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WO2006106438A2 - Procedes de modulation de l'activite de ppar - Google Patents

Procedes de modulation de l'activite de ppar Download PDF

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Publication number
WO2006106438A2
WO2006106438A2 PCT/IB2006/001421 IB2006001421W WO2006106438A2 WO 2006106438 A2 WO2006106438 A2 WO 2006106438A2 IB 2006001421 W IB2006001421 W IB 2006001421W WO 2006106438 A2 WO2006106438 A2 WO 2006106438A2
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Prior art keywords
optionally substituted
compound
oxo
ppar
hydroxy
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PCT/IB2006/001421
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WO2006106438A3 (fr
Inventor
Alexandra M.P. Santana Sorensen
Karsten Kristiansen
Lise Madsen
Rasmus K. Petersen
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Evolva Sa
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Publication of WO2006106438A2 publication Critical patent/WO2006106438A2/fr
Publication of WO2006106438A3 publication Critical patent/WO2006106438A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/336—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having three-membered rings, e.g. oxirane, fumagillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention is directed to certain fatty acid compounds having from 10-32 carbon atoms in the chain and their use in the treatment of a disease or condition dependent on PPAR modulation, such as insulin resistance, certain cancers, certain inflammations, certain infections, and the like.
  • Hepoxilins are products of an arachidonic acid pathway and are biologically active hydroxyl epoxide derivatives of arachidonic acid formed through the 12-lipoxygenase pathway.
  • Hepoxilin A3 [8(S,R)-hydroxy-11 (S), 12(S)-epoxy-eicosa-5Z, 9E 14Z- trienoic acid]
  • hepoxilin B3 [10(S, R)-hydroxy-11 (S),12(S)-epoxy-eicosa-5Z, 8Z, 14Z- trienoic acid] and their corresponding epimers.
  • WO94/22848 and WO01 /10422 A number of analogs have been described in WO94/22848 and WO01 /10422, as well as their uses as anti-inflammatory agents, anti-coagulants, for improving vascular tone, for treating lung fibrosis and in stimulating insulin secretion to treat diabetes.
  • WO 02/038157 and WO 03/099285 describes hepoxilins and their analogs for use in various diseases or conditions including thrombosis, cardiovascular disease (hypertension), diabetes mellitus (by increasing circulating insulin levels), septic shock, certain eye diseases, as well as cancer.
  • Peroxisome proliferator-activated receptors are nuclear hormone receptors. PPAR receptors activate transcription by binding to elements of DNA sequences, known as peroxisome proliferator response elements (PPRE), in the form of a heterodimer with retinoid X receptors (known as RXRs).
  • PPRE peroxisome proliferator response elements
  • RXRs retinoid X receptors
  • PPARalpha Three sub-types of human PPAR have been identified and described: PPARalpha, PPARgamma and PP ⁇ Rdelta (or NUCI).
  • PP ⁇ Ralpha is mainly expressed in the liver, while PPARdelta is ubiquitous.
  • PPARgamma is involved in regulating the differentiation of adipocytes, where it is highly expressed. It also has a key role in systemic lipid homeostasis.
  • PPARgamma subtypes A number of compounds that modulate the activity of PPARs have been identified including thiazolidinediones, which have been employed in the treat- ment of diabetes.
  • the DNA sequences of the PPARgamma subtypes are described in Elbrecht et al., BBRC 224; 431-437 (1996).
  • Peroxisome proliferators including fibrates and fatty acids activate the transciptional activity of PPARs.
  • Literature provides numerous examples illustrating that PPARs are closely involved in a wide array of diseases or pathological conditions which are associated with cells expressing these nuclear receptors. More specifically, PPARs are useful as drug targets in methods for reducing blood glucose, cholesterol, and triglyceride levels and are accordingly explored for the treatment and/or prophylaxis of insulin resistance, dyslipidemia, and other disorders related to Syndrome X (also designated "the metabolic syndrome) (WO 97/25042, WO 97/10813, WO 97/28149; see also Kaplan et al., 2001 , J Cardiovasc Risk, 8, 211-7) including obesity and atherosclerosis (Duez et al., 2001 , J. Cardiovasc. Risk, 8,185-186), coronary artery disease and certain other cardiovascular disorders. Further, PPARs have been shown to be potential targets for the treatment of certain inflammatory diseases such as cutaneous disorders (see Smith et al., 2001, J.
  • PPARs are useful for improving cognitive functions in neurologic diseases (Landreth and Heneka, 2001, Neurobiol Aging, 22,937-44) or in dementia, for treating psoriasis, polycystic ovarian syndrome (PCOS) or for preventing and treating bone loss, e. g. osteoporosis (see for example US 5,981,586, US 6,291,496 or WO 2005/054176).
  • PPARs are exciting targets for the development of therapeutic compounds.
  • the responses observed in the context of the various methods for treating and/or preventing diseases or pathological conditions are encouraging (for example, the thiazolidinedione (TZD) class of medications, e. g.
  • troglitazone, rosiglitazone or pioglitazone unambiguously plays a critical role in improving insulin sensitivity in patients with type 2 diabetes; see Cheng lai and Levine, 2000, Heart Dis., 2,326-333), they are not fully satisfactory treatments because of the occurrence of numerous serious undesirable side effects (for example, weight gain, hypertension, cardiac hypertrophy, haemodilution, liver toxicity, and oedema; see Haskins et al.,2001 , Arch Toxicol., 75,425-438; Yamamoto et al.,2001 , Life ScL, 70,471-482; Scheen, 2001, Diabetes Metab., 27,305-313; Gale, 2001, Lancet, 357, 1870-1875;Forman et al., 2000, Ann.
  • One aspect of the invention is a method for modulating the activity of a peroxisome- proliferator activated receptor (PPAR) in an individual comprising administering to said in- dividual a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, ester, or sugar derivative thereof, wherein the compound is represented by one of several formulae.
  • PPAR peroxisome- proliferator activated receptor
  • the formula is as shown in formula (A) herein:
  • X is -O-, -C n H 2n -(where n is 1 , 2, 3, or 4), -NH, or S;
  • R 1 is a hydrocarbon chain terminated with a C(O)A group, wherein the hydrocarbon chain (i) has four to twenty carbon atoms, (ii) has up to three non-adjacent double bonds, triple bonds, or a mixture thereof, and (iii) is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, -OPO 3 H, lower alkyl, or lower alkenyl, and wherein A is OH, optionally substituted lower alkoxy, optionally substituted lower cycloalkyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, an amino acid radical, a sugar moiety, or NHR 7 , wherein R 7 is H, optionally substituted alkyl, optionally substituted phenyl, optionally substituted benzyl, or optionally substituted heterocycle; and
  • R 2 is a hydrocarbon chain of two to ten carbon atoms; optionally up to three non-adjacent double bonds, triple bonds, or a mixture thereof; and is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, OPO 3 H, lower alkyl, or lower alkenyl.
  • formula B B is as shown as formula B B
  • R 1 is a hydrocarbon chain terminated with a C(O)A group, wherein the hydro- carbon chain (i) has four to twenty carbon atoms, (ii) has up to three non-adjacent double bonds, triple bonds, or a mixture thereof and (iii) is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, -OPO 3 H, lower alkyl, or lower alkenyl, and wherein A is OH, optionally substituted lower alkoxy, optionally substituted lower cycloalkyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, an amino acid radical, a sugar moiety, or NHR 7 , wherein R 7 is H, optionally substituted alkyl, optionally substituted phenyl, optionally substituted benzyl or optionally substituted heterocycle;
  • R 2 is a hydrocarbon chain of two to ten carbon atoms; optionally up to three non-adjacent double bonds, triple bonds, or a mixture thereof; and is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, OPO 3 H, lower alkyl, or lower al- kenyl;
  • R3 is -H, -OH, -CH3 or together with R4 is oxo;
  • R4 is -H, -OH, -CH3 or together with R3 is oxo;
  • R5 is -H, -OH, -CH3 or together with R6 is oxo;
  • R6 is -H, -OH, -CH3 or together with R5 is oxo, with the proviso that the car- bon chain including R 1 and R 2 has at least two substituents thereon.
  • R 1 is a hydrocarbon chain terminated with a C(O)A group, wherein the hydrocarbon chain (i) has six to twenty carbon atoms, (ii) has up to three non-adjacent double bonds, triple bonds, or a mixture thereof, and (iii) is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, -OPO 3 H, lower alkyl, or lower alkenyl, and wherein A is OH, optionally substituted lower alkoxy, optionally substituted lower cycloalkyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, an amino acid radical,, a sugar moiety, or NHR 7, wherein R 7 is H, optionally substituted alkyl, optionally substituted phenyl, optionally substituted benzyl, or optionally substituted heterocycle;
  • R 2 is a hydrocarbon chain of six to ten carbon atoms; has three non-adjacent double bonds; and is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , - NH 2 , -SH, OPO 3 H, lower alkyl, or lower alkenyl;
  • R 3 is -H, -OH, -CH 3 or together with R 4 is oxo;
  • R 4 is -H, -OH, -CH 3 or together with R 3 is oxo;
  • R 5 is -H, -OH, -CH 3 or together with R 6 is oxo; and
  • R 6 is -H, -OH, -CH 3 or together with R 5 is oxo.
  • formula B is as shown as formula B
  • Ri is a hydrocarbon chain terminated with a C(O)A group, wherein the hydrocarbon chain (i) has four to twenty carbon atoms, (ii) has up to three non-adjacent double bonds, triple bonds, or a mixture thereof, and is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, -OPO 3 H, lower alkyl, or lower alkenyl, and wherein A is OH, optionally substituted lower alkoxy, optionally substituted lower cycloalkyloxy, op- tionally substituted phenoxy, optionally substituted benzyloxy, an amino acid radical, a sugar moiety, or NHR 7 , wherein R 7 is H, optionally substituted alkyl, optionally substituted phenyl, optionally substituted benzyl, or optionally substituted heterocycle;
  • R 2 is a hydrocarbon chain of two to ten carbon atoms and optionally up to three non-adjacent double bonds, triple bonds, or a mixture thereof, and is optionally sub- stituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH 1 OPO 3 H, lower alkyl, or lower alkenyl;
  • R3 is -H, -OH, -CH3 or together with R4 is oxo;
  • R4 is -H, -OH 1 -CH3 or together with R3 is oxo;
  • R5 is -H, -OH, -CH3 or together with R6 is oxo; and
  • R6 is -H, -OH, -CH3 or together with R5 is oxo.
  • Another aspect of the invention is the use of the compounds as defined above and in further detail hereinafter to prepare a medicament composition useful for treating or preventing a clinical condition in a subject that is a PPAR-mediated disease or condition.
  • PPAR-mediated disease or condition includes, but is not limited to the metabolic syndrome, obesity, insulin resistance, pre-diabetes, diabetes, dyslipidemia, cardiovascular disease, such as hypertension, atherosclerosis, atherogenesis, vascular restinosis, cardiomyopathy and myocardial fibrosis, autoimmune disease, such as multiple sclerosis, psoriasis, atopic dermatitis, asthma and ulcerative colitis, cancer, such as liposarcoma, neuroblastoma, bladder, breast, colon, lung, pancreas and prostate cancers, inflammation, AIDS and wound healing.
  • a PPAR-mediated disease or condition includes, but is not limited to the metabolic syndrome, obesity, insulin resistance, pre-diabetes, diabetes, dyslipidemia, cardiovascular disease, such as hypertension, atherosclerosis, atherogenesis, vascular restinosis, cardiomyopathy and myocardial fibrosis, autoimmune disease, such as multiple sclerosis, psoriasis, atopic
  • Figure 1 illustrates a model of PPAR activation by a full agonist and a partial agonist, respectively.
  • Figure 2A illustrates activation of PPARgamma by rosiglitazone, Hepoxilin A3 and Hepox- ilin B3.
  • Figure 2B illustrates activation of PPARgamma by various concentrations of rosiglitazone, epoxilin A3 and Hepoxilin B3.
  • Figure 2C illustrates activation of PPARdelta by L165041 , but not by Hepoxilin A3 and Hepoxilin B3.
  • FIGS 2D and 3D illustrate activation of RxR by LG1069, but not by Hepoxilin A3, Hepoxilin B3 or 9-oxo OTE.
  • Figures 3A-3C illustrate results of PPARalpha activation assays.
  • Figure 4A-4C illustrate results of real-time PCR for specific markers for adipocyte differentiation.
  • Figures 5-7 illustrate results of partial PPARgamma competition assays.
  • Figures 8-10 illustrate results of PPARgamma ligand displacement assays.
  • FIGS 11-13 illustrate result of glucose uptake assays.
  • alkyl refers to a monovalent, saturated aliphatic hydrocarbon radical having the indicated number of carbon atoms, generally one to twenty two.
  • a "C 1-6 alkyl” or an “alkyl of 1-6 carbons” or “AIk 1-6” would refer to any alkyl group containing one to six carbons in the structure.
  • C 1-22 alkyl refers to any alkyl group having one to twenty two carbons.
  • C 1-10 alkyl would refer to an alkyl of one to ten carbons.
  • Alkyl may be a straight chain (i.e. linear) or a branched chain.
  • Lower alkyl refers to an alkyl of 1-6 carbons.
  • Representative examples of lower alkyl radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, sec-butyl, tert-butyl, sec- amyl, tert-pentyl, 2-ethylbutyl, 2,3-dimethylbutyl, and the like.
  • Higher alkyl refers to alkyls of seven carbons and above. These include n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, and the like, along with branched variations thereof.
  • the radical may be optionally substituted.
  • Alkenyl refers to a monovalent, aliphatic hydrocarbon radical having at least one carbon-carbon double bond and having the indicated number of carbon atoms.
  • C 2-6 alkenyl or an “alkenyl of 1-6 carbons,” or “alkenyl 1-6” would refer to an alkenyl group containing one to six carbon atoms in the structure.
  • C 1-20 alkenyl refers to any alkenyl group having one to twenty carbons.
  • Alkenyl may be a straight chain (i.e., linear) or a branched chain.
  • Lower alkenyl refers to an alkenyl of 1-6 carbons.
  • Rep- resentative examples of lower alkenyl radicals include ethenyl, 1-propenyl, 1-butenyl, 1- pentenyl, 1-hexenyl, isopropenyl, isobutenyl, and the like.
  • Higher alkenyl refers to alkenyls of seven carbons and above. These include 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-dodecenyl, 1-tetradecenyl, 1-hexadecenyl, 1-octadecenyl, 1-eicosenyl, and the like, along with branched variations thereof.
