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WO2006045581A1 - Utilisation de 1, 2, 4-thiadiazolidine-3, 5-diones en tant qu'activateurs de ppar - Google Patents

Utilisation de 1, 2, 4-thiadiazolidine-3, 5-diones en tant qu'activateurs de ppar Download PDF

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Publication number
WO2006045581A1
WO2006045581A1 PCT/EP2005/011414 EP2005011414W WO2006045581A1 WO 2006045581 A1 WO2006045581 A1 WO 2006045581A1 EP 2005011414 W EP2005011414 W EP 2005011414W WO 2006045581 A1 WO2006045581 A1 WO 2006045581A1
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substituted
disease
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Ana MARTÍNEZ GIL
Mercedes Alonso Cascón
María Luisa NAVARRO RICO
Miguel Medina Padilla
Susana Morales Alcelay
Ana PÉREZ CASTILLO
Rosario De Luna Medina
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Neuropharma, S.A.
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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

Definitions

  • the present invention relates to the use of some heterocyclic compounds, having a thiadiazolidine core, which act as peroxisome proliferator-activated receptor (PPAR) ligands, in particular gamma receptors (PPAR -gamma), thus being useful in the treatment of numerous diseases and conditions.
  • PPAR peroxisome proliferator-activated receptor
  • Peroxisome proliferator-activated receptors are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. They were first recognized for their roles in peroxisome synthesis, to which they owe their name. Their normal ligands are fatty acids or fatty acid derivatives, but they can also bind synthetic agonists and can be activated in the laboratory by genetic manipulation. So far three types of PPARs of this nuclear receptor superfamily have been described: PPAR-alpha, PPAR- gamma and PPAR-delta. Each one is coded by a different gene, and has different properties.
  • PPAR- gamma which is the most studied sub-type, is known to be expressed primarily in adipose tissue, spleen, colon and macrophages, but much less in liver, skeletal muscle, heart and pancreas; it is involved in turning on genes necessary to the differentiation of fibroblasts into adipocytes and genes that encode proteins required for lipid synthesis and storage in adipocytes, thus performing key functions in the regulation of the lipidic metabolism, in the glucose homeostasis, as well as in cell differentiation.
  • RXR nuclear receptor
  • Metabolic syndrome obesity and diabetes
  • Type II diabetes is a common metabolic disorder which has no effective treatment, and involves a subnormal or inadequate amount of circulating endogenous insulin.
  • PPAR-gamma agonists especially a family of compounds known as thiazolidinedione (TZD) derivatives have shown their clinical efficiency, causing an important decrease of the plasmatic levels of glucose, insulin, triglycerides and fatty acids (see for example "Experimental Approaches to Study PPAR-gamma Agonists as Antidiabetic Drugs", Methods Find Exp CHn Pharmacol 2002, 24(8): 515-523, Vazquez et al.; US 6,787,556 Bl and US 6,716,514 Bl).
  • the first TZD used in therapeutics was the troglitazone; another two TZD, rosiglitazone and pioglitazone, are used since 1999 for the treatment of diabetes II. These compounds are PPAR-gamma agonists and their action is due mainly to the activation of said receptor. It has been shown that there is a clear correlation between affinity towards PPAR-gamma and clinical efficiency (Plutzky J., 2003, "The potential role of PPARs on inflammation in type 2 diabetes mellitus and atherosclerosis". Am J Cardiol. 92: 34J-41J). Through TZD it has been possible to show that the stimulation of PPAR-gamma increases the sensibilization towards insulin and the adipogenesis; said activation conducts to biochemical and metabolic changes related to an increase in the sensibility towards insulin.
  • Sprome X also known as “methabolic syndrome”.
  • Afflicted people have insulin inefficiency or resistance to insulin in the liver, adipose tissue, and skeletal muscle. It is generally associated to the compensatory hypersecretion of insulin and, in the long run, to a progressive deterioration of the beta cells in the pancreas. This culminates in unhealthy cholesterol levels, high blood sugar levels and inflamed arteries; all these symptoms increase the likelihood of having a heart attack or a stroke.
  • the syndrome seems to be originated both in genetic factors and environmental factors (obesity, sedentary way of life, etc.).
  • PPARs The main target that is envisaged to treat this syndrome are PPARs, as it has been observed that the pharmacological activation of PPAR-gamma increases significantly the sensibility towards insulin of the peripheric tissues.
  • Drugs of the thiazolidinedione class (TZD) have also here clearly shown their clinical efficiency causing an important decrease of the plasmatic levels of glucose, insulin, triglycerides and fatty acids.
  • PPAR can participate in the regulation of inflammatory responses and can modulate the intensity, duration and consequences of inflammatory events. See for example Nature 391, 82-86 (1998), "PPAR-gamma agonists inhibit the production of monocyte inflammatory cytokines", Jiang et al.
  • PPAR-gamma specific ligands have been shown to have potent anti ⁇ inflammatory effects, as they inhibit the production of many inflammatory cytokines (such as tumour-necrosis factor (TNF), interleukin-l ⁇ (IL- l ⁇ ) and IL-6), the inducible nitric oxide synthase (iNOS), cyclooxygenase type 2 (COX2), and the expression of matrix metalloproteinase 9 (MMP9) and macrophage scavenger receptor 1 (MSRl) on various cell types, including monocytes, macrophages and epithelial cells.
  • cytokines such as tumour-necrosis factor (TNF), interleukin-l ⁇ (IL- l ⁇ ) and IL-6
  • iNOS inducible nitric oxide synthase
  • COX2 cyclooxygenase type 2
  • MMP9 matrix metalloproteinase 9
  • MSRl macrophage s
  • Inflammatory activation of neuronal, as well as glial cells is believed to contribute to cell death and damage during neurological disease.
