuscularly, intra-articularly, intradermally, or other parenteral route can be accomplished by injection, cannula or other invasive device designed to introduce precisely metered amounts of a desired formulation to a particular compartment or tissue.
  • delivery to certain areas within the eye, in situ can be accomplished by injection, cannula or other invasive device designed to introduce precisely metered amounts directly or contained in a reservoir for slow release in situ, of a desired formulation to a particular compartment or tissue within the eye (e.g. anterior or posterior chamber, uvea or retina).
  • a solid or semisolid implant can be delivered subretinally using the instrumentation and methods described in U.S. Patent 5,817,075 and U.S. Patent 5,868,728.
  • Therapeutic agents of the invention are usually delivered or administered topically for treating disorders involving the eye that are listed in Tables I through X. Oral administration is preferred for disorders in Tables I through X that cannot be treated effectively by topical therapy. Additionally, the agents can be delivered parenterally, especially for treatment of retinitis and degenerative retinal diseases, and for other conditions in Tables I through X, that do not respond to oral or topical therapy, or for conditions where oral or topical therapy is not feasible.
  • Parenteral therapy is typically oral, intraocular, transcutaneous, intradermal, intrathecal, intramuscular, intra-articular, by inhalation, intravascular, sublingual, by suppository (e.g. per-rectum or vaginal application), by inhalation, or other parenteral route.
  • a preferred way to practice the invention for dermatological or ophthalmic disorders in Tables I through X to which this method is applicable, is to apply the compound of interest, in a cream, lotion, ointment, or oil based carrier, or some other suitable vehicle directly to the lesion.
  • concentration of therapeutic compound in a cream, lotion, or oil is 0.025 to 2.5%.
  • the preferred route of administration is oral, topical, intraocular or parenteral.
  • Topical administration is preferred in treatment of lesions of the skin as in psoriasis, external eye as in conjunctivitis, keratitis, scleritis, squamous cell carcinoma, corneal erosion, dry eye syndrome, and anterior compartment of the eye as in glaucoma, uveitis and other diseases of the uveal tract, where such direct application is practical and clinically indicated.
  • Oral administration is a preferred alternative for treatment of other lesions discussed in Tables I through X, where direct topical application is not useful as in the treatment of chronic or acute systemic diseases, and diseases of the posterior segment of the eye, as in uveitis, glaucoma, optic neuritis or retinitis.
  • Intravascular (intravenous being the preferred route) administration may be necessary in disorders that cannot be effectively treated by topical or oral administration.
  • Administration by inhalation is preferred for lung diseases such as broncho-constrictive disease, asthma, and chronic obstructive pulmonary disease.
  • Intraocular, transcutaneous, intradermal, intrathecal, intramuscular, intra- articular injections or other invasive technique are preferred alternative in cases where the practitioner wishes to treat one or a few specific areas or lesions depending on their location within the eye.
  • the compound is delivered in an aqueous solution.
  • the therapeutic compounds are injected directly into lesions (intra-lesion administration) in appropriate cases.
  • Intradermal administration is an alternative for extraocular lesions.
  • Intra-lesional and intradermal injections are alternative routes of application for certain lesions, e.g. extraocular neoplastic or hyperplastic lesions such as squamous cell carcinoma and condyloma, respectively.
  • Inhalation therapy is preferred for pulmonary diseases
  • sublingual and intra-rectal suppository is preferred for rapid delivery or in clinical situations where delivery via the oral or intravascular route is inconvenient or problematic.
  • Application via vaginal topical formulation or via suppository formulation is preferred for diseases localized to the vagina or other segment of the uro genital tract.
  • the compounds of this invention can be formulated to have a wide spectrum of solubility properties, where the oil/water diffusion coefficient (o/w) values may range from ⁇ 1 (very hydrophihc) to > 6 (very hydrophobic).
  • preferred therapeutic compounds are ester derivatives, formulated into solutions, suspensions, aerosols and particulate dispersions appropriate for application to the pulmonary system.
  • the therapeutic agent may be inhaled via nebulizer, inhalation capsules, inhalation aerosol, nasal solution, intra-tracheal as a solution via syringe, or endotracheally tube as an aerosol or via as a nebulizer solution.
  • nebulizer inhalation capsules, inhalation aerosol, nasal solution, intra-tracheal as a solution via syringe, or endotracheally tube as an aerosol or via as a nebulizer solution.
  • structures derivitized as acetates, succinates, glycinates, etc., and rendered water soluble are best suited for delivery across the gastrointestinal mucosa.
  • An effective quantity of the compound of interest is employed in treatment.
  • the dosage of compounds used in accordance with the invention varies depending on the compound and the condition being treated. For example, the age, weight, and clinical condition of the recipient patient; and the experience and judgment of the clinician or practitioner administering the therapy are among the factors affecting the selected dosage. Other factors include: the route of administration, the patient, the patient's medical history, the severity of the disease process, and the potency of the particular compound.
  • the dose should be sufficient to ameliorate symptoms or signs of the disease treated without producing unacceptable toxicity to the patient.
