WO2002067912A2 - Methode de traitement de maladies ou de conditions induites par ppar gamma - Google Patents

Methode de traitement de maladies ou de conditions induites par ppar gamma Download PDF

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Publication number
WO2002067912A2
WO2002067912A2 PCT/US2002/005362 US0205362W WO02067912A2 WO 2002067912 A2 WO2002067912 A2 WO 2002067912A2 US 0205362 W US0205362 W US 0205362W WO 02067912 A2 WO02067912 A2 WO 02067912A2
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WO
WIPO (PCT)
Prior art keywords
methyl
hppar
phenyl
compound
thiazol
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PCT/US2002/005362
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English (en)
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William Roland Oliver, Jr.
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Smithkline Beecham Corporation
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Priority to EP02713662A priority Critical patent/EP1368011A1/fr
Priority to US10/468,065 priority patent/US20040077659A1/en
Publication of WO2002067912A2 publication Critical patent/WO2002067912A2/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • the present invention relates to the treatment of diseases, risk factors, or conditions associated with peroxisome proliferator activated receptor (“PPAR”) gamma.
  • PPAR peroxisome proliferator activated receptor
  • Peroxisome Proliferator Activated Receptors are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example, Willson, T. M. and Wahli, W., Curr. Opin. Chem. Biol., (1997), Vol. 1 , pp 235-241. Three mammalian PPARs have been identified which are termed PPAR-alpha, PPAR-gamma, and PPAR-delta. PPARs regulate expression of target genes by binding to DNA response elements as heterodimers with the retinoid X receptor.
  • Type 2 diabetes mellitus Treatment of type 2 diabetes mellitus usually begins with a combination of diet and exercise, with progression to oral hypoglycaemics (e.g. sulfonylureas) and in more severe cases, insulin.
  • oral hypoglycaemics e.g. sulfonylureas
  • insulin e.g. sulfonylureas
  • thiazolidinediones e.g. U.S. Pat Nos. 5,089,514, 4,342,771 , 4,367,234, 4,340,605, 5,306,726
  • target tissues skeletal muscle, liver, adipose
  • thiazolidinediones are potent and selective activators of PPAR gamma and bind directly to the PPAR gamma receptor (J. M. Lehmann et. al., J. Biol. Chem. 12953-12956, 270 (1995)), providing evidence that PPAR gamma is a possible target for the therapeutic actions of the thiazolidinediones.
  • Activators of the nuclear receptor PPAR ⁇ have been shown in the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects on reducing serum triglyceride levels in patients with type 2 diabetes. See, for example, D. E. Kelly et al., Curr. Opin. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson et al., Ann. Phar acother., 337-348, 32 (3), (1997); and M. repelnegger et al., Curr. Ther. Res., 403-416, 58 (7), (1997).
  • Activators of the nuclear receptor PPAR ⁇ have also been associated with certain undesired effects including fluid retention, hemodiiution, weight gain, edema, and cardiac hypertrophy. See, for example, T. M. Willson, et al., J. Med. Chem., Vol. 43 (4), pages 527-550 (Feb. 24, 2000), and B. M. Spiegelman, Perspectives in Diabetes, Vol. 47, pages 507-514 (April 1998).
  • the association with fluid retention and edema is of particular concern since edema and hemodiiution are clinically associated with an increased risk of congestive heart failure. See, for example, Pioglitazone, S. P. Gillies and J.C. Dunn, Drugs, Vol.
  • Rosiglitazone an agent from the thiazolidinedione class for the treatment of type 2 diabetes, A. Cheng-Lai and A. Levine, Heart Des., Vol. 2(4), pages 326-333 (2000).
  • PPAR delta PPAR delta.
  • the publication states that PPAR delta agonists have several desirable clinical effects.
  • the present invention discloses a method for treating a PPAR gamma mediated disease, risk factor, or condition in a human patient, comprising administration of a compound or combination of compounds exhibiting agonist activity at human PPAR ("hPPAR") gamma, alpha, and delta.
  • hPPAR human PPAR
  • Compounds exhibiting agonist activity at all three hPPAR subtypes can be referred to as "PPAR pan agonists”.