  • One of the hallmarks of neurodegenerative and inflammatory pathologies is the increased number of activated astrocytes and microglia in response to the pathological stimulus (Arvin et al., 1996,
  • TNF tumour necrosis factor
  • IL-6 IL-6
  • NO nitric oxide
  • PPAR-gamma ligands have also shown to reduce inflammatory cytokine production by macrophages, an effect which is anti ⁇ atherogenic. Actually, it has been shown that atherosclerosis is reduced in rodents and also in patients, which have been treated with PPAR-gamma ligands. (Mitchell A. Lazar, "Progress in cardiovascular biology: PPAR for the course", Nature Medicine, January 2001 vol. 7, NoI).
  • peroxisome proliferator-activated receptor- gamma (PPAR-gamma) ligands inhibit the growth of PPAR-gamma expressing cancer cells through terminal differentiation (see Int J Oncol. 2004 Sep; 25(3):631-9, "Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation- promoting effects"; and US 6,756,399 B2).
  • the authors of the above mentioned article have developed a rectal cancer xenograft animal model in which anti-tumour and anti- metastatic efficacy of agents can be evaluated.
  • TZD thiazolidinedione
  • TZD completely inhibited lymph node and lung metastasis in the xenograft animal model, and TZD inhibited growth of primary xenografts by 40%.
  • PPAR-gamma activating thiazolidinediones rosiglitazone and troglitazone induced G(O)-G(I) cell-cycle arrest and apoptosis in human, rat somatolactotroph, and murine gonadotroph pituitary tumour cells, and suppressed in vitro hormone secretion.
  • PPAR-gamma is an important molecular target in pituitary adenoma cells and PPAR-gamma ligands inhibit tumour cell growth and GH, PRL, and LH secretion in vitro and in vivo.
  • Rosiglitazone inhibits bovine capillary endothelial cell but not tumour cell proliferation at low doses in vitro and decreases VEGF production by tumor cells.
  • rosiglitazone suppressed angiogenesis in the chick chorioallantoic membrane, in the avascular cornea, and in a variety of primary tumours.
  • the results show that PPAR-gamma ligands may be useful in treating angiogenic diseases such as cancer by inhibiting angiogenesis.
  • the invention is directed to the use of a compound of general formula (I)
  • R 1 and R 2 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy or halogen; in the preparation of a medicament for the treatment of a PPAR mediated disease or condition or a disease or condition requiring activation of PPAR.
  • R a and R b are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, and -(CH 2 ) n -
  • At least one of R a or R b contains an aromatic group.
  • the sustituents R a and R b in the compounds of formula (I) are independently selected from methyl, ethyl, propyl, isopropil, adamantyl and -CH 2 -CO 2 -ethyl, or from benzyl, phenyl, naphthyl, phenylethyl, diphenylmethyl, 2- benzyl-phenyl or phenoxyphenyl optionally substituted with a group selected from methyl, ethyl, terbutyl, fluoro, chloro, bromo methoxy or methylendioxy.
  • R a in the compound of formula (I) is independently selected from phenyl, benzyl or -CH 2 -CO 2 EtIIyI.
  • R 1 is heterocyclyl or aryl.
  • the invention is directed to a use as defined above wherein the disease or condition is selected from diabetes, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia,
  • Huntingdon's disease AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis acute stroke, schizophrenia and bipolar disorders, cerebral bleeding due to solitary cerebral amyloid angiopathy, ischaemia, traumatic brain injury, neurogenic pain, cancer, atheriosclerosis, infarction, obesity, Syndrome X, inflammatory diseases, hyperplasias, immunodeficiency, asthma or allergies.
  • the invention is directed to a method of treating diabetes, Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis acute stroke, schizophrenia and bipolar disorders, cerebral bleeding due to solitary cerebral amyloid angiopathy, ischaemia, traumatic brain injury, neurogenic pain, cancer, atheriosclerosis, infarction, obesity, Syndrome X, inflammatory diseases, hyperplasias, immunodeficiency, asthma or allergies comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined above or or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • heterocyclic compounds having among others a core thiadiazolidine, in particular thiadiazolidindiones (TDZD) and other heterocyclic compounds, were initially described as the first non-ATP competitive inhibitors of glycogen synthase kinase-3 beta (GSK-3 ⁇ ) (see WO 01/85685). These thiadiazolidines and derivatives are small molecules with favourable ADME-Tox drugable properties, such as oral bioavailability and blood-brain barrier penetration. Surprisingly it has now been found that the heterocyclic compounds of general formula (I) as defined above do exhibit PPAR-gamma activating properties.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having one to 12 carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.
  • Alkyl radicals may be optionally substituted by one or more substituents such as a aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio, etc. If substituted by aryl we have an "Aralkyl” radical, such as benzyl and phenethyl.
  • alkenyl refers to an alkyl radical having at least 2 C atoms and having one or more unsaturated bonds.
  • Cycloalkyl refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl. Unless otherwise stated specifically in the specification, the term "cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.
  • Aryl refers to single and multiple ring radicals, including multiple ring radicals that contain separate and/or fused aryl groups. Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical.
  • the aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc.
  • Alkyl refers to an aryl group linked to an alkyl group. Preferred examples include benzyl and phenethyl.
  • Heterocyclyl refers to a stable 3-to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5-or 6-membered ring with one or more heteroatoms.
  • the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized ; and the heterocyclyl radical may be partially or fully saturated or aromatic.
  • heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarine, morpholine; pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