  • an effective amount of the compound is that which provides either subjective relief of symptoms or an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • a typical dose may range from 1 mg/day to 500 mg/day of the compound depending on the ability of the compound to influence the PPAR receptors of interest and the disease under consideration.
  • ligands that are dual activators (co-activators) of PPARgamma and PPARalpha are those compounds with an EC50 for PPARgamma transactivation within about 100-fold of the EC50 for PPARalpha transactivation. More typically, the preferred EC50s for PPARgamma and PPARalpha transactivation are within about 10 to 20-fold of one another. However, the EC50s for activation of PPARalpha and PPARgamma could be within 1000 fold of each other.
  • the EC 50 is the concentration of a compound required to bind to or activate 50% of the receptor in a sample or a subject.
  • troglitazone is a compound encompassed by the methods of this invention.
  • an effective dose of rosiglitazone in milligrams for an average man is (10) (0.06 x IO "6 mol/L) (0.72L/kg x 70kg) (304 g/mole) or 9.2 mg.
  • the dosage per day of the a PPAR ligand of this invention will depend on the its affinity for PPARgamma or PPARalpha or PPARdelta.
  • the dosages of compounds with high affinity e.g., like rosiglitazone, will fall between about 0.1 mg to about 10 mg per day.
  • the dosages of compounds of intermediate affinity e.g. like pioglitazone, will range from about 10 mg to about 100 mg per day.
  • the dosages of compounds with low affinity e.g., like troglitazone, will fall from about 100 mg to about 1000 mg per day.
  • An oral dosing schedule is typically, a single dose once a day. However, more than one dose can be given per day. Because of the lower incidence of undesirable side effects, the compounds of this invention can be given until improvement in the inflammatory process or disease involving neovascularization is observed. Because the compounds of this invention are to some degree fat-soluble, in a preferred embodiment, the compounds are administered with food. The fats in food provide a lipid micellular phase in which the particular PPAR ligand of this invention can solubilize and be more effectively absorbed.
  • a dosage range for local treatment is about 0.025% to about 10% (weight/volume) in a suitable solvent applied that permits release of the compound into the prostate tissue.
  • a preferred range is about 0.025%) to 0.1%.
  • a preferred range is about 0.1% to 0.5%.
  • a preferred range is about 0.5%> to 5%.
  • the PPAR ligands of this invention may have vastly different affinities for PPARalpha and PPARgamma, or the may be similar, i.e. within about one to two orders of magnitude.
  • the local dosage is administered at least once a day until a therapeutic result is achieved.
  • the dosage can be administered twice a day, but more or less frequent dosing can be recommended by the clinician.
  • the compound can be tapered or discontinued. Occasionally, side effects warrant discontinuation of therapy.
  • An effective quantity of the compound of interest is employed in treatment.
  • the dosage of compounds used in accordance with the invention varies depending on the compound and the condition being treated. The age, lean body weight, total weight, body surface area, and clinical condition of the recipient patient; and the experience and judgment of the clinician or practitioner administering the therapy are among the factors affecting the selected dosage. Other factors include the route of administration the patient, the patient's medical history, the severity of the disease process, and the potency of the particular compound.
  • the dose should be sufficient to ameliorate symptoms or signs of the disease treated without producing unacceptable toxicity to the patient.
  • an oral dosing schedule is from about 0.1 mg to about 1000 mg once or twice a day depending on the bindmg affinity of the compound for PPARgamma or PPARalpha or PPARdelta.
  • the typical oral dose of the thiazolidinediones, rosiglitazone and pioglitazone, presently approved for the treatment of type 2 diabetes mellitus is 4 to 8 mg and 15 mg to 45 mg daily, respectively.
  • a convenient oral dose for an adult patient is 4 to 8 mg once a day, or 2 to 4 mg twice a day.
  • a dosage range for topical treatment is about 0.1% to about 1% (weight/volume) in a gel, cream or ointment, applied twice a day.
  • a usual dose for intramuscular or intraocular injection is 0.25 to 2.5 mg, depending on the compartment of the eye to be treated and on the lean body mass of the patient.
  • a typical dosage for intra-dermal administration is about 2.5 to 25 mg per injection per site.
  • a typical dosage for intravenous or intramuscular administration in an adult patient would be between 50 and 250 mg per day given in single or divided doses depending on the judgement of the practitioner.
  • the dosage is administered at least once a day until a therapeutic result is achieved.
  • the dosage is administered twice a day, but more or less frequent dosing can be recommended by the clinician.
  • the drug can be tapered or discontinued. Occasionally, side effects warrant discontinuation of therapy.
  • an effective amount of the compound is that which provides either subjective relief of symptoms or an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • This invention further relates to the use of each of the subject compounds in the treatment of the diseases listed in Tables I through Table X, administered as either as a single agent, or in combination with a natural or synthetic compound selected from one or more of the following categories: PPARalpha agonist, a PPARdelta agonist, or PPARgamma agonist; a rexinoid or other RXR agonist; a vitamin D derivative or other VDR agonist; a glucocorticoid or other GR agonist; a LXR or LXR/RXR agonist (e.g. an oxysterol); a FXR or FXR/RXR agonist (e.g.