  • PPAR pan agonists By “compound or combination of compounds” is meant that this hPPAR gamma, alpha, and delta activity can occur in one compound or in two or more separate compounds.
  • the method of the present invention reduces the undesired effects associated with hPPAR gamma agonists, when compared to the action of a hPPAR gamma agonist alone, without reducing the desired effects associated with hPPAR gamma agonists.
  • PPAR pan agonism reduces undesired effects of PPAR gamma, such as edema and weight gain associated with hPPAR gamma agonism, while not inhibiting the desired effects, such as diabetic glycemic control and improved lipid profile.
  • edema and weight gain associated with hPPAR gamma agonism means that the edema or weight gain seen with 5 PPAR pan agonism is significantly less than that which would be expected for a hPPAR gamma agonist. For example, average weight gains of less than 5% in a human taking a therapeutically effective amount of a PPAR gamma or PPAR pan agonist would be less than expected.
  • Diseases, risk factors, and conditions mediated by PPAR gamma include type I diabetes, type 2 or non-insulin dependent diabetes, syndrome X, (including metabolic syndrome), insulin resistance, heart failure, dyslipidemia including diabetic dyslipidemia and mixed dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension and cardiovascular disease, including 15 atherosclerosis, arteriosclerosis and hypertriglyceridemia, epithelial hyperprol iterative diseases including eczema and psoriasis and conditions associated with the lung and gut osteoporosis, acne, cancer, and eating disorders or conditions such as obesity, bulimia, and anorexia nervosa.
  • type I diabetes type 2 or non-insulin dependent diabetes
  • syndrome X including metabolic syndrome
  • dyslipidemia including diabetic dyslipidemia and mixed dyslipidemia
  • hyperlipidemia hyperlipidemia
  • hypercholesterolemia hypertension and cardiovascular disease
  • cardiovascular disease including 15 atherosclerosis, arteriosclerosis and hypertriglyceridemia
  • the method of this invention is useful in the treatment and prevention of type 2 diabetes (NIDDM) and mixed dyslipidemia.
  • NIDDM type 2 diabetes
  • agonist or “activating compound”, or “activator”, “exhibiting agonist activity” or the like, is meant those compounds which have a pKi of at least 6.0 (preferably at least
  • hPPAR pan agonist activity may reside in a single compound or in a combination of two or more compounds.
  • Preferred compounds with hPPAR pan activity include:
  • a particularly preferred compound with hPPAR pan agonist activity is 2- ⁇ 4-[( ⁇ 4- ⁇ [4-(4- methoxyphenyl)-1-piperazinyl]methyl ⁇ -2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- 40 y
  • the compounds or combination of compounds may also be utilised in the form of a pharmaceutically acceptable salt or solvate thereof.
  • the physiologically acceptable salts include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts.
  • suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like.
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N- methylglucamine and procaine salts.
  • solvents for example, a complex with water is known as a "hydrate”.
  • Solvates are within the scope of the invention.
  • the compounds and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in a mixture with one or more physiologically acceptable carriers or excipients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the present invention further provides for a pharmaceutical formulation comprising a compound or combination of compounds exhibiting agonist activity at all three hPPAR subtypes or pharmaceutically acceptable salts or solvates thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
  • the formulations include those suitable for oral, parental (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredients may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a other conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, m
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the tablets may be coated according to methods well-known in the art.
  • the compounds may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example.
  • formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid.
  • suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats
  • emulsifying agents such as lecithin, sorbitan mono-oleate or acacia
  • non-aqueous vehicles which may
  • Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use.
  • a sterile liquid carrier for example, water-for-injection
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example, ion exchange resins
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.
  • amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
  • doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
  • the compound or combination of compounds exhibiting agonist activity at all three hPPAR subtypes for use in the instant invention may be used in combination with other therapeutic agents for example, statins and/or other lipid lowering drugs for example MTP inhibitors and LDLr upregulators.
  • the compounds of the invention may also be used in combination with antidiabetic agents, e.g. metformin, sulfonylureas.
  • the compounds may also be used in combination with antihypertensive agents such as angiotensin antagonists e.g. telmisartan, calcium channel antagonists e.g. lacidipine and ACE inhibitors e.g. enalapril.