  • the radical may be optionally substituted.
  • Alkoxy refers to a monovalent radical of the formula RO-, where R is an alkyl as defined herein.
  • Lower alkoxy refers to an alkoxy of 1-6 carbon atoms, with higher alkoxy being an alkoxy of seven or more carbon atoms.
  • Representative lower alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, isopentyloxy, amyloxy, sec-butoxy, tert-butoxy, tert-pentyloxy, and the like.
  • Higher alkoxy radicals include those corresponding to the higher alkyl radicals set forth herein.
  • the radical may be optionally substituted Cycloalkyl:
  • cycloalkyl refers to a monovalent, alicyclic, saturated hydrocarbon radical having three or more carbons forming the ring. While known cycloalkyl compounds may have up to 30 or more carbon atoms, generally there will be three to seven carbons in the ring. The latter include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the radical may be optionally substituted.
  • Cycloalkoxy refers to a monovalent radical of the formula RO-, where R is cycloalkyl as defined herein. While known cycloalkyoxy compounds may have up to 30 or more carbon atoms, generally there will be three to seven carbons in the ring. The latter include, for example, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and cycloheptoxy. The radical may be optionally substituted.
  • Halo is a monovalent halogen radical chosen from chloro, bromo, iodo, and fluoro.
  • a "halogenated” compound is one substituted with one or more halo sub- stituent.
  • Phenyl A "phenyl” is a radical formed by removal of a hydrogen from a benzene ring. The phenyl may be optionally substituted.
  • Phenoxy is a radical of the formula RO-, wherein the R is a phenyl radical.
  • Benzyl is a radical of the formula R-CH 2 -, wherein the R is a phenyl radical.
  • Benzyloxy is a radical of the formula RO-, wherein R is a benzyl radical.
  • Heterocycle A "heterocycle” or “heterocyclic entity”is a monovalent radical of a 5- or 6- member closed ring containing carbon and at least one other element, generally nitrogen, oxygen, or sulfur and may be fully saturated, partially saturated, or unsaturated (i.e., aromatic in nature). Generally the heterocycle will contain no more than two hetero atoms. Representative examples of unsaturated 5-membered heterocycles with only one hetero atom include 2- or 3-pyrrolyl, 2- or 3-furanyl, and 2- or 3-thiopenyI.
  • Corresponding partially saturated or fully saturated radicals include 3-pyrrolin-2-yl, 2- or 3-pyrrolindinyl, 2- or 3- tetrahydrofuranyl, and 2- or 3-tetrahydrothiophenyl.
  • Representative unsaturated 5- membered heterocyclic radicals having two hetero atoms include imidazolyl, oxazolyl, thia- zolyl, pyrazolyl, and the like.
  • the corresponding fully saturated and partially saturated radicals are also included.
  • Representative examples of unsaturated 6-membered heterocycles with only one hetero atom include 2-, 3-, or 4-pyridinyl, 2H-pyranyl, and 4H-pryanyl.
  • Corresponding partially saturated or fully saturated radicals include 2-, 3-, or 4-piperidinyl, 2-, 3-, or 4-tetrahydropyranyl and the like.
  • Representative unsaturated 6-membered heterocyclic radicals having two hetero atoms include 3- or 4-pyridazinyl, 2-, A-, or 5- pyrimidinyl, 2-pyrazinyl, morpholino, and the like.
  • the corresponding fully saturated and partially saturated radicals are also included, e.g. 2-piperazine.
  • the heterocyclic radical is bonded through an available carbon atom or hetero atom in the heterocyclic ring directly to the entity or through a linker such as an alkylene such as methylene or ethylene.
  • the het- erocycle may be optionally substituted.
  • a radical is referred to as "optionally substituted,” it means that the radical is unsubstituted or at least one-H of the radical is removed and another sub- stituent inserted in its place.
  • the radical may be optionally substituted with substituents at positions that do not significantly interfere with the preparation of compounds falling within the scope of this invention and that do not significantly adversely affect the biological activity of the compounds.
  • the radical is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of halo, lower alkoxy, hy- droxyl, cyano, nitro, amino, halo lower alkyl, halo lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino.
  • amino acid residue is any amino acid having the nitrogen available as the attachment point.
  • the linkage is that of an amide.
  • the linkage is -C(O)NH-CH 2 COOH.
  • the amino acid may include the natural amino acids (i.e. the -NH 2 group is at the alpha position) or other amino acids where the -NH 2 group is at the beta or gamma positions, e.g., gamma amino butyric acid (GABA).
  • alanine (Ala), arginine (Arg), asparagine (AspNH 2 ), and other amino acids at pages 1134-1135 of "Organic Chemisgtry” by Morrison & Boyd, 3 rd Edition (Allyn & Bacon) are useful, all of which are incorporated herein by reference.
  • hydroxycarbonyl is a monovolent radical having the formula -C(O)OH.
  • lower alkoxycarbonyl is a monovalent radical with the formula -C(O)OAIk, where AIk is lower alkyl.
  • lower alkylcarboxyloxy is a monovalent radical with the formula -OC(O)AIk, where AIk is lower alkyl.
  • a sugar moiety means a monosaccharide, a disaccharide or a polysaccharide. Suitable monosaccharides include pentose, hexose, or a heptose residues.
  • pentoses include arabinose, ribose, ribulose, xylose, lyxose, and xylu- lose.
  • hexoses include glucose, galactose, fructose, fucose, man- nose, allose, altrose, talose, idose, psicose, sorbose, and tagatose.
  • Non-limiting examples of heptoses include mannoheptulose and sedoheptulose.
  • the sugar moiety may be linked to the compound at any position of the sugar ring which can form an amide or ester bond.
  • Preferred saccharides are beta-glycosyl saccharides.
  • PPAR modulation is defined by reference to the natural situation, i. e. the basal level of PPAR dependent transcription of target genes in the absence of ligands, wherein modulation of PPAR activity is reflected by decrease or increase in said basal level of transcription in the presence of a compound capable of modulating PPAR activity.
  • an increase of said transcription is associated with an enhancement of PPAR activity and relates to compounds named activators or agonists.
  • a decrease of said tran- scription is associated with an inhibition of PPAR activity and relates to compounds named inhibitors or antagonists.
  • Partial agonists are compounds that result in PPAR dependent transcription of a subset of target genes while having no effect on other PPAR target genes.
  • Partial agonists may be viewed from biochemical or physiological viewpoint.
  • the biochemical view of a partial agonist is a compound that can compete out a full agonist and has a lower level of transactivation relative to a full agonist.
  • the physiological view of a partial agonist relates to the activation of different subsets of genes (even full activation of some target genes and no activation of other PPAR target genes). This results in only some of the physiological effects of a full agonist.
  • a “therapeutically effective amount” of compound means the amount that, when administered to a subject in need thereof, will produce the desired result over time for the condition being treated.
  • the desired effect is PPAR modulation and the biological activity associated therewith.
  • the compounds useful in this invention are depicted by various formulae in this application. By viewing the formulae, it will be apparent that the compounds often will have a chiral center, i.e., a carbon to which four different groups are attached, and these can exist as enan- tiomers. In addition, because of the presence in some cases of double bonds, a compound will have hindered rotation. The compound thus exhibits geometric isomerism, i.e. two forms can differ from each other in the way the atoms are oriented in space. With regard to the double bond, stereoisomers exist that are not mirror images of each other, and are referred to as diastereomers.
  • This invention is based in part on the discovery that certain compounds and their deriva- tives are capable of modulating the activity of at least one PPAR subtype, for example
  • PPARgamma or PPARdelta This discovery leads to the use of these compounds to treat conditions or diseases in mammals, such as humans, that are mediated by the operation of such PPARs.
  • the compounds that are useful in this invention are characterized by the presence of a hydrocarbon chain of variable length that is terminated at one end by a -COOH group or a salt or functional derivative thereof (e.g. an acid halide, an ester, an amide, and the like).
  • the compounds can be referred to as "fatty acids," or derivatives of fatty acids.
  • the hydrocarbon chain will generally have at least one unsaturated linkage, i.e. a double bond (al- kene) or a triple bond (alkyne), and may have multiple saturated linkages, e.g., 2, 3, 4, 5 or 6.
  • the number of carbons in the chain may range from 10 to 32 carbons, but will generally have an even number of carbons (10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32).
  • the preferred length is 16-22, but generally the length will be 18, 20 or 22 carbons.
  • the numbering of the chain starts with the -COOH carbon as number 1.
  • an 18 carbon compound is a dodecenoic acid derivative and 20 carbon compound would be an eicosaenoic acid derivitave.
  • the chain may be substituted with at least one substituent, as discussed hereinafter, or may be unsubstituted. It should be noted that the "COOH" entity is part of the carbon chain and is not considered a "substituent" on the chain.
  • a ring is formed between two adjacent carbons in the chain and a third atom outside the chain, e.g. a ring such as an epoxide (-0-), a cyclopropyl (-CH 2 -), a thiirane (-S-), or an aziridine (-NH-).
  • the ring will be in the R 1 R or S 1 S configuration and the bonds to the third atom will be shown as a broken line (" ") or a wavy line (" ww • ⁇ ).
  • One aspect of the invention is a method for modulating the activity of a peroxisome- proliferator activated receptor (PPAR) in an individual comprising administering to said individual a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, ester, or sugar derivative thereof, wherein the compound is represented by one of several formulae.
  • PPAR peroxisome- proliferator activated receptor
  • the formula is as shown in formula (A) herein:
  • X is -O-, -C n H 2n -(where n is 1 , 2, 3, or 4), -NH, or S;
  • Ri is a hydrocarbon chain terminated with a C(O)A group, wherein the hydrocarbon chain (i) has four to twenty carbon atoms, (ii) has up to three non-adjacent double bonds, triple bonds, or a mixture thereof, and (iii) is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, -OPO 3 H, lower alkyl, or lower alkenyl, and wherein A is OH, optionally substituted lower alkoxy, optionally substituted lower cycloalkyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, an amino acid radical, a sugar moiety, or NHR 7 , wherein R 7 is H, optionally
  • R 2 is a hydrocarbon chain of two to ten carbon atoms; optionally up to three non-adjacent double bonds, triple bonds, or a mixture thereof; and is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, OPO 3 H, lower alkyl, or lower alkenyl.
  • the length of the carbon chain that includes Ri and R 2 will preferably be 16 to 22 carbon atoms such that R 1 has four to 16 carbons, with R 2 having four to sixteen carbons. More preferably, the overall length of the carbon chain will be 16, 18 or 20 carbons. While the number of double and triple bonds may vary as set forth herein, preferably the carbon chain will have only double bonds present.
  • R 1 will have O, 1 , 2 or 3 double bonds, more preferably O, 1 or 2 double bonds, and generally 1 double bond or none.
  • R 2 will preferably have O, 1 or 2 double bonds.
  • the substituent is preferably halo, methyl, NH 2 , -OH or oxo, particularly -OH or oxo. Examples of specific compounds useful in this invention are found in Tables 1 and 2. Others will be apparent to one of skill in the art by referring to other parts of this application.
  • formula B is as shown as formula B
  • R 1 is a hydrocarbon chain terminated with a C(O)A group, wherein the hydrocarbon chain (i) has four to twenty carbon atoms, (ii) has up to three non-adjacent double bonds, triple bonds, or a mixture thereof and (iii) is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, -OPO 3 H, lower alkyl, or lower alkenyl, and wherein A is OH, optionally substituted lower alkoxy, optionally substituted lower cycloalkyloxy, optionally substituted phenoxy, optionally substituted benzyloxy, an amino acid radical, a sugar moiety, or NHR 7 , wherein R 7 is H, optionally substituted alkyl, optionally substituted phenyl, optionally substituted benzyl or optionally substituted heterocycle;
  • R 2 is a hydrocarbon chain of two to ten carbon atoms; optionally up to three non-adjacent double bonds, triple bonds, or a mixture thereof; and is optionally substituted with a -OH, oxo, halo, -CH 2 OH, -N 3 , -CH 2 N 3 , -NH 2 , -SH, OPO 3 H, lower alkyl, or lower alkenyl;
  • R3 is -H, -OH, -CH3 or together with R4 is oxo;
  • R4 is -H, -OH, -CH3 or together with R3 is oxo
  • R5 is -H, -OH, -CH3 or together with R6 is oxo
  • R6 is -H, -OH, -CH3 or together with R5 is oxo, with the proviso that the carbon chain including R 1 and R 2 has at least 2 substituents thereon.
  • the length of the carbon chain that includes R 1 and R 2 will preferably be 16 to 22 carbon atoms such that R t has four to 16 carbons, with R 2 having four to sixteen carbons. More preferably, the overall length of the carbon chain will be 16, 18 or 20 carbons. While the number of double and triple bonds may vary as set forth herein, preferably the carbon chain will have only double bonds present. Thus, it is preferred that R 1 will have O, 1 , 2 or 3 double bonds, more preferably O, 1 or 2 double bonds, and generally 1 double bond or none. R 2 will preferably have O, 1 or 2 double bonds.
  • R 1 or R 2 is substituted, the substituent is preferably -OH, CH 3 or oxo.
  • Examples of specific compounds useful in this invention are found in Tables 3 and 4. Others will be apparent to one of skill in the art by referring to other parts of this application.
  • Another aspect of the invention is the method where the compound is represented by formula B, where R 2 , R 3 , R 4 , Rs and R 6 are as defined above and is substituted lower alkoxy, substituted lower cycloalkoxy, optionally substituted phenoxy, optionally substituted benzyloxy, an amino acid radical, a sugar moiety, or NHR 7 (where R 9 is as defined).
  • the length of the carbon chain that includes R-i and R 2 will preferably be 16 to 22 carbon atoms such that Ri has four to sixteen carbons, with R 2 having four to sixteen carbons. More preferably, the overall length of the carbon chain will be 16, 18 or 20 carbons. While the number of double and triple bonds may vary as set forth herein, preferably the carbon chain will have only double bonds present.
  • R 1 will have 0, 1, 2 or 3 double bonds, more preferably 0, 1 or 2 double bonds, and generally 1 double bond or none.
  • R 2 will preferably have 0, 1 or 2 double bonds.
  • the substituent is preferably -OH, CH 3 or oxo. Examples of specific compounds useful in this invention are found in Tables 3 and 4. Others will be apparent to one of skill in the art by referring to other parts of this application.