  • a CETP inhibitor e.g. a substituted- 1,2,3 ,4- tetrahydroquinoline
  • a pharmacological agent that increases the expression or upregulates ABCl
  • a beta3-adrenoceptor agonist e.g. cyclosporine A, tacrolimus, sirolimus
  • ACE anti-hypertensive angiotensin converting enzyme
  • ARB anti-hypertensive angiotensin receptor blocker
  • Synergistic therapeutic effects can be achieved by oral or topical administration of the drugs encompassed in the current invention together with a second agent selected from the above-identified categories of compounds, administered orally, topically or intravenously.
  • a preferred dosage range for administration of a retinoic acid derivative or retinoid would typically be from 0.1 to 100 mg per square-meter of body surface area, depending on the drug's ability to bind to or modify the activity of its cognate nuclear receptor, given in single or divided doses, orally or by continuous infusion, two or three times per day.
  • the preferred dosages and routes and frequency of administration of the vitamin D analogs or retinoid compounds can be similar to the dosages and routes and frequency of administration ordinarily recommended for these agents when given without PPARgamma activators.
  • effective retinoids are 9-cis-retinoic acid, 13-cis-retinoic acid, all-trans-retinoic acid (at- RA).
  • Preferred retinoids for this purpose would include 13-cis-retinoic acid, tazarotene, or Targretin.
  • a preferred dosage range for systemic administration of a vitamin D analog would typically be from 0.1 to 100 mg per square-meter of body surface area, depending on the drug's ability to bind to and or activate its cognate vitamin D receptor, given in single or divided doses, orally or by continuous infusion, two or three times per day.
  • Examples of effective vitamin D analogs are 1,25-dihydroxy- vitamin D, calcipotriene and calcipotriol.
  • the dosage range and routes and frequency of administration of PPARgamma activators required to achieve synergistic effects when given with vitamin D or retinoid derivatives are the same as those described elsewhere in this disclosure.
  • the preferred mode of administration of these drugs for synergistic therapeutic purposes would be orally although alternatively one can use topical or parenteral routes of administration.
  • the dosages and the modes and frequency of administration of the vitamin D or retinoid related compounds for synergistic topical therapy would be similar to those ordinarily recommended for these agents when given without PPARgamma activators.
  • the dosage range and the modes and frequency required for topical administration of the flavonoid thiazolidine derivatives given in combination with vitamin D or retinoid related compounds are the same as those described elsewhere in this disclosure.
  • Synergistic therapeutic effects can be achieved by oral or topical administration of the drugs encompassed in the current invention together with orally, topically or intravenously administered natural or synthetic antioxidants.
  • natural or synthetic antioxidants include ascorbic acid and its derivatives (e.g. vitamin C), the tocopherols (e.g. vitamin E, vitamin E succinate), carotenes and carotenoids (e.g. beta-carotene), alpha-lipoic acid, probucols, flavones, isoflavones and flavonols (e.g. quercetin, genistein, catechin, apigenin, lutein, luteolin), glutathione and its derivatives (e.g.
  • the compounds of the instant invention are further useful to suppress the mediators of neurogenic inflammation (e.g. substance P or the tachykinins), and may be used in the treatment of rheumatoid arthritis; psoriasis; topical inflammation such as is associated with sunburn, eczema, or other sources of itching; and allergies, including asthma.
  • neurogenic inflammation e.g. substance P or the tachykinins
  • the compounds can also function as neuromodulators in the central nervous system, with useful applications in the treatment of Alzheimer's disease and other forms of dementia, pain (as a spinal analgesic), and headaches. Furthermore, in disorders involving myocardial fibrosis, myocardial ischemia, pathological conditions secondary to the autoimmune response to allograft transplantation, the splanchnic blood flow, including hepatic fibrosis, cirrhosis and oesophagal varices, the compounds of the invention can provide cytoprotection.
  • Assays for screening for compounds that modify the activity of PPARgamma and/or PPARalpha and/or PPARdelta can be conducted using methods known in the art such as PPAR transactivation (Willson et al. J. Med. Chem. 43:527-50 (2000)) and the fluorescence resonance energy (FRET) assay (Zhou G., et al, Mol Endocrinol 12(10):1594-604 (1998).
  • FRET fluorescence resonance energy
  • isolated human peripheral T lymphocytes from normal healthy donors or a mammalian cell line such as a Jurkat T cell line poorly express PPARalpha and PPARgamma can be used.
  • lymphocytes or Jurkat cells are transfected with the PPARgamma expression vector.
  • mixed PPARalpha and PPARgamma activating compounds PPARalpha/PPARgamma co-ligands
  • lymphocytes or Jurkat cells are transfected with both PPARalpha and PPARgamma expression vectors.
  • Other cells expressing PPARdelta may also be employed.
  • Transactivation is determined by cell-based assays which monitor this functional activity.