  • Alkoxycarbonyl refers to a radical of the formula-C (O) OR a where R a is an alkyl radical as defined above, e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.
  • Alkylthio refers to a radical of the formula-SR a where R a is an alkyl radical as defined above, e. g., methylthio, ethylthio, propylthio, etc.
  • Amino refers to a radical of the formula-NH 2 , -NHR a or -NR a R b , optionally quaternized.
  • Halo or hal refers to bromo, chloro, iodo or fluoro.
  • references herein to substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo and iodo ; cyano; hydroxyl ; nitro ; azido ; alkanoyl such as a C 1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thi
  • Particular individual compounds of the invention include the compounds 1-24 in the examples, either as salts or as free bases.
  • 2,4-dibenzyl-[l,2,4]thiadiazolidine-3,5-dione 4-benzyl- 2-naphthyl-[ 1 ,2,4]thiadiazolidine-3,5-dione, 2-ethyl-4-phenyl-[ 1 ,2,4]thiadiazolidine- 3,5-dione, 2,4-di(ethoxycarbonylmethyl)-[l,2,4]thiadiazolidine-3,5-dione or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • pharmaceutically acceptable salts, solvates, prodrugs refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein.
  • non- pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts, prodrugs and derivatives can be carried out by methods known in the art.
  • salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate.
  • mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p-toluenesulphonate.
  • alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • the compounds of formula (I) are also mean to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C- enriched carbon or
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al.
  • the compounds of the invention may be in crystalline form either as free compounds or as solvates and it is intended that both forms are within the scope of the present invention.
  • Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
  • the compounds of the present invention represented by the above described formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E).
  • the single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
  • sulfuryl chloride is added dropwise with stirring, under nitrogen atmosphere, at low temperature, preferably at about 5 0 C, to a solution of benzyl isothiocyanate and the isocyanate indicated in each case, in a suitable solvent such as hexane, eter or THF.
  • a suitable solvent such as hexane, eter or THF.
  • the mixture is left to react, for example by stirring for 20 hours at room temperature.
  • the resulting product is isolated by conventional methods such as suction filtration or solvent evaporation and then, the purification is performed (e.g. by recristallization or silica gel column chromatography using the appropriate eluent).
  • reaction products may, if desired, be purified by conventional methods, such as crystallisation, chromatography and trituration.
  • the compounds used in the invention are useful for treating diseases and conditions wherein an activation of PPAR-gamma is required.
  • diseases or conditions include, without limitation, diabetes, especially diabetes of type II, and conditions associated with diabetes; neurodegenerative conditions including dementias, especially those wherein an inflammatory process is involved, such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, fronto temporal dementia, Huntingdon's disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, mood disorders such as schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding (for example, due to
  • compositions comprising a compound of formula (I), a pharmaceutically acceptable salts, derivatives, prodrugs or stereoisomers thereof with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.
  • compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
  • the mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US
  • the use of the compounds of formula (I) may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.
  • the use of the compounds in an effective administered amount will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer.
  • active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
  • the compounds and compositions of this invention may be used with other drugs to provide a combination therapy.
  • the other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.
  • the compounds of general formula (I) are used for the treatment of a neurodegenerative disease, preferably selected from Alzheimer's Disease, Parkinson's Disease, stroke and ischemia.
  • the compounds of formula (I) are used for the treatment of any of diabetes, metabolic syndrome, obesity, and any cardiovascular disease.
  • PPAR-gamma activation was measured as an increase in light intensity after transfection of CHO cells with plasmid p(A-Ox 3 )-TKSL, containing PPAR-gamma consensus binding sites (PPRE) linked to tk-luciferase as a reporter gene (for details, see Tugwood JD et al., EMBO J. 1992, 11 : 433-9).
  • PPRE PPAR-gamma consensus binding sites
  • CHO-Kl cells (ATCC # CCL-61) were maintained in Ham's Fl 2 Medium (Invitrogen) containing 10% Fetal Bovine Serum (FBS), 2mM glutamine and Penicillin: Streptomycin (100 U/ml : 100 ⁇ /ml) at 37 0 C with 5% CO 2 .
  • Rosiglitazone (30 ⁇ M) (Calbiochem, CA, USA) described as a selective activator of the peroxisome receptor.
  • PPAR-gamma antagonist GW 9662 (30 ⁇ M) (Cayman Chemical, MI, USA) was also used.
  • Lactate Dehydrogenase (LDH, Citotoxicity Detection Kit Roche, Mannheim, Germany) released from the cytosol of damaged cells into the supernatant was measured in parallel.
  • the criteria used to determine whether a compound acted as a PPAR-gamma activator was the following: compounds for which the luminescence increased compared to the basal value (that is, when no PPAR-gamma activator was added), were considered as PPAR-gamma activators; compounds for which the luminescence was equal or below the basal value, were considered as not activating PPAR-gamma.
  • the compounds tested are considered as activators of PPAR-gamma (shown with + symbol in the table), at the concentration written within brackets behind the symbol.