  • the invention thus provides in a further aspect the use of a combination comprising a compound of formula (I) with a further therapeutic agent in the treatment of a hPPAR gamma mediated disease.
  • the compounds When the compound or combination of compounds exhibiting agonist activity at all three hPPAR subtypes are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further . spsct of the invention.
  • the individual components of such combination. may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the compounds When combined in the same formulation it will be appreciated that the compounds must be stable and compatible with each other and the other components of the formulation and may be formulated for administration.
  • each compound When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.
  • dose of each compound When of a compound or combination of compounds exhibiting agonist activity at all three hPPAR subtypes is used in combination with a second therapeutic agent active against the same hPPAR gamma mediated disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • the reaction was monitored by 1 H NMR and was determined to be composed of a 9:1 mixture of mono- bromination product (i.e. desired product) and di-bromination product with a 90% conversion. After cooling to 0°C (to precipitate out the succinimide) the reaction was filtered through Celite and the solvent was removed under reduced pressure to yield a brown oil. The oil was crystallized using hexanes to yield 100g (94%) of an off-white product of 90% purity.
  • Triethylamine (6.6ml, 46.92mmoles, 1.5eq) was added dropwise over 20 minutes maintaining the internal temperature below 5°C and was stirred at 0°C for 30 minutes.
  • the reaction mixture was transferred to a separatory funnel and washed with H 2 0, brine and the organic fraction was dried over Na 2 S0 4 . After filtration the solvent was removed under reduced pressure to yield the corresponding mesylate in quantitative yield. Because of the unstable nature of the mesylate, the product was not characterized and was progressed onto the next stage without purification.
  • This compound was made using the same alkylation protocol as described above, from 4- methoxphenyl piperazine and ethyl ⁇ 2-ethyl-4-t( ⁇ 4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl ⁇ methyl)sulfanyl]phenoxy ⁇ acetate.
  • PPAR ligand-binding domain (LBD) was expressed in E. coli as polyHis tagged fusion proteins and purified. The LBD was then labelled with biotin and immobilised on streptavidin-modified scintillation proximity beads. The beads were then incubated with a constant amount of the appropriate radioligand and variable concentrations of test compound, and after equilibration the radioactivity bound to the beads was measured by a scintillation counter.
  • radioligands used were: 3H-rosiglitazone for PPARgamma (Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. J. Biol. Chem. 1995 , 270, 12953-6.); radiolabelled 2-(4-(2-(2,3-Ditritio-1-heptyl-3-(2,4- difluorophenyl)ureido)ethyl)phenoxy)-2-methylbutanoic acid for hPPAR alpha (see (see Kliewer, S. A.; Sundseth, S. S.; Jones, S.
  • the ligand binding domains for murine and human PPAR alpha, PPAR gamma, and PPAR delta were each fused to the yeast transcription factor GAL4 DNA binding domain.
  • CV-1 cells were transiently transfected with expression vectors for the respective PPAR chimera along with a reporter construct containing five copies of the GAL4 DNA binding site driving expression of secreted placental alkaline phosphatase (SPAP) and beta-galactosidase. After 16 h, the medium was exchanged to DME medium supplemented with 10% delipidated fetal calf serum and the test compound at the appropriate concentration.
  • SFP secreted placental alkaline phosphatase
  • beta-galactosidase beta-galactosidase
  • the positive control for PPAR delta assays was 2- ⁇ 2- methyl-4-t( ⁇ 4-methyl-2- ⁇ trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl ⁇ methyl)sulfanyl]phenoxy ⁇ acetic acid (see WO 01/00603).
  • the positive control in the hPPAR alpha assays was 2-[4-(2-(3-(4-fluorophenyl)- 1-heptylureido)ethyl)-phenoxy]-2-methylpropionic acid, which can be prepared as described in Brown, Peter J., et. al. Synthesis Issue 7, 778-782 (1997), or patent publication WO 9736579.
  • the five PPAR pan agonist molecules prepared above were administered by oral gavage to genetically altered rodents that simulate the human disease of type 2 Diabetes Mellitus (Zucker Diabetic Fatty rats (ZDF fa/fa)).