  • Transactivation assays use cells that have been transfected with a vector expressing the receptor as well as a second vector containing a DNA direct repeat (DR-1) response element and a reporter gene, which encodes an enzyme such as chloramphenicol acetyltransferase, secreted placental alkaline phosphatase, or firefly luciferase.
  • DR-1 DNA direct repeat
  • a procedure used to test the compounds of this invention is the PPAR-GAL4 transactivation assay, which uses chimeric receptors where the PPAR LBD is fused to the DBD of the yeast transcription factor GAL4 and employs a reporter gene containing a GAL4 response element, and has previously been described in detail (Lehmann et al., J. Biol. Chem. 1995, 270, 12953-12956). Briefly, cells are incubated with 10% delipidated fetal calf serum and the test compound at the appropriate concentration.
  • cell extracts are prepared and assayed for alkaline phosphatase and beta- galactosidase activity.
  • Alkaline phosphatase activity was corrected for transfection efficiency using the beta-galactosidase activity as an internal standard.
  • Compounds which elicited on average at least 70% activation of PPAR versus rosiglitazone (positive control for PPARgamma specific activation) or versus Wy- 14643 (positive control for PPARalpha specific activation) were considered full agonists (Willson et al., J. Med. Chem. 2000; 43:527-50; Henke et al. J. Med. Chem. 1998; 41:5020-36).
  • Example 1 Method for evaluating the activity of compounds developed using this invention - Binding Assay
  • bacterial expression plasmids for the ligand binding domains of the PPAR subtypes cDNAs encoding the hinge and ligand binding domains of hPPAR (amino acids 167-468), mPPAR (amino acids 167-468), xPPAR (amino acids 174-474), and xPPAR (amino acids 178-477) are obtained.
  • GST-PPAR fusion proteins or glutathione S-transferase (GST) alone as a control are expressed in BL21(DE3) plysS cells and extracts prepared by freeze-thawing the cells in bacterial lysis buffer (10 mM Tris, pH 8.0/250 mM KCl/1 mM DTT/1% Triton X-100) followed by centrifugation at 40,000 x g for 30 min. Glycerol is added to the bacterial extracts to a final concentration of 10%). Bacterial extracts are dialyzed extensively against bacterial lysis buffer containing 10% glycerol to remove glutathione that might interfere with the stability of the various FAs and eicosanoids in the competition binding assays.
  • bacterial extracts 50 microg protein containing either GST-xPPAR or GST-xPPAR are incubated at 4°C for 2-3 hr in buffer containing 10 mM Tris (pH 8.0), 50 mM KCl, and 10 mM DTT with [3H]GW2331 in the presence or absence of unlabeled GW2331 or the various FAs or eicosanoids.
  • Bound radioactivity was separated from free radioactivity by elution through 1 ml Sephadex G-25 protein desalting columns (Boehringer Mannheim). Bound radioactivity eluted in the column void volume and was quantitated by liquid scintillation counting.
  • radiohgands are now available for use in conventional competition binding assays: [3H]GW 2331 for PPARalpha; [3H]rosiglitazone (BRL49653), [3H]AD- 5075, and [125I]SB-23663643 for PPARgamma; and [3H]GW 243344 and [3H]L- 78348345 for PPARdelta. Each of these radiohgands is reported to show specific binding to the corresponding PPAR subtype.
  • Initial PPAR binding assays used gel filtration to separate the bound radioligand from the free ligand.
  • SPA scintillation proximity assay
  • SPA beads emit light when held in close proximity to a suitable radionuclide (e.g. 3H or 1251). If the receptor is attached to the SPA bead, binding of a radioligand to the PPAR LBD leads to a readily detectable signal. Displacement of the radioligand by a test compound leaves the free radioligand in solution, where it can no longer promote emission by the SPA bead. This technology removes the need to separate free radioligand from the bound ligand, greatly simplifying automated high-throughput screening.
  • the homogeneous format of the SPA binding assay allows determination of equilibrium binding affinities and also permits the use of relatively low-affinity radiohgands.
  • Example 2 Method for evaluating PPAR activity of the compounds of this invention using a transactivation assay or FRET assay
  • Transactivation assays use cells that have been transfected with a vector expressing the receptor as well as a second vector containing a DR-1 response element and a reporter gene, which encodes an enzyme such as chloramphenicol acetyltransferase, secreted placental alkaline phosphatase (SPAP), or firefly luciferase.
  • Activation of the receptor by agonist ligands leads to induction of reporter enzyme expression, which can be conveniently assayed using standard colorimetric or photometric plate readers.
  • an ideal assay is the PPAR-GAL4 transactivation assay useing chimeric receptors where the PPAR LBD is fused to the DBD of the yeast transcription factor GAL4.
  • This assay employs a reporter gene containing a GAL4 response element. Since mammalian cells do not contain GAL4, only the transfected PPAR-GAL4 chimeric receptors can activate the reporter gene, effectively eliminating interference from endogenous nuclear receptors.
  • PPAR agonists show comparable potency and efficacy in assays using either the PPAR-GAL4 chimeras or the full-length receptors.