  • Compounds of formulae I and Il The present invention relates to compounds capable of modulating the activity of at least one PPAR subtype, for example PPARgamma and/or PPARdelta and methods for use of such compounds-
  • a further depiction of the compounds of the invention is shown in the general formulae I or Il (see below) or a pharmaceutically acceptable salt, ester, or sugar derivative thereof.
  • X is O, C n H 2n , NH or S, wherein n is 1 , 2, 3 or 4; preferably X is O or C n H 2n , wherein n is 1 , 2, 3 or 4, preferably n is 1 or 2, more preferably n is 1 ;
  • R 1 is H, OH, halogen, N 3, CH 2 N 3, NH 2 , SH, OPO 3 H, lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or hydroxy lower alkyl, preferably R 1 is -H or -OH;
  • R 3 is H, OH, halogen or CH 3 ; preferably R 3 is -H or -OH;
  • R 5 is lower alkyl, lower alkenyl, hydroxy lower alkyl, or hydroxy lower alkenyl; or YR 2 , wherein Y is a single bond or a C 1 -C 10 carbon chain optionally substituted with -OH or halogen and optionally containing up to three double bonds, wherein R 2 is C 1 -C 10 alkyl optionally substituted with OH, oxo, halo, -CH 2 OH, N 3 , -CH 2 N 3 , -NH 2 , -SH, -OPO 3 H, lower alkyl or lower alkenyl, or COOR 4 or CONHR 4 ; preferably R 2 is COOR 4 or CONHR 4 , when Y is a CrC- I0 carbon chain, wherein R 4 is H, C 5 or C 6 cycloalkyl, benzyl, phenyl, a sugar moiety, lower alkyl, or lower alkenyl optionally substituted with COOH, a heterocycle
  • R 7 is -H, -OH, -CH 3 , or together with R 10 is an oxo, preferably R 7 is -OH;
  • R 8 is -H, -OH, -CH 3 or together with R 9 forms an oxo when R 7 together with R 10 is not oxo;
  • R 9 is -H, -OH, or -CH 3, or together with R 8 is an oxo.
  • the dotted line in the carbon chain indicates a single, double or triple bond.
  • none of b-i, b 2 and b 3 are a triple bond and only one of b-i, b 2 and b 3 may be a double bond at the same time, and only one of b 4 and b 5 may be a double bond at the same time.
  • R 7 , R 8 , R 9 and R 10 are -OH and the remainder are H or R 7 and Ri 0 , together form oxo when R 8 and R 9 are each -H or vice versa. Accordingly, if R 7 and R 10 each is -H, then preferably R 8 is -OH or is oxo with R 9 . Similarly, if each of R 8 and R 9 is -H, then R 7 is preferably -OH or with R 10 is oxo. If R 7 is -OH, then R 8 preferably is -H or -OH.
  • the overall chain length of compounds useful in the invention can be viewed as the number of carbons in R 6 , plus those in C 5 , plus 6.
  • the overall chain length of the compound is in the range of Ci 5 to C 30 , preferably in the range of Ci 6 to C 25 , more preferably in the range of C 17 to C 23 , yet more preferably in the range of Ci 8 to C 22 . It is even more preferred that the overall chain length is C 18 or C 20 or C 22 . Accordingly, if the chain length of R 5 is designated C x and the chain length of R 6 is designated C y and both x and y are integers, then it is preferred that x+y is an integer in the range of 10 to 18, preferably in the range of 11 to 17, more preferably in the range of 12 to 16. It is even more preferred that x+y is 12. In another embodiment it is more preferred that x+y is 14. In yet another embodiment it is more preferred that x+y is 16.
  • the compounds according to the present invention comprise at least one double bond and the preferred compounds may thus be regarded as substituted alkenes.
  • the compounds may comprise more than one double bond, such as 2, 3, 4, or 5 double bonds, for example.
  • the compounds comprise at least 2 double bonds. These at least two double bonds may be positioned in any suitable manner in relation to each other, however, frequently the at least two double bonds are sepa- rated by two single bonds. Thus, the compound may for example comprise at least 3 double bonds positioned two single bonds apart. It is also possible that the at least two double bonds are separated by only one single bond or in other arrangements as is apparent to one of ordinary skill in the art.
  • X is O, C n H 2n , NH or S, wherein n is 1 , 2, 3 or 4; preferably X is O or C n H 2n , wherein n is 1 , 2, 3 or 4; more preferably n is 1 , 3 or 4, even more preferably n is 1 ;
  • R 1 is H, OH, halogen, CH 3 , CH 2 OH, N 3, CH 2 N 3 , NH 2 , SH, OPO 3 H, lower alkyl or alkenyl, lower alcohol or O-lower alkyl or alkenyl; preferably R 1 is -H or -OH;
  • R 3 is H, OH, halogen or CH 3 , preferably R 3 is -H or -OH;
  • R 5 is lower aikyl or alkenyl; lower alcohol, saturated or unsaturated; or
  • Y is a single bond or a C 1 -C 10 carbon chain optionally substituted with -OH and/or halogen and/or optionally containing up to three double or triple bonds or a mixture of double and triple bonds up to a maximum of three;
  • R 2 is C 1 -C 10 alkyl OH, C 1 -C 10 alkyl-halide, C 1 -C 10 alkyl N 3 , C 1 -C 10 alkyl -NH 2 or COOR 4 or CONHR 4 , preferably R 2 is COOR 4 or CONHR 4 ; wherein R 4 is H, C 5 or C 6 cycloalkyl, C 5 -C 6 aryl, a sugar moiety or C 1 -C 10 alkyl or alkenyl optionally substituted with COOH, C 5 -C 6 aryl, heteroaromatic ring or a sugar moiety, preferably R 4 is -CH 3 , -H, alkyl substituted with COOH or a heteroaromatic ring;
  • R 6 is a C 4 -C- I5 carbon chain optionally substituted with -ORi 0 , wherein R 10 is -H, lower alkyl or alkenyl; preferably R 6 is an unsubstituted C 4 to C 10 chain; wherein R 6 optionally contains up to three double or triple bonds or a mixture of double and triple bonds up to a maximum of three; and indicates a single, double or triple bond.
  • X is O, C n H 2n , NH or S, preferably X is O or C n H 2n , wherein n is 1 , 2, 3 or 4, preferably n is 1 , 3 or 4, more preferably n is 1 ;
  • R 1 is -H, -OH, halogen, CH 3 , CH 2 OH, NH 2 or CH 2 NH 2 ; preferably R 1 is -OH or -H
  • R 2 is C 1 -C 10 alkyl OH, C 1 -C 10 alkyl-halide, C 1 -C 10 alkyl N 3 , C 1 -Ci 0 alkyl -NH 2 or COOR 4 Or CONHR 4 , preferably R 2 is COOR 4 or CONHR 4 ;
  • R 3 is H, halogen or CH 3 ;
  • R 4 is H, C 1 -Ci 0 alkyl or alkenyl, C 5 or C 6 cycloalkyl, C 5 -C 6 aryl or a sugar moiety or alkyl substituted with COOH or a heteroaromatic ring, preferably R 4 is -CH 3 , -H or alkyl substituted with COOH; and indicates a single, double or triple bond.
  • the compound is of formula III, IV, V or Vl, and X is C n H 2n , NH or S, preferably X is C n H 2n , wherein n is 1 , 2, 3 or 4, preferably 1 , 3 or 4, more preferably 1.
  • X may in a preferred embodiment be CH 2 .
  • the compound is of any of the above-mentioned formulae, wherein
  • R 1 is -OH
  • R 3 is H
  • R 2 is COOH or COOCH 3 .
  • the compound is a naturally occurring Hepoxilin, preferably Hepoxilin A or hepoxilin B, more preferably hepoxilin A3, such as hepoxilin A3 of the 8S form or hepoxilin A3 of the 8R form; or hepoxilin B3, such as hepoxilin B3 of the 1OS form or hepoxilin B3 of the 1OR form.
  • X O, CH 2 , S or NH, preferably X is CH 2
  • Ri is OH, halogen, NH 2 , SH, OPO 3 H, lower alkyl or alkenyl, lower alcohol or O-lower alkyl or alkenyl;
  • R 3 is H and
  • the compound may be an analogue of a naturally occurring hepoxilin, such as hepoxilin A3 or B3, wherein the the epoxy group has been exchanged with a cyclopropyl group.
  • the compound may be selected from the group consisting of: 8(S)-hydroxy-11 , 12- cyclopropyl-eicosa- ⁇ Z, 9E, 14Z- trienoic acid and derivatives thereof; 8(R)-hydroxy-11 , ⁇ -cyclopropyl-eicosa- ⁇ Z, 9E, 14Z- trienoic acid and derivatives thereof;
  • X is O, C n H 2n , NH or S, wherein n is 1 , 2, 3 or 4, preferably X is O or C n H 2n and n is 1 , 2, 3 or 4;
  • R 1 is H or OH, preferably H;
  • R 3 is H or OH, preferably H;
  • R 5 is Y — R 2 , wherein Y is a single bond or a C 1 -C 10 carbon chain optionally substituted with OH and/or optionally containing up to three double bonds, preferably Y is a C 6 -Ci 0 carbon chain and R 2 is COOR 4 ; preferably R 5 is -C m H 2m COOR 4 , wherein m is O - 7, wherein R 4 is H or C 1 -C 10 alkyl, preferably methyl and R 6 is a C 4 -C 13 carbon chain optionally substituted with -OH and/or halogen and/or optionally containing up to three double bonds;
  • Another aspect of the invention is the use of a compound of the formula l.i, l.ii, II. i or II. ii as a medicament.
  • X is O, C n H 2n , NH or S, wherein n is 1 , 2, 3 or 4;
  • R 1 is H, OH, halogen, CH 3 , CH 2 OH, N 3 , CH 2 N 3 , NH 2 , SH, OPO 3 H, lower alkyl or alkenyl, lower alcohol or O-lower alkyl or alkenyl;
  • R 3 is H, OH, halogen or CH 3 ;
  • R 5 is lower alkyl or alkenyl; lower alcohol (C1 to C22), saturated or unsaturated; or Y — R 2 , wherein Y is a single bond or a C 1 -C 10 carbon chain optionally substituted with -OH and/or halogen and/or optionally containing up to three double or triple bonds or a mixture of double and triple bonds up to a maximum of three;
  • R 2 is C 1 -Ci 0 alkyl OH, C 1 -C 10 alkyl- halide,C r C 10 alkyl N 3 , C 1 -C 10 alkyl -NH 2 , or COOR 4 or CONHR 4 , wherein R 4 is H, C5 or C6 cycloalkyl, C5-C6 aryl or C 1 -C 10 alkyl or alkenyl optionally substituted with COOH, C5-C6 aryl, a heteroaromatic ring or a sugar; R 6 is a C 4 -C
  • R 8 is -H, -OH or -CH 3 or together with R 9 forms a carbonyl group provided that R 7 is not carbonyl; and R 9 is otherwise -H or CH 3 , and wherein indicates a single, double or triple bond, with the proviso that none of bi, b 2 and b 3 are a triple bond and only one of b-i, b 2 and b 3 and only one of b 4 and b 5 may be a double bond, and with the proviso, that when R 1 is -OH and R 3 is -H, then R 6 of compounds of formula I is not C 7 alkenyl.
  • Another aspect of the invention is a compound of formulae III or IV.
  • preferred compounds to be used with the methods according to the present invention are also PPAR agonists, PPAR antagonist, or PPAR partial agonists, preferably PPAR partial agonists.
  • Methods for determining functionalities as PPAR agonist/antagonist/partial agonist are described herein be- low in the section "Functionalities of compounds" and "Clinical Conditions.”
  • the compounds are useful for treating the following diseases or conditions: anorexia, obesity (i.e., decreasing body weight, insulin resistance, diabetes (along with obesity)), a chronic inflammatory disorder mediated by PPARgamma, inflammatory bowel disease, ulcerative colitis or Crohn's disease, arthritis, notably rheumatoid arthritis, polyarthritis and asthma, atherosclerosis, a skin disorder (notably psoriasis), hyperlypidemia, a cancer responsive to activation of PP ⁇ Rgamma or the cancer expresses functional PPARgamma (e.g., the
  • X is O, C n H 2n , NH or S, wherein n is 1 , 2, 3 or 4, for example X may be C n H 2n and n is 1, 2, 3 or 4;
  • R 1 is H, OH, halogen, CH 3 , CH 2 OH, N 3, CH 2 N 3 , NH 2 , SH, OPO 3 H, lower alkyl or alkenyl, lower alcohol or 0-lower alkyl or alkenyl; preferably R 1 is -H;
  • R 3 is -H, -OH, halogen or -CH 3 , preferably R 3 is -H;
  • R 5 is lower alkyl or alkenyl; lower alcohol, saturated or unsaturated; or Y — R 2 , wherein Y is a single bond or a C 1 -C 10, preferably a C 6 -C 10 carbon chain, optionally substituted (for example with -OH and/or halogen) and/or optionally containing up to three double or triple bonds or a mixture of double and triple bonds up to a maximum of three;
  • R 2 is C 1 -C 10 alkyl OH, C 1 -C 10 alkyl-halide, C 1 -C 10 alkyl N 3 , C 1 -C 10 alkyl -NH 2 or COOR 4 or CONHR 4 , wherein R 4 is H, C 5 or C 6 cycloalkyl, C 5 -C 6 aryl or C 1 -C 10 alkyl or alkenyl optionally substituted with COOH, C5-C6 aryl, a heteroaromatic ring or a sugar moiety, preferably
  • R 6 is a C 4 -C 15 carbon chain optionally substituted with one or more halides Or -O-R 10 , wherein R 10 is -H, lower alkyl, alkenyl, phenyl or substituted phenyl and/or optionally containing up to three double or triple bonds or a mixture of double and triple bonds up to a maximum of three; and
  • R 7 is -H or -OH or is oxo together with R 10 ;
  • R 8 is -H, -OH, or -CH 3 or together with R 9 forms an oxo group provided that R 7 and R 10 do not form oxo, and R g is otherwise H, OH or CH 3 ; preferably at least one of R 7 and R 8 is -OH or, together with Ri 0 and R 9 respectively is, oxo,
  • X is O, C n H 2n , NH or S, wherein n is 1 , 2, 3 or 4, for example X is C n H 2n , wherein n is 1 , 2, 3 or 4;
  • Ri is H, halogen or OH, preferably -H
  • R 3 is H, halogen or OH, preferably -H
  • R 5 is Y — R 2 , wherein Y is a single bond or a C 1 -C 10 carbon chain, preferably a C 6 to C 10 carbon chain, optionally substituted with OH and/or halogen and/or optionally containing up to three double bonds;
  • R 2 is COOR 4 , wherein R 4 is H or C 1 -C 10 alkyl and R 6 is a C 4 -C 10 carbon chain optionally substituted with -OH and/or halogen, preferably R 4 is methyl or -H; wherein R 5 optionally contains up to three double bonds; and indicates a single or double bond, preferably a single bond with the proviso, that when R-i is -OH and R 3 is -H, then R 6 is not C 7 alkenyl.