  • a PPAR gamma agonist 2-[2-(methoxycarbonyl)anilino]- 3- ⁇ 4-[2-(5-methyl-2-phenyl-1 ,3-oxazol-4-yl)ethoxy]phenyl ⁇ propanoic acid was also tested.
  • This PPAR gamma agonist can be prepared as described in Cobb, J. E. r et al., N-(2-Benzoylphenyl)-L-tyrosine PPARg agonists.
  • the PPAR pan agonist molecules differed from the PPAR gamma agonist molecule in that there was little to no weight gain relative to control animals. Weight gain has been associated with edema in humans. In rodents, weight gain may be used as a potential surrogate marker for edema based on comparison of data generated with other insulin sensitising agents in rodents and their effects in humans.
  • the PPAR gamma agonist increased body weight by 11 % to 17% after 7 days of treatment, relative to same-age vehicle control animals. All five PPAR pan agonist molecules produced weight gain of less than 5% relative to same-age vehicle control animals after 7 days of treatment. Hemodiiution, as measured by plasma hematocrit and total serum protein, was also much less with the five PPAR pan agonists than with the PPAR gamma agonist, following 7 days of treatment.
  • the data show that both the PPAR gamma agonist and the PPAR pan agonist lowered insulin and maintained glycemic control relative to vehicle treatment.
  • the data also show that body weight increased with the PPAR gamma agonist by 120% from the start of dosing, whereas body weight gain with the PPAR pan agonist was not significantly different from the vehicle treated animals.
  • Hematocrit and total serum protein was also measured after 28 days.
  • the group treated with vehicle had hematocrit (% RBC volume) of 49 + 0.3 and total serum protein (mg/dL) of 7.5 ⁇ 0.2.
  • the group treated with the PPAR gamma agonist had hematocrit (% RBC volume) of 43 ⁇ 1.0 and total serum protein (mg/dL) of 6.0 ⁇ 0.1.
  • the group treated with the PPAR pan agonist had hematocrit (% RBC volume) of 48 ⁇ 0.9 and total serum protein (mg/dL) of 7.2 ⁇ 0.2.
  • the animals were dosed at 0 mg/kg (control), 1 mg/kg, 5 mg/kg, and 15 mg/kg of the PPAR pan agonist. The animals were carefully observed for signs of edema and or hemodiiution. Methods of evaluation during the in-life portion of the study included visual observation of swelling, particularly around the eyes and or genitals by a Board Certified pathologist, as well as evaluation of clinical hematology (red blood cell volume) and clinical chemistries (total serum protein) as evidence of hemodiiution. At necropsy, careful examination for gross evidence of edema was based on palpation and careful examination of all tissue. Special emphasis was given to the gross evaluation of subcutaneous tissue, all fat stores, lungs and all serous cavities. No evidence of edema was present in any of the tissues examined histologically. There were no signs or suggestions of edema or hemodiiution during the in-life or necropsy portions of the study.

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PCT/US2002/005362 2001-02-22 2002-02-21 Methode de traitement de maladies ou de conditions induites par ppar gamma WO2002067912A2 (fr)

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EP02713662A EP1368011A1 (fr) 2001-02-22 2002-02-21 Methode de traitement de maladies ou de conditions induites par ppar gamma
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007102515A1 (fr) * 2006-03-07 2007-09-13 Astellas Pharma Inc. Derive de phenylthiazole
EP2083006A1 (fr) 2004-04-01 2009-07-29 Sanofi-Aventis Deutschland GmbH Oxadiazolones, leurs procédés de préparation et leur utilisant en tant que produits pharmaceutiques
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
US8648208B2 (en) 2008-04-15 2014-02-11 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2083006A1 (fr) 2004-04-01 2009-07-29 Sanofi-Aventis Deutschland GmbH Oxadiazolones, leurs procédés de préparation et leur utilisant en tant que produits pharmaceutiques
WO2007102515A1 (fr) * 2006-03-07 2007-09-13 Astellas Pharma Inc. Derive de phenylthiazole
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
US8648208B2 (en) 2008-04-15 2014-02-11 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor

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