  • COS-1 cells are maintained as described above for the mammalian two-hybrid system.
  • the following plasmids are used for transfection: respective reporter plasmid (1 microg) containing the pGL-GAL4-UAS (17-mer x 2— globin promoter-luciferase) cotransfected with 0.1 microg of pM(GAL4-DBD)-PPAR (DEF) or pM-PPAR (DEF-AF- 2) with or without 1 microg of SRC-1, TIF2, or TRAP220 expression vector.
  • pM(GAL4-DBD)-PPAR DEF
  • pM-PPAR DEF-AF- 2
  • SRC-1 SRC-1
  • TIF220 TRAP220 expression vector.
  • 10 ng of pRL-CMV plasmid Promega
  • Bluescribe Ml 3+ (Stratagene) is used as the carrier to adjust the total amount of DNA to 3 microg. added to the medium 12 h after transfection and every 8 h thereafter at each exchange of medium. After 48 h, firefly luciferase activity (from GAL4-UAS) is used to measure transfection efficiency by Renilla luciferase activity (from pRL-CMV) as described previously.
  • FRET fluorescence resonance energy tranfer
  • Example 3 Method for Screening for Compounds that Modify the Activity of PPARgamma and PPARalpha based on Inhibition of NF-kappaB activation
  • NF-kappaB Human endothelial cells and vascular smooth muscle cells (VSMC) are known to express both PPARgamma and PPARalpha (Neve BP, et al. Biochem Pharmacol. 2000; 60:1245-1250).
  • VSMC vascular smooth muscle cells
  • isolated human peripheral T lymphocytes from normal healthy donors or a mammalian cell line such as a Jurkat T cell line transfected with the PPARalpha and/or the PPARgamma expression vector may be used in these experiments.
  • One of these selected cell types is stimulated with a concentration of one or a combination of: phytohemagglutinin/phorbol-12-myristate-13-acetate (PHA/PMA), TNF- alpha, interferon-gamma or some other factor that activates NF-kappaB.
  • PHA/PMA phytohemagglutinin/phorbol-12-myristate-13-acetate
  • TNF- alpha TNF- alpha
  • interferon-gamma interferon-gamma or some other factor that activates NF-kappaB.
  • Activation of NF-kappaB is determined by electrophoretic mobility shift assay similar to that previously described (Rossi A, et al. Proc Natl Acad Sci USA 1997; 94:746-50).
  • Example 4 Method for Screening for Compounds that Modify the Activity of PPARgamma and PPARalpha based on Inhibition of NFAT activation
  • Isolated human peripheral T lymphocytes from normal healthy donors or a mammalian cell line such as a Jurkat T cell line transfected with the PPARalpha and/or the PPARgamma expression vector is stimulated with a concentration of one or a combination of PHA/PMA, TNF-alpha, interferon-gamma or some other factor that activates NFAT.
  • Transcriptional activation of NFAT is determined by electrophoretic mobility shift assay similar to that described by Yang et al., J Biol Chem. 2000; 275:4541-4. Preincubation of the same cells with 5 micromolar of the test compound for 2 hours prior to addition of an activator of NFAT inhibits the activation of NFAT otherwise observed in the absence of said compound.
  • Example 5 Method for Screening for Compounds that Modify the Activity of PPARgamma and PPARalpha based on Inhibition of IL-2 production
  • Isolated human T lymphocytes or a mammalian cell line such as a Jurkat T cell line transfected with the PPARalpha and/or the PPARgamma expression vector is stimulated with a concentration of one or a combination of PHA/PMA, TNF-alpha, interferon-gamma or some other factor that activates induction of IL-2 gene expression.
  • Production of IL-2 is determined measuring the concentration of IL-2 in the supernatant from cells using Endogen kits (Wolburn), as described by Yang et al., J. Biol. Chem.. 2000; 275:4541-4. Preincubation of the same cells with 5 micromolar of the test compound for 12 hours prior to addition of an activator of IL-2 production inhibits the activation of IL-2 production otherwise observed in the absence of said compound.
  • Example 6 Methods of determining the anti-apoptotic effect of PPAR ligands in PPARalpha and/or PPARgamma-expressing cells
  • apoptosis (cell death) is induced by adding TNF-alpha (10 ng/ml) and interferon(INF)-gamma (10 ng/ml) (Genzyme, USA).
  • TNF-alpha 10 ng/ml
  • INF interferon(INF)-gamma
  • the inhibitory activity of a test compound in preventing this apoptosis is determined by using dexamethasone as the standard, a compound known to have apoptosis inhibitory activity.
  • RPMI-1640 culture medium containing 10 weight % of fetal bovine serum
  • a test solution of the candidate compound in dimethylsulfoxide is added to the culture medium to give the desired final concentration (0.1 to 10 micromolar).