  • the specific compound may be any of the compounds described herein above in the section "Compounds of formulae I and II", with the proviso, that when R 1 is -OH and R 3 is -H, then R 6 of compounds of formula I is not C 7 alkenyl.
  • the specific compound may be any of the compounds described herein above in the section "Compounds of formulae I and II", with the proviso, that when R 1 is -OH and R 3 is -H, then R 6 of compounds of formula I or Il is not C 7 alkenyl.
  • the specific compound may be any of the compounds of formula III, IV, V or Vl mentioned herein above in the section "Compounds of formulae I or II", with the proviso that when Ri is -OH and R 3 is -H, then R 6 is not C 7 alkenyl.
  • R 6 is not C 7 alkenyl, more preferred that when R 1 is -OH and R 3 is -H, then R 6 is C 8 to C 15 (preferably alkyl or alkenyl optionally substituted), even more preferred, when Ri is -OH and R 3 is -H, then R 6 is C 4 to C 6 (preferably alkyl or alkenyl optionally substituted).
  • aforementioned proviso only applies to compounds of formula U 1 Ui 1 III, IV, V, or Vl mentioned herein above in the section "Compounds of formulae I or II” or to compounds of formula U, Ui, III and IV mentioned above in this section.
  • R 5 is -C m H 2m COOR 4 , wherein m is O - 7.
  • R 5 is -C m H 2m CONHR 4 , wherein m is O - 7.
  • the compound is a compound of formula I, II, III or IV, preferably of formula III, wherein [X is CH 2 or O] or [R 7 or R 8 is -OH]; and/or R 1 is -H; and/or R 3 is -H; and/or R 5 is (CH 2 )n-COOH or (CHz) n -COOCH 3 , preferably (CH 2 ) ⁇ -COOH, wherein n is O to 10, preferably n is 0; and/or
  • R 6 is Cio to Ci5 alkyl or alkenyl, preferably C 13 alkenyl, more preferably the compound is (+/-)5,6-epoxyeicosa-8Z, 11Z, 14Z-trienoic acid.
  • the compound is a compound of formula I, II, III or IV, preferably of formula IV, wherein
  • R 5 is (CH 2 ) n -COOH or (CH 2 ) n -COOCH 3 , preferably (CH 2 ) n -COOH wherein n is O to 10, preferably n is 3; and/or
  • R 6 is C 8 to C 12 alkyl or alkenyl, preferably Ci 0 alkenyl, more preferably the compound is (+/-)8,9-epoxyeicosa-5Z, 11Z, 14Z-trienoic acid.
  • the compound is a compound of formula I, II, III or IV, preferably of formula IV, wherein
  • R 6 is C 5 to C 9 alkyl or alkenyl, preferably C 7 alkenyl, more preferably the compound is (+/-)11 ,12-epoxyeicosa-5Z, 8Z, 14Z-trienoic acid.
  • the compound is a compound of formula I, II, III or IV, preferably of formula IV, wherein [X is CH 2 or O] or [R 7 or R 8 is -OH]; and/or R 1 is -H; and/or R 3 is -H; and/or
  • R 6 is C 2 to C 6 alkyl or alkenyl, preferably C 4 alkyl, more preferably the compound is (+/-)14,15-epoxyeicosa-5Z, 8Z, 11Z-trienoic acid.
  • the compound is a compound of formula I, II, III or IV, preferably of formula IV, wherein
  • [X is CH 2 or O] or [R 7 or R 8 is -OH]; and/or R 1 is -H; and/or R 3 is -H; and/or R 5 is (CH 2 ) n -COOCH 3 wherein n is 1 to 5, preferably n is 3; and/or R 6 is C 8 to C 12 alkyl or alkenyl, preferably C 10 alkenyl, more preferably the compound is (+/-)8,9-epoxy-5Z, 11Z, 14Z-eicosatrienoic acid, methyl ester (Available from Cayman Chemical).
  • the compound is a compound of formula I, II, III or IV, preferably of formula IV, wherein
  • [X is CH 2 or O] or [R 7 or R 8 is -OH]; and/or R 1 is -H; and/or R 3 is -H; and/or R 5 is (CH 2 ) n -COOH or (CH 2 ) n -COOCH 3 , preferably (CH 2 ) n -COOH, wherein n is 1 to 5, preferably n is 3; and/or
  • R 6 is C 5 to Cg alkyl or alkenyl, preferably C 7 alkenyl, more preferably the compound is (+/-)9,10-epoxy-12Z-octadecenoic acid, available from Cayman Chemical).
  • the compound is a compound of formula I 1 II, III or IV, preferably of formula II. ii, wherein
  • [X is CH 2 or O] or [R 7 or R 8 is -OH, preferably R 8 is -OH]; and/or Ri is -H; and/or R 3 is -H; and/or
  • R 5 is (CHa) n -COOH or (CHa) n -COOCH 3 , preferably (CH 2 ) n -COOH, wherein n is 1 to 5, preferably n is 3; and/or
  • R 6 is C 8 to Ci 2 alkyl or alkenyl, preferably C 10 alkenyl more preferably the compound is 8(S)-hydroxyeicosa-5Z, 9E, 11Z, 14Z-tetraenoic acid.
  • the compound is a compound of formula I, II, III or IV, preferably of formula II. ii, wherein
  • [X is CH 2 or O] or [R 7 and/or R 8 is -OH, preferably R 7 and R 8 is -OH]; and/or R 1 is -H; and/or R 3 is -H; and/or
  • R 5 is (CH 2 )n-COOH or (CH 2 ) n -COOCH 3 , preferably (CH 2 ) n -COOH, wherein n is 1 to 5, preferably n is 3; and/or
  • R 6 is C 8 to C 12 alkyl or alkenyl, preferably C 10 alkenyl, more preferably the compound is (+/-)8,9-dihydroxy-5Z, 11Z, 14Z-eicosatrienoic acid, available from Cayman Chemical).
  • the compound is a compound of formula I, II, III or IV, preferably of formula II. i, wherein [X is CH 2 or O] or [R 7 or R 8 is -OH, preferably R 8 is -OH]; and/or R 1 is -H; and/or R 3 is -H; and/or
  • R 5 is (CH 2 ) n -COOH or (CH 2 ) n -COOCH 3 , preferably (CH 2 ) n -COOH, wherein n is 1 to 5, preferably n is 3; and/or R 6 is C 10 to Ci 4 alkyl or alkenyl, preferably C 12 alkenyl more preferably the compound is (+/-)8- hydroxy-4Z, 6E, 1OZ, 13Z, 16Z, 19Z- docosahexaenoic acid, available from Cayman Chemical).
  • the compound is a compound of formula I, II, III or IV, preferably of formula II. ii, wherein
  • R 6 is C 5 to C 9 alkyl or alkenyl, preferably C 7 alkenyl, more preferably the compound is (+/-)11-hydroxy-5Z, 8Z, 12E, 14Z, 17Z-eicosapentaenoic acid, available from Cayman Chemical).
  • the compound is a compound of formula I, II, III or IV, preferably of formula II. ii, wherein
  • [X is CH 2 or O] or [R 7 or R 8 is -OH, preferably R 8 is -OH]; and/or R 1 is -H; and/or R 3 is -H; and/or
  • R 5 is (CH 2 ) n -COOH or (CH 2 ) n -COOCH 3 , preferably (CH 2 ) n -COOH, wherein n is 4 to 8, preferably n is 6; and/or
  • R 6 is C 5 to C 9 alkyl or alkenyl, preferably C 7 alkenyl, more preferably the compound is (+/-)11-hydroxy-12E, 14Z-eicosadienoic acid, available from Cayman Chemical).
  • the compound is a compound of formula I, II, III or IV, preferably of formula IV, wherein [X is CH 2 or O] or [R 7 or R 8 is -OH]; and/or R 1 is -OH; and/or R 3 is -H; and/or
  • R 6 is C 2 to C 6 alkyl or alkenyl, preferably C 4 alkyl, more preferably the compound is methyl-13-hydroxy-14S,15S-epoxy-5Z, 8Z, 11Z- eicosatrienoate (available from Larodan, Sweden).
  • the compound is a compound of formula I 1 II, III or IV, preferably of formula III, wherein
  • R 6 is C 2 to C 6 alkyl or alkenyl, preferably C 4 alkyl, more preferably the compound is methyl-11(R,S)-hydroxy-14S,15S-epoxy-5Z,8Z,12E- eicosatrienoate (available from Larodan, Sweden).
  • the compound is a compound of formula I 1 II, III or IV, preferably of formula IU 1 wherein
  • [X is CH 2 or O] or [R 7 or R 8 is carbonyl, preferably R 8 is carbonyl]; and/or R 1 is -OH; and/or R 3 is -H; and/or
  • R 5 is (CHs) n -COOH or (CH 2 ) n -COOCH 3 , preferably (CH 2 ) n -COOH , wherein n is 5 to 9, preferably n is 7; and/or
  • R 6 is C 2 to C 6 alkyl or alkenyl, preferably C 4 alkyl, more preferably the compound is ⁇ -hydroxy- ⁇ -oxo-IOE-octadecenoic acid (available from Larodan, Sweden).
  • the compound is a compound of formula I, II, III or IV, preferably of formula IV, wherein
  • R 5 is (CH 2 ) n -COOCH 3 or (CH 2 VCOOH, preferably (CH 2 ) n -COOCH 3, wherein n is 3 to 7, preferably n is 5; and/or
  • R 6 is C 4 to C 8 alkyl or alkenyl, preferably C 6 alkyl, more preferably the compound is MethyI-10S,11S-epoxy-9S-hydroxy-12Z-octadecenoate or the threo isomer thereof (both available from Larodan, Sweden).
  • the compound is a compound of formula I, II, III or IV, preferably of formula III, wherein
  • [X is CH 2 or O] or [R 7 or R 8 is -OH]; and/or R 1 is -H; and/or R 3 is -OH; and/or R 5 is (CHs) n -COOCH 3 or (CH 2 ) n -COOH, preferably (CH 2 ) n -COOCH 3, wherein n is 4 to 8, preferably n is 6; and/or
  • R 6 is C 3 to C 7 alkyl or alkenyl, preferably C 5 alkyl, more preferably the compound is Methyl-11S,12S-epoxy-13S-hydroxy-9Z-octadecenoate or the threo isomer thereof (both available from Larodan, Sweden).
  • the compound is a compound of formula I, II, III or IV, preferably of formula III, wherein
  • [X is CH 2 or O] or [R 7 or R 8 is -OH]; and/or R 1 is -OH; and/or R 3 is -H; and/or R 5 is (CH 2 ) n -COOCH 3 or (CH 2 ) n -COOH, preferably (CH 2 ) n -COOCH 3i wherein n is 5 to 9, preferably n is 7; and/or
  • R 6 is C 2 to C 6 alkyl or alkenyl, preferably C 4 alkyl, more preferably the compound is Methyl-12R,13S-epoxy-9S-hydroxy-10E-octadecenoate (available from Larodan, Sweden).
  • the compound is a compound of formula I, II, III or IV, preferably of formula III, wherein
  • R 5 is (CH 2 ) n -COOCH 3 or (CH 2 ) n -COOH, preferably (CH 2 ) n -COOCH 3, wherein n is 2 to 6, preferably n is 4; and/or
  • R 6 is C 5 to C 9 alkyl or alkenyl substituted with -OH, preferably C 7 alkyl substituted with -OH, more preferably the compound is Methyl-9S,10R-epoxy-13S-hydroxy-11 E-octadecenoate (available from Larodan, Sweden).
  • the compound is a compound of formula I, II, III or IV, preferably of formula II, wherein [X is CH 2 or O] or [R 7 or R 8 is carbonyl, preferably R 8 is carbonyl]; and/or R 1 is -H; and/or R 3 is -H; and/or
  • R 5 is (CH 2 ) n -COOH or (CH 2 ) n -COOCH 3 , preferably (CH 2 ) n -COOH wherein n is 2 to 6, preferably n is 4; and/or - R 6 is C 5 to C 9 alkyl or alkenyl, preferably C 7 alkenyl, more preferably the compound is ⁇ -oxo-IOE. ⁇ Z.I ⁇ Z-octadecatrienoic acid (available from Larodan, Sweden).
  • the compound is a compound of formula I, II, III or IV, preferably of formula II. i, wherein [X is CH 2 or O] or [R 7 or R 8 is carbonyl, preferably R 8 is carbonyl]; and/or R 1 is -OH; and/or R 3 is -H; and/or
  • R 5 is (CH 2 )n-COOH or (CH 2 )n-COOCH 3 , preferably (CH 2 ) n -COOH wherein n is 5 to 9, pref- erably n is 7; and/or
  • R 6 is C 2 to C 6 alkyl or alkenyl, preferably C 4 alkenyl, more preferably the compound is 9-hydroxy-12-oxo-10E,15Z-octadecadienoic acid (available from Larodan, Sweden).
  • the compound is a compound of formula I 1 II, III or IV, preferably of formula IV, wherein
  • [X is CH 2 or O] or [R 7 or R 8 is -OH]; and/or R 1 is -OH; and/or R 3 is -H; and/or R 5 is (CH 2 ) n -COOCH 3 or (CH 2 ) n -COOH, preferably (CH 2 ) n -COOCH 3, wherein n is 3 to 7, preferably n is 5; and/or
  • R 6 is C 4 to C 8 alkyl or alkenyl, preferably C 6 alkenyl, more preferably the compound is Methyl-10S,11S-epoxy-9S-hydroxy-12Z,15Z- octadecadienoate or the threo isomer thereof.