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Abstract

L'invention concerne l'utilisation d'une famille de composés de structures distinctes possédant un noyau hétérocyclique de thiadiazolidine et constituant des ligands puissants de PPAR, tout en possédant de bonnes propriétés pharmacologiques. Ces composés servent à traiter des maladies ou des états nécessitant l'activation de PPAR ou dans lesquels PPAR jouent un rôle d'intermédiaire.
PCT/EP2005/011414 2004-10-21 2005-10-21 Utilisation de 1, 2, 4-thiadiazolidine-3, 5-diones en tant qu'activateurs de ppar WO2006045581A1 (fr)

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WO2006084934A1 (fr) * 2005-02-10 2006-08-17 Neuropharma, S.A. Utilisation de composes derives de tiadazolidines comme agents neurogeniques
US20100063109A1 (en) * 2006-07-18 2010-03-11 University Of Rochester Thiadiazolidinone derivatives
WO2011004162A3 (fr) * 2009-07-08 2011-03-03 Betagenon Ab Composés utilisés en tant que médicaments
EP2394647A1 (fr) 2006-11-02 2011-12-14 Aestus Therapeutics, Inc. Procédés pour traiter la douleur neuropathique par la modulation des voies de la glycogénolyse ou de la glycolyse
WO2013070586A1 (fr) * 2011-11-11 2013-05-16 The Wistar Institute Of Anatomy And Biology Modulateurs à petite molécule d'inactivation de prb
CN113827592A (zh) * 2020-06-24 2021-12-24 中国科学院上海药物研究所 一种噻二唑烷二酮基化合物在治疗致病性感染中的应用
WO2022170437A1 (fr) * 2021-02-11 2022-08-18 Venca Research, Inc. Compositions et méthodes de traitement d'une cardiomyopathie arythmogène
CN115197167A (zh) * 2022-07-22 2022-10-18 中国药科大学 1,2,4-噻二唑烷-3,5-二酮化合物及其制备方法和应用
JP2022553268A (ja) * 2019-10-18 2022-12-22 ベタゲノン アーベー 新製剤

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CN113827592A (zh) * 2020-06-24 2021-12-24 中国科学院上海药物研究所 一种噻二唑烷二酮基化合物在治疗致病性感染中的应用
CN113827592B (zh) * 2020-06-24 2024-06-18 中国科学院上海药物研究所 一种噻二唑烷二酮基化合物在治疗致病性感染中的应用
WO2022170437A1 (fr) * 2021-02-11 2022-08-18 Venca Research, Inc. Compositions et méthodes de traitement d'une cardiomyopathie arythmogène
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