  • TNF-alpha 40 ng/ml, final concentration
  • INF-gamma 10 ng/ml
  • Example 7 Treatment of Primary or Secondary Glaucoma and Glaucomatous Retinopathy by Oral Administration of a Compound of this Invention: - A Clinical Trial
  • Early disease A patient having early ophthalmic manifestations of glaucoma and increased intra-ocular pressure is selected for therapy.
  • the patient weighs 70 kilograms, and if female of child-bearing capacity, is given a pregnancy test to confirm that she is not pregnant.
  • a compound of this invention is screened and it's ED50 for PPAR subtypes determined.
  • a therapeutically efficacious dose is selected by one skilled in the art.
  • the patient is evaluated by an ophthalmologist experienced in the ophthalmic manifestations of glaucoma and glaucomatous lesions.
  • Regression of the disease or improvement in his clinical status is evaluated by monitoring intraocular pressure, visual fields, and visual reflexes.
  • the daily oral dose is increased about 1 to 3 fold.
  • a complete blood count including white cell count and differential, a platelet count, and liver function tests (such as levels of alkaline phosphatase, lactate dehydrogenase, and aminotransferases) are checked prior to treatment and monthly thereafter.
  • the selected dosage is continued, depending on the response to therapy.
  • the dose may be tapered to a lower (maintenance) dose, again depending on the response to therapy.
  • Late disease A similar patient with late ophthalmic manifestations of chronic glaucoma, in particular, with retinal manifestations including maculopathy, retinopathy and retinal ischemia, is selected for therapy. The approach is the same as for the foregoing patient, except that the starting doses are generally higher.
  • Example 8 Treatment of Optic Neuritis, or a Retinitis, or a Retinopathy. or Macular Degeneration by Oral Administration of a Compound of this Invention - A Clinical Trial
  • Early disease A patient having early ophthalmic manifestations of retinitis pigmentosa is selected for therapy. The patient weighs 70 kilograms, and if female of child-bearing capacity, is given a pregnancy test to confirm that she is not pregnant. Provided that the patient is not pregnant and does not plan to become pregnant during treatment, a compound of this invention is screened and it's ED50 for PPAR subtypes determined. Using the mathematical algorithm described above, a therapeutically efficacious dose is selected by one skilled in the art. The patient is evaluated by an ophthalmologist experienced in the ophthalmic manifestations of retinitis pigmentosa lesions. Regression of the disease or improvement in his clinical status is evaluated by monitoring the visual fields.
  • a complete blood count, white cell count and differential, a platelet count, and liver function tests are checked prior to treatment and monthly thereafter.
  • the dosage is tapered to a maintenance dose of 4 mg.
  • Late disease A similar patient with late ophthalmic manifestations of retinitis pigmentosa is selected for therapy. The approach is the same as for the foregoing patient, except that the doses are generally higher. After 12 months, the dose is decreased to a lower (maintenance) dose of 4 mg or 8 mg once daily.
  • a patient who is a candidate for kidney, liver or heart transplantation or other form of organ transplantation is selected for a therapy.
  • the patient may or may not be receiving other therapies for transplant rejection.
  • a compound of this invention, referred to as the test drug is orally administered in a dosage effective to achieve suppression of T cell activation as known to those with skill in the art.
  • a therapeutically efficacious dose is selected by one skilled in the art. Therapy is initiated 2 weeks prior to transplantation.
  • a complete blood count including white cell count and differential, a platelet count, and plasma IL-2 levels, serum creatinine and BUN levels, liver function tests (such as levels of alkaline phosphatase, lactose dehydrogenase, and transaminases), lipid profile, blood glucose, urinary protein and other tests or evaluations known to a practitioner skilled in the art of managing post-transplantation allograft rejection/survival, are checked prior to allograft transplantation, immediately post-operatively (for monitoring acute rejection) and periodically thereafter for the ensuing months, up to 6 months (for monitoring chronic rejection).
  • Administration of a compound of this invention prevents or decreases signs or symptoms of allograft rejection.
  • the administration of the therapy also enables the clinician to decrease the dose of other conventionally used immunosuppressive agents without increasing the risk of allograft rejection. The patient experiences fewer side effects associated with the other conventional immunosuppressive agents.
  • Example 10 A Clinical Trial, Synergistic (Adiunctive) Therapy for Preventing Acute and Chronic Allograft Rejection
  • a PPARgamma agonist or a PPARgamma/PPARalpha co-agonist of this invention is used as effective adjunctive therapy for preventing acute and chronic allograft rejection.
  • the PPARgamma agonist is useful for providing reduced dosing of immunosuppressive therapy, including cyclosporine A, tacrolimus, azathioprine, mycophenolate or other related therapy to preventing allograft rejection throughout both early and late phases post-transplantation.
  • the PPARgamma agonist is used with one or more anti-rejection drug, or in combination with a RXR agonist, or a PPARgamma/RXR agonist, and/or a vitamin D receptor agonist, and/or a glucocorticoid receptor agonist, and/or an estrogen receptor agonist, and/or an androgen receptor agonist.
  • the treatment can be modified to include combination therapy with a PPARgamma/RXR heterodimer ligand (a rexinoid) or another immunosuppressive compound traditionally used for preventing allograft rejection.