  • the compound is a compound of formula I, II, III or IV, preferably of formula III, wherein
  • R 5 is (CH 2 ) n -COOCH 3 or (CH 2 ) n -COOH, preferably (CH 2 ) n -COOCH 3, wherein n is 4 to 8, preferably n is 6; and/or
  • R 6 is C 3 to C 7 alkyl or alkenyl, preferably C 5 alkenyl, more preferably the compound is Methyl-11S,12S-epoxy-13S-hydroxy-9Z,15Z- octadecadienoate or the threo isomer thereof.
  • the compound is a compound of formula I, II, III or IV, preferably of formula III, wherein
  • R 5 is (CH 2 VCOOCH 3 or (CH 2 ) n -COOH, preferably (CH 2 ) n -COOCH 3, wherein n is 5 to 9, preferably n is 7; and/or
  • R 6 is C 2 to C 6 alkyl or alkenyl, preferably C 4 alkenyl, more preferably the compound is MethyI-12R,13S-epoxy-9S-hydroxy-10E,15Z- octadecadienoate.
  • the compound is a compound of formula I, II, III or IV, preferably of formula III, wherein [X is CH 2 or O] or [R 7 or R 8 is -OH]; and/or Ri is -H; and/or R 3 is -H; and/or
  • R 5 is (CH 2 ) n -COOCH 3 or (CH 2 ) n -COOH, preferably (CH 2 ) n -COOCH 3 ⁇ wherein n is 2 to 6, preferably n is 4; and/or R 6 is C 5 to C 9 alkyl or alkenyl substituted with -OH, preferably C 7 alkenyl substituted with OH, more preferably the compound is Methyl-9S,10R-epoxy-13S-hydroxy-11E,15Z- octadecadienoate.
  • the compound is a compound of formula I, II, III or IV, preferably of formula II. i, wherein
  • [X is -CH 2 ] or [R 8 and R 9 are methyl]; and/or Ri is -H; and/or R 3 is -H; and/or R 5 is (CH 2 ) n -COOH or (CH 2 )n-COOCH 3 , preferably (CH 2 ) n -COOH, wherein n is 1 to 4, preferably n is 2; and/or
  • R 6 is C 9 to Ci3 alkyl or alkenyl, preferably Cu alkyl, more preferably the compound is 7,7-dimethyl-(5Z,8Z)-eicosadienoic acid (available from Sigma Aldrich).
  • the compound is a compound of formula I, II, III or IV, preferably of formula II. ii, wherein
  • [X is CH 2 or O] or [R 7 and R 8 is -H, thereby forming a double bond; and/or R 1 is -H; and/or R 3 is -H; and/or
  • the compound is a compound of formula I 1 II, III or IV, preferably of formula II. ii, wherein
  • [X is CH 2 or O] or [R 7 and R 8 is -H]; and/or R 1 is -H; and/or R 3 is -H; and/or
  • R 6 is C 5 to C 9 alkyl or alkenyl, preferably C 7 alkenyl, more preferably the compound is N-Arachidonoyl- ⁇ -Aminobutyric acid (available from Cayman Chemical, United States).
  • the compound is a compound of formula I, II, III or IV, preferably of formula II. ii, wherein
  • [X is CH 2 or O] or [R 7 and R 8 is -H]; and/or R 1 is -H; and/or R 3 is -H; and/or
  • eroaromatic ring has the structure ;
  • R 6 is C 5 to C 9 alkyl or alkenyl, preferably C 7 alkenyl, more preferably the compound is N-(3-furanylmethyl)-5Z, 8Z, 11 Z, 14Z- eicosatetraenamide, available from Cayman Chemical, United States).
  • preferred compounds to be used with the methods according to the present invention are also PPAR agonists, PPAR antagonists, or PPAR partial agonists, preferably PPAR partial agonists.
  • Methods for determining functionalities as PPAR agonist/antagonist/partial agonist are described herein below in the section "Functionalities of compounds"
  • the compounds are similar in structure to hepoxilin A3.
  • the compounds are of the formula l.i or II. i
  • X is O, C n H 2n , NH or S, wherein n is 1, 2, 3 or 4; preferably X is O or C n H 2n , more preferably C n H 2n wherein n is 1 , 2, 3 or 4, preferably n is 1 , 3 or 4, more preferably n is 1 ;
  • R 1 is H, OH, halogen, CH 3 , CH 2 OH, N 3 , CH 2 N 3, NH 2 , SH, OPO 3 H, lower alkyl or alkenyl, lower alcohol or O-lower alkyl or alkenyl; preferably R 1 is -OH.
  • R 3 is H, OH or CH 3 ; preferably R 3 is -H or -OH;
  • R 5 is lower alkyl or alkenyl; lower alcohol, saturated or unsaturated; or
  • Y is a single bond or a Ci-C 10 carbon chain optionally substituted with -OH and/or halogen and/or optionally containing up to three double or triple bonds or a mixture of double and triple bonds up to a maximum of three;
  • R 2 is C 1 -C 10 alkyl OH, C 1 -C 10 alkyl-halide, C 1 -C 10 alkyl N 3 , C 1 -C 10 alkyl -NH 2 , CNHR 4 or COOR 4 or CONHR 4 ; preferably R 2 is COOR 4 or CONHR 4 ,
  • R 4 is H, C 5 or C 6 cycloalkyl, C 5 -C 6 aryl, a sugar moiety or C 1 -C 10 alkyl or alkenyl optionally substituted with COOH, C 5 -C 6 aryl, a heteroaromatic ring or a sugar moiety; preferably R 4 is -CH 3 , -H or alkyl substituted with COOH or a heteroaromatic ring,
  • R 6 is a C 4 -C 15 carbon chain optionally substituted with one or more halides or -0-R 10 , wherein R 10 is H, lower alkyl, alkenyl, phenyl or substituted phenyl, preferably R 6 is an un- substituted C 4 to C 15 carbon chain; wherein R 6 optionally contains up to three double or triple bonds or a mixture of double and triple bonds up to a maximum of three; and R 7 is -H, -OH or carbonyl;
  • R 8 is -H, -OH or -CH 3 or together with R 9 forms a carbonyl group provided that R 7 is not carbonyl, preferably -OH or forming a carbonyl; and R 9 is otherwise -H or -CH 3 ;
  • R 7 and R 8 is not -H, more preferably at least one of R 7 and R 8 is -OH or oxo. Accordingly, if R 7 is -H, then preferably R 8 is -OH. oxo or CH 3, more preferably -OH or oxo, even more preferably -OH. Similarly, if R 8 is -H, then R 7 is prefera- bly -OH or oxo. If R 7 is -OH, then R 8 preferably is -H or -OH.
  • very preferred compounds are hepoxilin A3 and 8(S/R)-hydroxy-11 ,12-cyclopropyl-eicosa-5Z,10E,14Z,trienoic acid and derivatives thereof, more preferred hepoxilin A3 and 8(S/R)-hydroxy-11 ,12-cyclopropyl-eicosa- 5Z,10E,14Z,trienoic acid, yet more preferred hepoxilin A3, as well as other cycloalkyl analogs.
  • Hepoxilin B3 is also useful.
  • preferred Hepoxilin A3 analogues according to the present invention are also partial PPAR agonists, in particular it is preferred that said compounds are capable of activating PPAR transactivation, and at the same time have reduced adipocyte differentiation inducing potential. Methods for determining said functionalities as well as preferred functionalities are described herein below in the section "Functionalities of compounds”.
  • Table 1 refers to compounds of formula
  • Table 2 refers to compounds of formula IV.
  • Table 3 refers to compounds of formula IU.
  • Table 4 refers to compounds of formula IMi.
  • Table 5 refers to compounds of formula B.
  • each of the free carboxylic acids that are set forth in Tables 1-5 can be converted to the corresponding ester or amide derivative.
  • the sugar moiety that can be used for esterification can either be a monosaccharide, a disac- charide or a polysaccharide.
  • Suitable monosaccharides include pentose, hexose, or a heptose residues.
  • pentoses include arabinose, ribose, ribulose, xylose, lyxose, and xylulose.
  • hexoses include glucose, galac- tose, fructose, fucose, mannose, allose, altrose, talose, idose, psicose, sorbose, and taga- tose.
  • heptoses include mannoheptulose and sedoheptulose.
  • the sugar moiety may be linked to the compound at any position of the sugar ring which can form an ester bond.
  • Preferred saccharides are beta-glycosyl saccharides.
  • the amides can be prepared by reacting with methyl amine, ethyl amine, propyl amine, aniline, and amino acids. Also, the hydroxyl group in some of these compounds can be converted to the corresponding halide using one of the several halogenating agents such as halogen acids, thionyl chloride, and the like.
  • the halide can in turn be converted to the corresponding azide via nucleophilic substitution with a reagent such as sodium azide and the azide can then be reduced to an amine using reagents such as sodium borohydride, triphenyl phosphine and the like.
  • a reagent such as sodium azide
  • the azide can then be reduced to an amine using reagents such as sodium borohydride, triphenyl phosphine and the like.
  • the hydroxyl group in some of these compounds can be glycosylated using a sugar moiety such as a monosaccharide, a disaccharide or a polysaccharide. Suitable monosaccharides include pentose, hexose, or a heptose residues.
  • Non-limiting examples of pentoses include arabinose, ribose, ribulose, xylose, lyxose, and xylulose.
  • Non-limiting examples of hexoses include glucose, galactose, fructose, fucose, mannose, allose, altrose, talose, idose, psicose, sorbose, and tagatose.
  • Non-limiting examples of heptoses include mannoheptulose and sedoheptulose.
  • the sugar moiety may be linked to the compound at any position of the sugar ring which can form an ether bond.
  • Preferred saccharides are beta-glycosyl saccharides.
  • WO 94/22848 describes a synthetic scheme for preparing certain hepoxilin analogs (see pages 11-13 and Figs. 1 and 2 thereof, which are hereby incorporated by reference).
  • WO 02/38157 describes the synthesis of sugar amide and sugar ester hepoxilin analogs.
  • the hepoxilin analog methyl ester is synthesized as described in USPN 5,616,607, the contents of which are herein incorporated by reference.
  • methyl ester is hydrolysed to give the free acid by conventional methods, followed by the formation of hydroxy suc- cinimide ester, which is then converted to a sugar amide as described in WO02/38157. See also pages 14-15 of WO03/099285, which is hereby incorporated by reference.
  • the genes of the arachidonic acid pathway can be selected to produce precursor compounds.
  • Such genes are published at for exam- pie http://www.genome.jp/kegg/pathway/map/map01130.html or Shankaranarayanan et all, 2003, FEBS Letters, 107 or Reynaud et all, 1999, JBC, 274, 28213, and can be used to express desired precursors and compounds of formulae I or II, such as Arachidonic acid or the hepoxilin compounds.
  • PPAR ligands Compounds capable of modulating the activity of PPAR (herein also referred to as PPAR ligands) can be grouped into three distinct classes: Full agonists, partial agonists/partial antagonists, and full antagonists. Agonists and antagonists are characterized by their binding affinities, dictating potency/EC50/IC50 values, and by the level of activity, which is attained in the presence of saturating levels of the compounds, i.e. efficacy. A partial agonist/partial antagonist is also characterized by its binding affinity, and efficacy.
  • a partial agonist/partial antagonist is unable to fully activate the cognate PPAR and can in a com- petitive manner displace a full agonist from the receptor and thereby diminish the level of transactivation.
  • Full and partial agonists furthermore may recruit different complements of cofactors, and the nature of the cofactors recruited to a given PPAR subtype may profoundly influence the pattern of genes activated by a given agonist.
  • the ligand-binding pockets of the PPARs are large compared with other nuclear receptors, and this may in part explain the large variety of compounds that are able to bind to and activate the PPARs.
  • several natural and synthetic ligands exhibit a great degree of selectivity, and the most selective ligands today differ by more than 3 orders of magnitude with regard to the concentration needed to activate the individual PPAR subtypes.
  • SPPARMs selective PPAR modulators
  • Partial agonists or antagonists This class of ligand comprises partial agonists/antagonists that upon binding to the PPAR(s) introduce different conformations leading to recruitment of different sets of coactivators.
  • a SPPARM would be able to activate only a subset of PPAR target genes thereby possibly promoting specific expression of a desirable set of genes.
  • a model of PPAR activation by a full agonist and a partial agonist is given in Fig. , 1.
  • Preferred compounds according to the present invention are partial PPAR agonists.
  • PPAR modulating activity can be easily determined by any number of methods known in the art or adaptations thereof.
  • PPAR modulating activity may be determined by a transactivation assay.
  • a non-limiting example of a useful transactivation assay for determining PPARgamma modulating activity is described in example 1
  • a non-limiting example of a useful transactivation assay for determining PPARdelta modulating activity is described in example 2.
  • Example 1 below illustrates a method where compounds are added to cells transfected with a construct encoding a PPAR-GAL4 (DNA binding domain) fusion protein and a construct encoding a GAL4 dependent reporter construct.
  • any number of possible constructs can be used, such as using different DNA binding domains to activate transcription or different reporter genes (for example, fluorescent proteins, beta-galactosidase, peroxidase, luciferase, or the like). It will also be apparent to one of ordinary skill in the art that depending on which PPAR activity it is desirable to determine, the construct preferably encodes said PPAR or a ligand binding domain thereof. Upon activation of PPAR (i.e., in the pres- ence of a PPAR agonist or partial agonist), PPAR transactivates the reporter construct, optionally in a quantitative manner.
  • PPAR i.e., in the pres- ence of a PPAR agonist or partial agonist
  • PPAR modulators may also be identified using a reporter gene comprising a first nucleic acid operably under control of a second nucleic acid comprising at least one PPRE.
  • the first nucleic acid preferably encodes a reporter protein, such as a fluorescent protein, beta- galactosidase, peroxidase, luciferase, or the like.
  • Said reporter construct should be inserted into a cell expressing one or more PPARs, such as PPARgamma and/or delta.
  • PPAR agonists can thus be identified as compounds capable of activating transcription of the first nucleic acid.
  • the preferred compounds are PPAR and/or PPAR LBD agonists or partial agonists.
  • PPAR LBD refers to the ligand binding domain of PPAR.
  • the compounds and compositions of the present invention are PPARgamma and/or PPARgamma LBD agonists.
  • agonist is meant a compound or composition which when combined with an intracellular receptor stimulates or increases a reaction typical for the receptor, e.g., transcription activation activity.
  • said agonist is a PPARgamma agonist, i.e., a PPAR ligand which potentiates, stimulates, induces or otherwise enhances the transcriptional activity of a PPARgamma receptor, e.g., such as by mimicking a natural physiological ligand for the receptor.
  • Said PPAR modulating activity may be determined using the transactivation assays described herein above.
  • Suitable standard agonists include rosiglitazone for PPARgamma and (4-[3-(2-Propyl-3-hydroxy-4-acetyl)phenoxy]propyloxyphenoxy-acetic acid (U 65041 , commercially available) for PPARdelta.
  • Potential agonists that exhibit less than 50% trans- activation than a standard agonist may still be useful, in particular for the development of new compounds or active derivatives.
  • the compounds and compositions of the present invention are PPAR and/or PPAR LBD partial-agonists, and more particularly, the compounds and compositions of the present invention are PPARgamma and/or PPARgamma LBD partial-agonists.
  • a drug that produces less than the possible maximal effect i.e. the maximal effect produced by a full agonist, or reference molecule
  • a partial agonist A drug that produces less than the possible maximal effect (i.e. the maximal effect produced by a full agonist, or reference molecule) is called a partial agonist.
  • the partial agonist property of the compounds and compositions of the present invention can be defined by reference to rosiglitazone (AvandiaTM, Glaxo- SmithKline) which is a full agonist. This is in particular the case for PPARgamma partial agonists.
  • Potency and efficacy are two key features in analysing ligand agonist, including partial agonist, properties.
  • Potency is the relative biological or pharmacological activity of a dose of a compound compared with the dose of a different agent producing the same effect. Potency is the strength of that effect, as compared to "activity," which is the particular effect itself, in this case PPAR agonist effect. Potency can be calculated through dose response experiments in a given functional assay, e.g. a transactivation assay.
  • the dose of a compound (often measured in molar concentration) necessary to achieve 50% of the maximal effect in a particular assay is referred to as the EC50.
  • Efficacy refers to the ability of a compound to initiate a biological response and is defined by the maximum effect that can be achieved in a functional assay that assesses the tested compound's effect on the PPAR, and more particularly PPARgamma, for example in a transactivation assay. Without wishing to be bound by any particular theory, the applicants postulate that too high a level of efficacy can be associated with detrimental undesirable side effects.
  • the present invention relates to potent PPAR ligands, especially PPARgamma ligands, with reduced efficacy (compared to rosiglitazone, for example) which should result in safer drugs.
  • preferred compounds of the present invention are partial agonists in the sense that their maximal efficacy is less than about 80% of the maximal efficacy.
  • their maximal efficacy is within the range of 30 to 80%, such as within the range of 30 to 70%, for example within the range of 30 to
  • one such assay is a transactivation assay, such as the transactivation assay described in example 1.
  • the partial agonist property of the compounds and compositions of the present invention may also be defined by reference to L165041 (commercially available). This is in particular the case for PPARdelta partial agonists.
  • preferred compounds of the present invention are partial agonists in the sense that their maximal efficacy is less than about 80% of the maximal efficacy.
  • their maximal efficacy is comprised within the range of 30 to 80%, such as within the range of 30 to 70%, for example within the range of 30 to 60% of the L165041 maximal efficacy in one or more assays.
  • one such transactivation assay is the transactivation assay described in example 2.
  • the compounds of the invention are selective for activation of PPAR.
  • the compound does not significantly activate RxR and/or RxR LBD transactivation, preferably RxR transcription is less than 2 times background levels, such as less than 1.5 times background levels, for example approximately equal to or less than background level.
  • RxR transactivation may be determined by an RxR transactivation assay, for example as described in example 3. Background level is transactivation in the absence of an added ligand.
  • the compounds of the present invention have a potency comprised between 1 nanomolar (nM) and 2 micromolar ( ⁇ M), such as between 1 nM and 500 nM, for example between 250 nM and 750 nM, such as between 500 and 1 ⁇ M, for example between 750 nM and 1 ,25 ⁇ M, such as between 1 ⁇ M and 1.5 ⁇ M, for example between 1 ,25 ⁇ M and 1,75 ⁇ M, such as between 1.5 ⁇ M and 2 ⁇ M, for example between 100 nM and 1.5 ⁇ M, such as between 500 and 1 ⁇ M.
  • the compounds and compositions of the present invention are both PPAR and/or PPAR LBD partial agonists.
  • the compounds are PPAR antagonists.
  • antagonist is meant a compound, which when combined with PPAR interferes or decreases a reaction typical for said PPAR, e.g., transcription activation.
  • PPAR antagonist designates a PPAR ligand which can inhibit the activity of a corresponding PPAR agonist. More generally, these agonist/antagonist/partial agonist activities may be measured by assays widely known to one skilled in the art, such as, for example, those which are disclosed in WO99/50664 or WO96/41013.
  • the compounds and compositions of the invention are further characterized by their biological activities when administered to a patient having a condition or disease that is affected by modulation of PPAR activity.
  • Preferred compounds according to the present invention are compounds capable of lowering one or more of the following biological entities in a patient in need thereof: glucose, triglycerides, fatty acids, cholesterol, bile acid, and the like, with better or equivalent efficacy and potency, but with lower toxicity and/or occurrence of fewer undesirable side effects compared to known molecules in the art (e.g., thia- zolidinediones).
  • said compounds preferably lead to less induction of adipocyte differentiation and weight gain.
  • Such compounds may in particular be any of the compounds described in section C. herein above.
  • adipocyte differentiation uses beneficial methods for determining adipocyte differentiation to present beneficial activities towards insulin resistance (diminished effectiveness of insulin to lower plasma glucose levels) and/or adipogenesis. It has been shown that many compounds that activate PPARgamma (e.g. thiazolidinediones) further induce adipocyte differentiation (i.e., exhibit an adipogenic, or lipogenic, effect) and thus result in body weight increase in treated patients. Therefore, it is highly desirable that the next generation of such compounds show reduced activity and preferably are devoid of such activity.
  • PPARgamma e.g. thiazolidinediones
  • adipocyte differentiation i.e., exhibit an adipogenic, or lipogenic, effect
  • preferred compounds display at least about 50%, preferably at least about 60%, more preferably at least about 70%, and even more preferably at least 80%, of the rosiglitazone property regarding insulin resistance, which, for example, may be determined by determining glucose levels in patients suffering from insulin resistance. Ideally, it will be 100% or more.
  • preferred compounds display less than about 80%, preferably less than about 50%, more preferably less than about 40%, and even more preferably less than about 30%, of the rosiglitazone property towards adipocyte differentiation. Ideally this will be less than 20% of the rosiglitazone property towards adipocyte differentiation.
  • Adipocyte differenta- tion may, for example, be determined as described herein below in example 4.
  • the preferred compounds have both above-mentioned properties.
  • the compounds are capable of inducing PPAR activity as determined in a transactivation assay to an extent which is at least 50% that of rosiglitazone and display the above-mentioned property towards adipocyte differentiation.
  • the compounds may in particular be any of the compounds described in section C. herein above. However, also the other compounds of the invention described herein may be use- ful in this embodiment.
  • the in vivo occurrence of undesirable side effects such as haemodilution, oedema, adipocyte differentiation, or obesity may be predicted by determining the cofactor recruitment profile of said compounds, for example as described in EP1267171.
  • preferred compounds are compounds which are predicted to have low in vivo occurrence of undesirable side effects.
  • nuclear receptors such as PPARgamma
  • PPARgamma achieve trancriptional activation or repression by binding to cognate sequences in the promoter regions of target genes and by recruiting numerous cofactor complexes whose activities range from chromatin remodeling, histone and cofactor modification, to basic transcription machinery recruitment (Glass, & Rosenfeld, 2000, Genes Dev., 14, 121-141).
  • cofactors may to a large extent determine the specificity of the action of nuclear receptors and integrate their action in a network of stimuli whose proper orchestration leads to a specific cellular response.
  • the determination of the multiple partnerships in which each nuclear receptor is engaged, as a function of time and cell type will lead to a better understanding of the activity of nuclear receptors in transcriptional regulation.
  • PPAR partial agonists will in general have a particular coactivator recruitment profile, thus compounds with particular coactivator recruitment profiles are preferred.
  • the compounds and compositions of the present invention are furthermore characterized by a restricted cofactor(s) recruitment pattern.
  • said pattern results in distinct effects on the regulation of the transcriptional activity of said nuclear receptors allowing a very finely tuned regulation which results in the activation of specific metabolic processes as well as the elimination of unwanted side effects.
  • the compounds and compositions of the present invention are furthermore able to inhibit the interaction of PPAR receptor, more preferably PPAR receptor LBD with cofactor TIF2.
  • the compounds and compositions of the invention are additionally able to enhance the interaction of PPAR receptor, more preferably PPAR receptor LBD, with cofactor SRC-1.
  • PPAR receptor more preferably PPAR receptor LBD
  • cofactor SRC-1 cofactor SRC-1
  • said PPAR receptor is PPARgamma receptor.
  • the compounds of the invention when bound to PPARgamma will allow recruitment of SRC1 to the LBD with an EC50 which is at least one log greater than the one for TIF2, with at least 2 log being preferred.
  • preferred compounds due to their agonistic, particularly partial agonistic, or antagonistic property towards natural physiological ligands of the PPAR receptors, especially those of the PPARgamma receptor are capable of serving as pharmaceuticals for controlling the biological effects of PPAR mediated transcriptional control and the attendant physiological effects produced thereby. More specifically, they can modulate a cellular physiology to reduce an associated pathology or provide or enhance prophylaxis.
  • preferred compounds are compounds which are agonists (or preferably partial agonists) of more than one PPAR, for example of both PPARgamma and PPARdelta.
  • Such agonists may be identified by transactivation assays for PPARgamma and PPARdelta, respectively, for example as described herein.
  • Non- limiting useful methods for determining PPARgamma and PPARdelta activity are described herein below in examples 1 and 2, respectively.
  • Clinical conditions The present invention relates to methods of treatment of clinical conditions comprising administration of above-mentioned compounds, as well as to uses of said compounds for preparation of a medicament for treatment of a clinical condition.
  • Modulators of PPAR activity may be employed in weight control.
  • the clinical condition may in one embodiment be an eating disorder such as anorexia nervosa (also abbreviated “anorexia” herein) or bulimia.
  • the "compounds of formulae I or II" disclosed herein above may also be employed in methods for increasing or decreasing body weight, in particular for decreasing body weight.
  • the clinical condition may thus be obesity.
  • Adiposity is an excessive build-up of fatty tissue. Recent investigations have shown that PPAR in particular PPARgamma plays a central role in gene expression and differentiation of adipocytes.
  • PPARgamma subtypes are involved in the activation of adipocyte differentiation, but play a less important role in the stimulation of peroxisome proliferation in the liver.
  • Activation of PPARgamma typically contributes to adipocyte differentiation by activating the adipocyte-specific gene expression (Lehmann, Moore, Smith-Oliver, Wilkison, Willson, Kliewer, J. Biol. Chem., 270:12953-12956, 1995).
  • a PPAR agonist can be used to gain fatty tissue.
  • PPAR partial agonists may be selected for properties useful in treating excessive build-up of fatty tissue.
  • the invention relates to methods for treating insulin resistance by administering any of the compounds described in the section "Compounds of formulae I or II" herein above to an individual in need thereof.
  • the invention also relates to use of any of said compounds for preparation of a medicament for the treatment of insulin resistance.
  • the invention relates to methods for increasing insulin sensitivity by administration of said compounds, as well as to use of said compounds for the preparation of a medicament for increasing insulin sensitivity.
  • Acute and transient disorders in insulin sensitivity such as those that may occur following trauma, surgery, or myocardial infarc- tion, may be treated as taught herein.
  • Insulin resistance is involved in a number of clinical conditions. Insulin resistance is manifested by the diminished ability of insulin to exert its biological action across a broad range of concentrations. During early stages of insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect. Even though blood insulin levels are chronically high, the impaired metabolic response of active muscle cells to insulin make them unable to take up glucose effectively. It is now increasingly being recognized that insulin resistance and resulting hyperinsulinemia may contribute to several clinical conditions, for example to the metabolic syndrome (also designated syndrome X). The metabolic syndrome is characterized by a first insulin-resistant stage which causes hyperinsulinemia, dyslipidemia and reduced glucose tolerance. Patients with the metabolic syndrome have been shown to be at an increased risk of developing cardiovascular disease and/or type Il diabetes. A patient is said to suffer from the metabolic syndrome when at least three of the following criteria applies:
  • the clinical condition according to the present invention may be hyperlipidemia, such as familial hyperlipidemia.
  • hyperlipidemia is characterised by hypercholesterolemia and/or hypertriglyceridemia.
  • the clinical condition may also include dyslipidemia and diabetic dyslipidemia.
  • the compounds included herein may also be utilized to lower serum triglyceride levels or raise the plasma level of HDL.
  • the clinical condition may also be atherosclerosis or atherosclerotic disorders.
  • PPAR agonists may have direct atheroprotective actions (Frick, M. H. et al., 1997, Circulation 96:2137-2143, de Faire et al., 1997, Cardiovasc. Drugs Ther. 11 Suppl. 1 :257-63).
  • Atherosclerotic disorders include vascular disorders, coronary heart disease, cerebrovascular disorders, and disorders of the peripheral vessels.
  • Coronary heart disease includes, myocardial infarction and coronary revascularization.
  • Cerebrovascular diseases include ischemic and hemorrhagic infarcts and transient ischemic attacks.
  • ischemia reperfusion injury including stroke
  • arteriosclerosis arteriosclerosis
  • heart failure and coagulopathy.
  • the clinical condition is an inflammatory disorder mediated by PPARgamma.
  • PPARgamma By the term "mediated by PPARgamma,” it should be understood that PPARgamma plays a role in the manifestation of the condition. For example, PPARgamma is considered not to play a role in inflammation associated with neutrophil activation, such as acute inflammations.
  • agonists of PPARgamma may be effective anti-inflammatory drugs by directly associating with and inhibiting NF ⁇ B-mediated transcription and thus modulating various inflammatory reactions, such as, for example, the enzyme paths of inducible nitrous oxide synthase (NOS) and cyclooxygenase-2 (COX-2) (Pineda-Torra, I. et al., 1999, Curr. Opinion in Lipidology, 10, 151-9).
  • NOS inducible nitrous oxide synthase
  • COX-2 cyclooxygenase-2
  • the chronic inflammatory disorder may for example be inflammatory bowel disease, ulcerative colitis, or Crohn's disease.