  • a PPARgamma/RXR heterodimer ligand a rexinoid
  • another immunosuppressive compound traditionally used for preventing allograft rejection.
  • ligands for the glucocorticoid nuclear receptor ligand e.g. prednisone
  • inhibitors of purine synthesis e.g. azathioprine and mycophenolate
  • inhibitors of the calcineurin-dependent cytokine synthesis in activated lymphocytes e.g.
  • cyclosporine tacrolimus, sirolimus
  • One or a combination of these compounds are employed (at dosages described above in . the section on Dosase and Schedules ' ) in clinical trials similar to the one described above in Examples 5 and 6, or in doses sufficient to prevent or treat allograft rejection.
  • Examples of synergistic combinations are as follows: a. A PPARgamma or a PPARalpha/PPARgamma co-activator, both compounds of this invention, is administered in combination with prednisone at an FDA-approved dose. b.
  • a PPARgamma or a PPARalpha/PPARgamma co-activator is administered in combination with prednisone and cyclosporine A or tacrolimus at an FDA-approved dose, or sirolimus at a dose use in clinical trials.
  • a PPARgamma or a PPARalpha/PPARgamma co-activator is administered in combination with prednisone and cyclosporine A or tacrolimus or sirolimus, and azathioprine or mycophenolate.
  • a PPARgamma or a PPARalpha/PPARgamma co-activator is administered in combination with one or more FDA-approved immunosuppressive transplant rejection therapeutic compound, as described in examples a, b and c above.
  • FDA-approved immunosuppressive transplant rejection therapeutic compound as described in examples a, b and c above.
  • a rexinoid PPARgamma/RXR heterodimer ligand e.g. LG100754
  • Example 11 Treatment of Chronic Recalcitrant Multiple Sclerosis by Oral Administration of a Compound of this Invention - A Clinical Trial
  • a compound of this invention is administered daily during the acute episode, and is titrated up 0.5 to 3- fold higher doses at weekly intervals. Regression of the disease or improvement in his clinical status is evaluated by monitoring improvement in motor deficits. Reduction of the systemic inflammation associated with the disease is assessed by performing bimonthly measurements of high sensitivity-C-reactive protein (hs-CRP). A reduction in the hs-CRP by 50% within 3 months of initiating therapy is considered to be a positive response to the therapy.
  • hs-CRP high sensitivity-C-reactive protein
  • a complete blood count, white cell count and differential, a platelet count, liver function tests (such as levels of alkaline phosphatase, lactate dehydrogenase, and aminotransferases), erythrocyte sedimentation rate and plasma interleukin-2 levels are checked prior to treatment and monthly thereafter. After 6 months treatment, the dosage is tapered to a lower (maintenance) dose.
  • Example 12 Combination Treatment of a PPAR-Mediated Inflammatory, Proliferative Dermatological (Skin) Disease with PPARgamma Agonist or a Mixed PPARgamma/PPARalpha Agonist (Co-Ligand) and a Vitamin D Derivative - A Clinical Trial
  • the PPAR-mediated disease is an inflammatory, proliferative or degenerative skin disease such as psoriasis, keratitis, hidradenitis, ichthyosis, acne, rosacea, verrucae and other HPV infections, atopic dermatitis, allergic dermatitis, chemical (irritant) dermatitis, seborrheic dermatitis, solar dermatitis, acute and chronic eczema, seborrheic keratosis, senile keratosis, actinic keratosis, photo-induced keratosis, skin aging, thinning skin, dry skin, wrinkle formation, photo-induced skin aging, keloids, lichen planus.
  • the PPARgamma agonist or mixed PPARgamma PPARalpha agonist of this invention is administered at doses consistent with the EC50 for PPARalpha and PPARgamma, and with the pharmacokinetic area under the curve (AUC), and is given as a once or twice daily oral dose, or in a pharmaceutical composition for topical administration, with active ingredient at a concentration ranging from 0.01 to 2.0%, 0.25% of the preferred PPAR agonist are selected.
  • An orally administered vitamin D derivative is selected from: dihydrotachysterol (1 mg daily), 1,25- dihydroxycholecalciferol (1 meg daily), 25-hydroxycholecalciferol (0.1 mg daily), ergocholecalciferol (1.25 mg daily), and cholecalciferol (1 mg daily).
  • Synthetic vitamin D derivatives are administered topically and is selected from the group consisting of calcipotriene and calcitriol (both at a concentration of 0.005% in an ointment or lotion or shampoo). These pharmacological compositions may be used to treat acute or chronic disease or may be used prophylactically to prevent the onset of the disease.
  • Example 13 Use of Compounds of this Invention as Synergistic (Adiunctive) Therapy in the Treatment of a Neuro-Degenerative Disease or an Autoimmune Disease - A Clinical Trial
  • Multiple sclerosis is the example of the neuro-degenerative, autoimmune disease.
  • Current therapies for MS consist of three interferonbeta preparations (Betaseron, Avonex, and Rebif), Copolymer 1 (Copaxone), and Novantrone.