  • the chronic inflammatory disorder may also be arthritis, notably rheumatoid arthritis and polyarthritis.
  • the chronic inflammatory disorder could also be an inflammatory skin disease, notably acne vulgaris, atopic dermatitis, cutaneous disorders with barrier dysfunction, cutaneous effects of aging or psoriasis, in particular psoriasis.
  • the chronic inflammatory disorder may also be an inflammatory neurodegenerative disease, such as multiple sclerosis or Alzheimer's disease.
  • the clinical condition may also be gastrointestinal diseases and renal diseases, including glomerulonephritis, glomeruloscle- rosis, nephritic syndrome, and hypertensive nephrosclerosis.
  • the clinical condition is a cancer responsive to activation of PPARgamma.
  • the clinical condition may for example be a disorder characterized by aberrant cell growth of PPAR-responsive cells such as hyperplastic or neoplastic disorders arising in adipose tissue, such as adipose cell tumors, e. g. , lipomas, fibrolipo- mas, lipoblastomas, lipomatosis, hibernomas, hemangiomas, and/or liposarcomas.
  • certain cancers of prostate, stomach, lung and pancreas have been demonstrated to be responsive to treatment with PPARgamma agonists.
  • cancers of a given type may not be responsive.
  • loss-of- function mutations of PPARgamma frequently occur in cancer and such cancers will in general not be responsive.
  • the cancer expresses functional PPARgamma.
  • the clinical condition may also be an infection, such as a viral infection, notably AIDS or infection by HIV or infection by the hepatitis C virus.
  • a viral infection notably AIDS or infection by HIV or infection by the hepatitis C virus.
  • the PPAR ligands of the invention may be useful for improving cognitive functions in neurologic diseases or in dementia or for treating polycystic ovarian syndrome or for preventing and treating bone loss, e.g., osteoporosis.
  • the clinical condition may also be a liver disease, notably infection by the hepatitis C virus, or fatty liver, liver inflammation, liver lesions, liver cirrhosis, or post-hepatic cancer, whether or not associated with a hepatitis C virus infection, but preferably responsive to PPAR modulation.
  • a liver disease notably infection by the hepatitis C virus, or fatty liver, liver inflammation, liver lesions, liver cirrhosis, or post-hepatic cancer, whether or not associated with a hepatitis C virus infection, but preferably responsive to PPAR modulation.
  • PPARdelta has been associated with lipid metabolism disorders and wound heal- ing, in particular epidermal wound healing (Soon Tan et all, 2004, Expert Opinion in Molecular Targets, 39).
  • the clinical condition may also be wound healing, including epidermal wound healing.
  • Insulin sensitizers e.g., glitazones
  • Glitazones thiazolidinediones or TZDs
  • TZDs thiazolidinediones
  • Treatments with said agents have been tested in several animal models of diabetes and resulted in complete correction of the elevated plasma levels of glucose, triglycerides, and nonesteri- fied free fatty acids without any occurrence of hypoglycemic reactions (Cheng Lai and Le- vine, 2000, Heart Dis., 2,326-333).
  • thiazolidinediones examples include rosiglitazone, pioglitazone and troglitazone.
  • these compounds suffer from numerous serious undesirable side effects including hemodilution (including oedema), liver toxicity, body weight increase (including body fat increase from increased adipocyte differentiation, plasma volume increase, and cardiac hypertrophy), modest but significant LDL-cholesterol increase and anaemia (for a review, see Lebovitz, 2002, Diabetes Metab. Res. Rev, 18, Suppl 2, S23-9).
  • a number of available treat- ments for diabetes are associated with weight gain, a problem of high significance for the long-term management of the disease.
  • there is much need for alternative, more effective therapeutic agents that can be used in the management of obesity, diabetes and the commonly associated disorders such as cardiovascular and hepatic disease.
  • the invention relates to simultaneous treatment and/or prevention of obesity and diabetes by administering the compounds of the invention to an individual: i. suffering from obesity and diabetes, or ii. at risk of acquiring diabetes, and of getting obese, or iii. suffering from obesity and at risk of acquiring diabetes, or iv. suffering from diabetes and at risk of getting obese.
  • the invention also relates to use of the compounds of the invention for preparation of a medicament for the simultaneous treatment and/or prevention of obesity and diabetes.
  • the compounds may be any of the compounds described hereinabove in the section "Compounds of formulae I or II," however, preferably, the compound is one of the compounds described herein above in the section "Hepoxilin A3 analogues", such as hepoxilin A3 or its cycloalkyl analog.
  • diabetes is preferably diabetes type II.
  • Said individual at risk of acquiring diabetes may, for example, be an individual suffering from the metabolic syndrome described herein above.
  • Said individual at risk of getting obese may, for example, be an individual under medical treatment with an anti-diabetic compound having the side-effect of weight gain.
  • the invention relates to methods of treatment of a clinical condition by administering at least one of the specific compounds described in the section "Specific compounds of formulae I or II".
  • the invention also relates to use of any of the specific compounds described in the section "Specific compounds of formulae I or II" above for the preparation of a medicament for treatment or prevention of a clinical condition.
  • the clinical condition may be selected from the group consisting of the metabolic syndrome, dislipide- mia, obesity, diabetes mellitus, insulin resistance or any of the conditions related to insulin resistance described above, hypertension, cardiovascular disease, autoimmune diseases (such as asthmas, multiple sclerosis, psoriasis, topical dermatitis, and ulcerative colititis), cancer, inflammation, wound healing, lipid metabolism disorders, liver disease (such as infection by the hepatitis C virus, or fatty liver, liver inflammation, liver lesions, liver cirrhosis or post-hepatic cancer whether or not associated with a hepatitis C virus infection), gastrointestinal or renal disease (such as glomerulonephritis, glomerulosclerosis, nephritic syndrome, or hypertensive nephrosclerosis), infection (in particular viral infection), cognitive function disorders (such as neurologic disorders or dementia), polycystic ovarian syndrome, bone loss (such as osteoporosis) and AIDS .
  • autoimmune diseases such as
  • Cancer may be any cancer, for example any of the following: carcinomas, sarcomas, leu- kemias, and lymphomas; tumor angiogenesis and metastasis; skeletal dysplasia; hepatic disorders; and hematopoietic and/or myeloproliferative disorders.
  • Exemplary disorders include, but are not limited to, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell 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
  • the cancer is one of the above-mentioned cancers responsive to activation of PPARgamma.
  • Cardiovascular diseases may, for example, be atherogenesis, atherosclerosis or atherosclerotic disorders, vascular restinosis, cardiomyopathy, or myocardial fibrosis, or any of the cardiovascular diseases mentioned above.
  • the inflammation may be, for example, a chronic inflammation, preferably any of the chronic inflammations mentioned herein above.
  • Diabetes mellitus refers to a disease process derived from multiple causative factors and characterized by elevated levels of glucose in blood, or hyperglycemia. Uncontrolled hy- perglycemia is associated with increased and premature morbidity and mortality. At least two types of diabetes mellitus have been identified : (i) Type I diabetes, or Insulin Dependent Diabetes Mellitus (IDDM), which is the result of a complete lack of insulin, the hormone that regulates glucose utilization under normal physiological conditions, and (ii) the Type Il diabetes, or Non Insulin Dependent Diabetes Mellitus (NIDDM). NIDDM is a complex dis- ease derived from multiple causative factors, which can be addressed in some cases by increasing circulating insulin levels.
  • IDDM Insulin Dependent Diabetes Mellitus
  • compositions of the invention may be administered to a mammal in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compositions of the invention may be administered orally or parenterally, the latter route including intravenous and subcutaneous administration.
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • Forms for injectable use include sterile aqueous solutions or dispersion and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • a hepoxilin analog may be incorporated with excipient and used in the form in ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.
  • compositions containing one or more compounds of the present invention can also be administered in a solution or emulsion contained within phospholipid vesicles called liposomes.
  • the liposomes may be unilamellar or multilamellar and are formed of constituents selected from phosphatidylcholine, dipalmitoylphosphatidylcholine, cholesterol, phosphatidylethanolamtine, phosphatidylserine, dimyristoylphosphatidylcholine and combinations thereof.
  • the multilamellar liposomes comprise multilamellar vesicles of similar composition to unilamellar vesicles, but are prepared so as to result in a plurality of compartments in which the compounds in solution or emulsion is entrapped. Additionally, other adjuvants and modifiers may be included in the liposomal formulation such as polyethyleneglycol, or other materials.
  • the liposomes containing the hepoxilin or hepoxilin analog compositions may also have modifications such as having antibodies immobilized on the surface of the liposome in order to target their delivery.
  • the present invention is a pharmaceutical composition for administration to subjects in a biologically compatible form suitable for administration in vivo for treating one of the clinical conditions described above in the section "Clinical conditions," said method comprising a safe and effective amount of a compound alone, or in combination with other agents and/or pharmaceutical carriers.
  • the compounds of the invention may be used to treat insulin resistance and/or diabetes in combination with an agent effective against dislipidemia, such as a drug of the fibrate class, e.g., Bezafibrate.
  • Some other agents are insulin sensitizers, PPARy agonists, glitazones, troglitazone, pioglitazone, englitazone, MCC-555, BRL 49653, biguanides, metformin, phenformin, insulin, insulin minetics, sufonylureas, tolbutamide, glipizide, alpha-glucosidase inhibitors, acarbose, cholesterol lowering agent, HMG-CoA reductase inhibitors, lovastatin, simvastatin, pravastatin, fluvastatin, atrovastatin, rivastatin, other statins, sequestrates, cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran, nicotinyl alcohol, nicotinic acid: a nicotinic acid salt, PPARalpha agonists, fenofibric
  • composition may be administered to any living organism in need of such treatment including humans and animals as the composition has efficacy in vivo.
  • safe and effective as used herein, is meant providing sufficient potency in order to decrease, prevent, ameliorate, or treat the disease affecting the subject while avoiding serious side effects.
  • a safe and effective amount will vary depending on the age of the subject, the physical condition of the subject being treated, the severity of the disorder, the duration of treatment and the nature of any concurrent therapy, and its determination is within the skill of the ordinary physician.
  • the compositions are formulated and administered in the same general manner as described herein.
  • the compounds of the present invention may be used effectively alone or in combination with one or more additional active agents.
  • Combination therapy includes administration of a single pharmaceutical dosage composition, which contains a compound of the present invention and one or more additional active agents, as well as administration of a compound of the present invention and each active agent in its own separate pharmaceutical dosage.
  • a compound of the present invention and an insulin secretogogue such as sulfonylureas, thiazolidinediones, biguanides, meglitinides, insulin or ⁇ -glucosidose inhibitors can be administered to the patient together in a single oral dosage composition such as a capsule or tablet, or each agent administered in separate oral dosages.
  • a compound of the present invention and one or more additional active agents can be administered at essentially the same time, i.e., concurrently or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens.
  • a therapeutically active amount of a pharmaceutical composition of the present invention may also vary according to factors such as the disease state, age, sex, and weight of the subject and the ability of a compound, e.g., a hepoxilin or hepoxilin analog, to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. Hepoxilin analogs are known from previous studies to be non-toxic and well tolerated in mammals at doses of up to 40 mg/kg.
  • a dose of around 4mg/kg is likely a suitable initial dosage for a mammal and this dosage may be adjusted as required to provide a safe and effective amount.
  • the dosage will initially typically be 0.1 to 20 mg/kg, preferably 0.5 to 10mg/kg, more preferably 1 to 5mg/kg.
  • pharmaceutically acceptable carrier as used herein is meant one or more compatible solid or liquid delivery systems have innocuous physiological reactions when administered to a subject.
  • Some examples include but are not limited to starches, sugars, cellulose and its derivatives, powdered tragacanth, malt, gelatin, collagen, talc, stearic acids, magnesium stearate, calcium sulfate, vegetable oils, polyols, agar, alginic acids, pyrogen free water, isotonic saline, phosphate buffer, and other suitable non-toxic substances used in pharmaceutical formulations.
  • Other excipients such as wetting agents and lubricants, tableting agents, stabilizers, anti-oxidants, and preservatives are also contemplated.
  • compositions described herein can be prepared by known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of the compounds or analogs is combined in a mixture with a pharmaceutical acceptable carrier.
  • Suitable carriers are described for example in
  • compositions include, albeit not exclusively, solutions of the compounds in association with one or more pharmaceutical acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
  • Gal4-PPARgammal_BD Helledie et al 2000
  • UASx4-TK luc Choen and Evans, 1995
  • CMV-beta-galactosidase available commercially, e.g. Clontech
  • the UASx4-TK-luc reporter construct contains four Gal4-responsive elements.
  • the plasmid Gal4-PPARgammaLBD encodes a Gal4-DBD-PPARgamma-LBD fusion protein (i.e.
  • the CMV-beta-galactosidase plasmid (where CMV is cytomegalovirus) is used for normalization of experimental values.
  • MEFs Mouse embryonic fibroblasts
  • AmnioMax basal medium Gibco
  • Amniomax supplement C-100 Gibco
  • Fetal Bovine Serum FBS
  • 2 mM Glutamine 62.5 microg/ml penicillin and 100 microg/ml Streptomycin
  • ME3 cells were grown in DMEM supplemented with 10% Calf Se- rum (CS), 62.5 microg/ml penicillin and 100 microg/ml Streptomycin (growth medium). The cells were replated, typically in 24 well plates, so that at the time of transfection the cells are 50-70% confluent.
  • the cells were transfected with Gal4-PPARgammaLBD (Helledie et al 2000), UASx4-TK luc (Chen and Evans, 1995) and CMV-beta-galactosidase (available commercially, e.g. Clontech) using Lipofectamin Plus (Invitrogen) or Metaffectane (Biontex) according to the manufacturer's instructions.
  • UASx4TKIuc (0.2 microg) Gal4-PPARgammaLBD (or pM-hPPARgamma-LBD; 0.1 microg) and CMV-beta- galactosidase (0.05 microg) in 30 ⁇ l_ DMEM (free of serum and antibiotics) is mixed with 30 microL DMEM (free of serum and antibiotics) containing 1 microL metafectenein. The mixture is incubated at room temperature for 20 min to allow formation of nucleic acid-lipid complexes and then approximately 60 microL is added to each well containing the 50-70% confluent cells.
  • the cells are then incubated at 37 0 C in a CO 2 incubator for 6 to 12 hours and then the medium is replaced with medium supplemented with antibiotics and the ligand of interest (e.g., hepoxilin A3 (Biomol), hepoxilin B3 (Biomol), compounds referred to in Table 6 or rosiglitazone (Avandia) as a positive control, all dissolved in DMSO) or a comparable volume of DMSO ( ⁇ 0.5% of total cell culture volume).
  • the ligand of interest e.g., hepoxilin A3 (Biomol), hepoxilin B3 (Biomol), compounds referred to in Table 6 or rosiglitazone (Avandia) as a positive control, all dissolved in DMSO) or a comparable volume of DMSO ( ⁇ 0.5% of total cell culture volume).
  • PPAR transactivation was over 5-fold higher with rosiglitazone (a known PPARgamma agonist) than with DMSO alone, and 3-4 fold higher with 10 microM hepoxilin A3 or hepox- ilin B3 (see fig. 2A). Significant transactivation was also observed with 0.1 and 1 microM hepoxilin A (see fig. 2B). Thus both hepoxilin A3 and hepoxilin B3 are PPARgamma agonists.
  • Table 6 summarises the ability of a number of other tested ligands to activate PPAR in the trans-activation assay.
  • gradings -: no effect, number indicates fold activation compared to vehicle Diff gradings, Dex: -: no effect, +: stimulation to ⁇ 20% diff, ++: 20-50% diff, +++: >50% diff. Diff gradings, DMl: -: no effect, ⁇ : inhibition to >80% diff, ⁇ : 50-80% diff, ⁇ : ⁇ 50% diff.
  • This example describes a transactivation assay for determining PPARdelta modulating activity.
  • Hepoxilin A3 and hepoxilin B3 and other ligands were tested for their ability to transactivate PPARdelta essentially as described in Example 1.
  • the transactivating construct was mPPARdeltaLBD, where the PPARdelta ligand binding domain replaces that of PPARgamma and L165041 (commercially available) was used as a selective PPARdelta agonist instead of rosiglitazone.
  • L165041 was shown to increase PPARdelta transactivation by over 3.5-fold, whereas hepoxilin A3 and hepoxilin B3 resulted in no or less than 1.5-fold increase in transactivation, respectively (see fig. 2C).
  • both hepoxilin A3 and hepoxilin B3 show selectivity for PPARgamma.
  • 9-OXO-1 OE, 12Z,15Z-octadecatrienoic acid was shown to increase PPARdelta activa- tion by 18+/-6% of the activation achieved with L165041 , demonstrating that this ligand is a dual PPARgamma/PPARdelta agonist.
  • ⁇ -oxo-IOE. ⁇ Z.I ⁇ Z-octadecatrienoic acid has been shown to transactivate full length human PPARgamma and PPARdelta.
  • This example describes a transactivation assay for determining PPARalpha modulating activity.
  • Hepoxilin A3 and hepoxilin B3 and other ligands were tested for their ability to transactivate PPARalpha essentially as described in Example 1.
  • the transactivating construct was mPPARalphaLBD, where the PPARdelta ligand binding domain replaces that of PPARgamma and 61333 (commercially available) or a full PPARdelta agonist as the full agonist, instead of rosiglitazone.
  • 61333 was shown to increase PPARalpha transactivation by over 2.5- to 3-fold, whereas hepoxilin A3 and hepoxilin B3 resulted in no or less than 1.5-fold increase in transactivation, respectively (see Figs.
  • This example describes a retinoic acid X receptor transactivation assay.
  • LG1069 was shown to increase RXR transactivation by over 5-fold, whereas hepoxilin A3, hepoxilin B3 and ⁇ -oxo-IOE. ⁇ Z.I ⁇ Z-octadecatrienoic acid resulted in no transactivation (see Fig. 2D and 3D). Therefore both hepoxilin A3 and hepoxilin B3 again show selectivity for PPARgamma.
  • Example 5 Adipocyte Differentiation Assays This example describes an assay for determining adipocyte differention. Compounds are tested to see whether they induce adipocyte differentiation and also to see whether they inhibit adipocyte differention.
  • MEFs were grown in AmnioMax basal medium (Gibco) supplemented with 7.5 % Amnio- max supplement C-100 (Gibco), 7.5% Fetal Bovine Serum (FBS), 2 mM Glutamine, 62.5 ⁇ g/ml penicillin and 100 ⁇ g/ml Streptomycin (growth medium). MEFs were induced to differentiation in growth medium with the addition of 1 microM dexamethasone (Sigma) 0.5 mM isobutylmethylxanthine (Sigma), 5 microg/ml insulin (Sigma) and 10 microM hepoxilin A3 or hepoxilin B3 dissolved in DMSO or DMSO alone. Medium was subsequently renewed every 24 hrs with growth media supplemented with 5 microg/ml Insulin and ligand or DMSO.
  • AmnioMax basal medium Gibco
  • FBS Fetal Bovine Serum
  • FBS Fetal Bovine Serum
  • 3T3-L1 were grown to confluence in DMEM with 10% Calf serum (CS), typically in 24 well dishes.
  • CS Calf serum
  • cells were induced to differentiate with DMEM supplemented with 10% fetal bovine serum (FBS), 1 ⁇ M dexamethasone and the test compound (01 , 1 and 10 mi- croM).
  • FBS fetal bovine serum
  • BRL49653 1.0 ⁇ M dissolved in 100% Me2SO
  • the cells are re-fed with DMEM containing 10% FBS with supplements and the test compound or the positive control. From day 4, cells are grown in DMEM with 10% FBS and are changed every second day until day 8. At day 8, cells were stained with Oil Red O as decribed below.
  • 3T3-L1 cells are grown as above until two-day postconfluence (designated day 0), after which the cells are induced to differentiate with DMEM containing 10% fetal bovine serum (FBS), 1 ⁇ M dexamethasone (Sigma), 0.5 mM methylisobutylxanthine (Sigma), 1 ⁇ g/ml insulin (Roche Molecular Bio- chemicals) and the test-compound. Cells induced to differentiate in presence of solvent of the test-compounds are used as control. After 48 h, the cells are re-fed with DMEM containing 10% FBS supplemented with and the test compound or the positive control. From day 4, cells are grown in DMEM with 10% FBS and are changed every second day until day 8. At day 8, cells were stained with Oil Red O as decribed below. Oil Red O staining
  • Oil Red O solution stock solution is prepared by dissolving 0.5 g of Oil Red O (Sigma) in 100 ml of isopropanol.
  • Oil red O working solution is prepared by diluting a stock solution with water (6:4) followed by filtration.
  • Hepoxilin B3 induced a high degree of red staining of cells in culture, surprisingly hepoxilin A3 induced very little.
  • DMSO induced no red staining.
  • DMI in the Table refers to "dexamethazone, mix, and insulin" to indicate that adipocytes are induced differ- entiate and inhibitors of adipocyte differentiation identified.
  • 9-oxo- ( ⁇ -oxo-IOE. ⁇ Z ⁇ Z-octadecatrienoic acid) does not differentiate human preadipocytes.
  • TATA-binding protein TATA-binding protein
  • C/EBP CCAAT Enhancer-binding Protein alpha
  • aP2 adipocyte fatty acid-binding protein
  • hepoxilin B3 induced all three of these adipocyte differentiation markers (C/EBP about 3-fold, TBP about 6-fold and aP2 about 9- fold), hepoxilin A3 had no effect, as did DMSO alone (see Figs. 4a, b and c). Thus, hepox- ilin A3 does not appear to induce adipocyte differentiation in cell culture.
  • This example describes an assay for determining partial PPAR agonists, which are particularly desirable as pharmaceuticals.
  • transactivation assays are carried out essentially as described in Example 1 but 10OnM Avandia (a full agonist) is added to each well, together with increasing concentrations of test compound (or no test compound as control). Telmisartan, having selective PPARgamma modulating activity is included as a control for the assay.
  • Compounds that reduce the transactivation by Avandia are PPAR partial agonists. The results are depicted in Figs. 5-6 and 7.
  • PPARgamma partial agonists are identified in this example by their ability to displace a known PPARgamma agonist from binding to PPARgamma, e.g., Avandia in this case.
  • a known PPARgamma agonist from binding to PPARgamma
  • other known full agonists can be used, for example 30OnM L165041 to identify partial agonists of PPARdelta using the transactivation assay essentially as described in Example 2.
  • a further assay to identify partial PPARgamma agonists was performed using the Invitro- gen PolarScreenTM PPAR competition assay, as follows for analysis of binding to the PPARgamma ligand-binding pocket.
  • PPAR agonists also produce a physiological effect in cellular assays, expected of a PPAR agonist, namely an effect on glucose uptake.
  • Glucose uptake assays are important to establish the suitability of a compound for the treatment of insulin resistance.
  • 3T3-L1 preadipocytes are grown in 12-well plates until confluence. Cells are washed with serum-free DMEM and incubated with 1 ml of the same medium at 37 0 C for 1- 2 h. The cells are then washed with Krebs-Ringer-Hepes (KRP) buffer and then incubated with 0.9 ml KRP buffer at 37°C for 30 min. Insulin is added to the cells at 0, 0.3, 1 and 3 ⁇ M final concentration and incubated for 15min at 37°C.
  • KRP Krebs-Ringer-Hepes
  • Glucose uptake is initiated by the addition of 0.1 ml of Krebs-Ringer phosphate (KRP) buffer supplemented with 1OmM [ 3 H] 2- deoxy-D-glucose (1 mCi/l). After a 10 minute incubation at 37 0 C, the medium is aspirated and plates washed with ice-cold PBS to terminate the induced glucose uptake. The cells are lyzed with 0.5 ml 1% Triton X-100 and radioactivity levels determined using a scintillation counter. The results are depicted in Figs. 11, 12 and 13.
  • Example 9 Psoriasis model assays This example illustrates a further physiological effect of a PPAR agonist, namely in the treatment of psoriasis.
  • Compounds are tested by applying topically, once daily, 5 times a week for two weeks to a mouse tail.
  • Anti- psoriatic drugs enhance orthokeratotic cell differentiation in the epidermal scales allowing direct measurement of drug efficacy in an animal model. Two hours after the last treatment, the animals are sacrificed. Longitudinal sections of tail skin are made and prepared for histological examination (hematoxylin-eosin staining). The number of scale regions with a continuous granular layer is counted as an indicator of orthokeratosis. An increase in orthokeratosis (i.e., an increase in a continuous granular layer) is indicative of an anti- psoriasis agent.

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Abstract

Procédés de modulation de l'activité du récepteur activé de la prolifération des peroxysomes (PPAR) chez un individu : administration de quantité thérapeutiquement efficace de composé caractérisé par la présence de chaîne hydrocarbure à longueur variable, par exemple 10-32 atomes de carbone, se terminant à une extrémité par un groupe -COOH ou un sel, ou un dérivé fonctionnel correspondant. Les composés peuvent être représentés par les formules A et B, sachant que R1, R2, R3, R4, R5, R6 et X sont tels que spécifiés dans la description.
PCT/IB2006/001421 2005-01-11 2006-01-11 Procedes de modulation de l'activite de ppar WO2006106438A2 (fr)

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JP2015140323A (ja) * 2014-01-29 2015-08-03 岩手県 Ｐｐａｒ活性化剤
US10085953B2 (en) 2014-05-27 2018-10-02 Avexxin As Skin cancer treatment
WO2019010414A1 (fr) * 2017-07-07 2019-01-10 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Dérivés d'acides gras et utilisation associée
US10953004B2 (en) 2016-03-14 2021-03-23 Avexxin As Combination therapy for proliferative diseases
WO2021124272A1 (fr) * 2019-12-19 2021-06-24 Liminal Biosciences Limited Acides carboxyliques contenant un cycloalkyle et leurs utilisations
US11351127B2 (en) 2016-09-21 2022-06-07 Avexxin As Pharmaceutical composition
EP4199895A4 (fr) * 2020-08-18 2024-11-20 The Regents of The University of Michigan Produits d'acides aminés n-acyle et leurs utilisations
WO2025023183A1 (fr) * 2023-07-21 2025-01-30 国立大学法人大阪大学 Métabolite d'acide gras qui supprime une maladie inflammatoire de l'intestin

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US9682930B2 (en) 2010-09-02 2017-06-20 Avexxin As Rheumatoid arthritis treatment
WO2012028688A1 (fr) * 2010-09-02 2012-03-08 Avexxin As Traitement de la polyarthrite rhumatoïde au moyen de cétones polyinsaturées à chaîne longue
JP2015140323A (ja) * 2014-01-29 2015-08-03 岩手県 Ｐｐａｒ活性化剤
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US11351127B2 (en) 2016-09-21 2022-06-07 Avexxin As Pharmaceutical composition
KR102725883B1 (ko) 2017-07-07 2024-11-01 더 유나이티드 스테이츠 오브 어메리카, 애즈 리프리젠티드 바이 더 세크러테리, 디파트먼트 오브 헬쓰 앤드 휴먼 서비씨즈 지방산 유도체 및 이의 용도
WO2019010414A1 (fr) * 2017-07-07 2019-01-10 The United States Of America, As Represented By The Secretary, Department Of Health & Human Services Dérivés d'acides gras et utilisation associée
CN110869354A (zh) * 2017-07-07 2020-03-06 美国政府(由卫生和人类服务部的部长所代表) 脂肪酸衍生物及其用途
KR20200027545A (ko) * 2017-07-07 2020-03-12 더 유나이티드 스테이츠 오브 어메리카, 애즈 리프리젠티드 바이 더 세크러테리, 디파트먼트 오브 헬쓰 앤드 휴먼 서비씨즈 지방산 유도체 및 이의 용도
AU2018297192B2 (en) * 2017-07-07 2022-02-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Fatty acid derivatives and their use
US11555021B2 (en) 2017-07-07 2023-01-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Fatty acid derivatives and their use
WO2021124272A1 (fr) * 2019-12-19 2021-06-24 Liminal Biosciences Limited Acides carboxyliques contenant un cycloalkyle et leurs utilisations
US20230107538A1 (en) * 2019-12-19 2023-04-06 Liminal Biosciences Limited Cycloalkyl-containing carboxylic acids and uses thereof
EP4199895A4 (fr) * 2020-08-18 2024-11-20 The Regents of The University of Michigan Produits d'acides aminés n-acyle et leurs utilisations
WO2025023183A1 (fr) * 2023-07-21 2025-01-30 国立大学法人大阪大学 Métabolite d'acide gras qui supprime une maladie inflammatoire de l'intestin

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