  • a PPARalpha and/or PPARgamma agonist may be used adjunctively in combination therapy with any of the existing (approved) therapies (identified above) for treating MS.
  • a compound of this invention, a PPARgamma agonist or a PPARgamma/PPARalpha co-agonist is selected for adjunctive use, and doses are selected as outlined above.
  • the patient presents acutely with the neurological manifestations of multiple sclerosis, and the diagnosis is confirmed by clinical laboratory and pathological diagnostic tests.
  • the patient is evaluated by a neurologist experienced in the clinical and laboratory manifestations of multiple sclerosis lesions.
  • the patient is a male weighing 70 kilograms or a female weighing 50 kilograms and being treated with an interferonbeta preparation, Copaxone, or Novantrone.
  • An adjunctive PPARgamma agonist, or a PPARalpha and PPARgamma co-agonist (co- activator) is selected from the compounds described in this invention.
  • Adjunctive therapy is initiated at one-half the preferred dose as indicated above.
  • the dose is doubled within 6 to 8 wks of initiation of said adjunctive therapy.
  • the patient is monitored for improvement based on laboratory and clinical findings. The regime is continued as medically indicated to one of skill in the art of treating MS.
  • Phenylvaleric acid 6 (0.126 g or 1.0 mmol) was dissolved in 50 ml of dichloromethane in a separate round bottomed flask and was cooled to 0 ° C. To this was added triethylamine
  • 5-Cyclopentylvaleric acid 5 (0.120 g or 1.0 mmol) was dissolved in 50 ml of dichloromethane in a separate round bottomed flask and was cooled to 0 ° C. To this was added triethylamine (0.1ml or 0.9mmol) followed by the dropwise addition over 5 minutes of 0.08 ml of isobutyl chloroformate. The mixture was stirred for an additional

Abstract

L'invention concerne des entités chimiques utiles dans le traitement de troubles cliniques variés y compris de ceux qui sont influencés par l'activité de récepteurs activés du proliférateur de peroxysome (PPAR) incluant PPARalpha, PPARdelta, et/ou PPARgamma. Elle concerne aussi les structures de ces composés, et les procédés de conception, de fabrication et d'utilisation de ces composés. Elle concerne enfin des tautomères, des stéréoisomères et des dérivés de ces composés, ainsi que des sels et des solvates de ces composés, acceptables sur le plan pharmaceutique, et leurs utilisations dans le traitement de maladies métaboliques, inflammatoires, auto-immunes, prolifératives et dégénératives.
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WO2004101776A3 (fr) * 2003-05-14 2005-05-12 Univ Debrecen Nouveaux emplois des modulateurs du recepteur ppar et cellules presentant l'antigene a usage professionnel manipulees par lesdits modulateurs
WO2004101776A2 (fr) 2003-05-14 2004-11-25 University Of Debrecen Nouveaux emplois des modulateurs du recepteur ppar et cellules presentant l'antigene a usage professionnel manipulees par lesdits modulateurs
US7339065B2 (en) 2003-07-21 2008-03-04 Bethesda Pharmaceuticals, Inc. Design and synthesis of optimized ligands for PPAR
WO2005009437A1 (fr) * 2003-07-21 2005-02-03 Bethesda Pharmaceuticals, Inc. Conception et synthese de ligands optimise pour ppar
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US7307083B2 (en) 2005-01-27 2007-12-11 Alma Mater Studiorum-Universita'di Bologna Tetrahydro-acridine and dithiolane derivatives
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EP1858512A2 (fr) * 2005-03-14 2007-11-28 Immunomedics, Inc. Methodes de traitement du cancer au moyen d'antagonistes de ppar-gamma
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WO2007061094A1 (fr) * 2005-11-28 2007-05-31 Senju Pharmaceutical Co., Ltd. Médicament qui comprend un agoniste ppar
US9096538B2 (en) 2005-11-28 2015-08-04 Senju Pharmaceutical Co., Ltd. Pharmaceutical comprising PPAR agonist
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CN101336113B (zh) * 2005-11-28 2015-07-29 千寿制药株式会社 包括ppar激动剂的药物
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US8802705B2 (en) 2007-05-21 2014-08-12 Senju Pharmaceutical Co., Ltd. Pharmaceutical containing PPAR delta agonist
JP5247686B2 (ja) * 2007-05-21 2013-07-24 千寿製薬株式会社 ＰＰＡＲδアゴニスト含有医薬
WO2008143254A1 (fr) 2007-05-21 2008-11-27 Senju Pharmaceutical Co., Ltd. Produit pharmaceutique contenant un agoniste de pparδ
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US8731655B2 (en) 2009-05-12 2014-05-20 Mallinckrodt Llc Compounds containing acyclic N-N bonds for phototherapy
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WO2015196144A3 (fr) * 2014-06-20 2016-02-11 England Pamela M Antagonistes du récepteur des androgènes
US10053433B2 (en) 2014-06-20 2018-08-21 The Regents Of The University Of California Androgen receptor antagonists
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