WO2007009353A1 - Composes thiazol-4-one substitues, leurs procedes de fabrication et leur utilisation - Google Patents

Composes thiazol-4-one substitues, leurs procedes de fabrication et leur utilisation Download PDF

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Publication number
WO2007009353A1
WO2007009353A1 PCT/CN2006/001657 CN2006001657W WO2007009353A1 WO 2007009353 A1 WO2007009353 A1 WO 2007009353A1 CN 2006001657 W CN2006001657 W CN 2006001657W WO 2007009353 A1 WO2007009353 A1 WO 2007009353A1
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group
substituted
aldehyde
amide
ester
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PCT/CN2006/001657
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English (en)
Chinese (zh)
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Mingwei Wang
Qing Liu
Caihong Zhou
Mengneng Ning
Bin Wu
Xin Hui
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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Publication of WO2007009353A1 publication Critical patent/WO2007009353A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—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
    • A61P3/08—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

Definitions

  • the present invention relates to a peroxisome Proliferator-activated Receptor- ⁇ (PPAR- ⁇ ) agonist, specifically a small molecule organic compound substituted with a thiazol-4-one derivative. It serves as a medical use of PPAR-gamma agonists in the treatment and prevention of diabetes and its complications.
  • the invention also relates to a process for the preparation of such compounds.
  • Diabetes is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is mainly divided into type 1 and type 2.
  • the basic pathophysiology of type 1 diabetes is absolute insulin secretion, and clinical treatment is mainly supplemented with insulin.
  • Type 2 diabetes accounts for more than 95% of the diseased population.
  • Clinical studies have found that most patients with type 2 diabetes can synthesize normal or even excess insulin, but the sensitivity of target cells to insulin is reduced (also known as "insulin resistance"). Insufficient insulin. Insulin resistance is a key factor in the development and progression of type 2 diabetes.
  • the research on insulin sensitizers mainly focuses on the following aspects: 1) Thiazolidinediones (TZD), such as Troglitazone, Rosiglitazone and Pioglitazone (Pioglitazone) ); 2) biguanides, such as metformin, phenformin, and buformin; 3) ⁇ -adrenergic receptor agonists and glucagon receptor antagonists; 4) fatty acid metabolism interfering agents, such as etomimus (Etomoxir) and so on.
  • ZD Thiazolidinediones
  • biguanides such as metformin, phenformin, and buformin
  • ⁇ -adrenergic receptor agonists and glucagon receptor antagonists such as etomimus (Etomoxir) and so on.
  • TZD drugs can significantly improve insulin resistance and correct abnormalities in sugar and lipid metabolism during clinical application, thus showing great market value.
  • TZD was originally discovered as an analog of clofibrate, and subsequent studies have shown that TZD significantly enhances the insulin-targeting tissue's response to insulin, whereas in the absence of insulin, TZD does not lower blood sugar. .
  • the molecular target of TZD drugs in vivo was Peroxisome Proliferator Activated Receptor- ⁇ (PPAR- ⁇ ) [Lehmann JM, Moore LB, Oliver S" et al An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). 1995, J. Biol. Chem., Vol. (270): 12953-12956].
  • PPAR- ⁇ is encoded by a single-copy gene located on human chromosome 3, with 468, 441 and 479 amino acids, respectively, consisting of six domains from A to F (Fig. 1).
  • the A/B domain at the amino terminus is the activated transcribed region
  • the C domain is the DNA binding region (DBD)
  • the E/F domain at the carboxy terminus is the ligand binding region (LBD) [Desvergne B., Wahli W. Peroxisome proliferator-activated Endorser: nuclear control of metabolism. Endocr Rev.
  • PPAR- ⁇ is activated by small molecule ligands, forms a heterodimer with retinoic acid receptor X (RXR), and then binds The specific DNA sequence called PPAR Response Element (PPRE) regulates transcription of target genes with the help of co-transfer factors [Blanquart C, Barbier 0., Fruchart JC, et al. Peroxisome proliferator-activated receptors : regulation of transcriptional activities and roles in inflammation. J Steroid Biochem Mol Biol. 2003, 85(2-5): 267-73].
  • RXR retinoic acid receptor X
  • PPRE PPAR Response Element
  • PPRE is present upstream of multiple genes involved in regulation of lipid metabolism and glucose metabolism [Juge-Aubry C, Pernin A., Favez T” et al. DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance Of the 5'-flanldng region. J Biol Chem. 1997, 272(40): 25252-9].
  • PPAR- ⁇ is mainly distributed in tissues such as fat, immune system, large intestine and retina.
  • PPAR- ⁇ is a key regulator of adipocyte differentiation, which positively regulates the differentiation of adipocytes, induces the formation of adipocytes, inhibits the expression of leptin, and promotes the end of 3T3-L1 preadipocytes.
  • End stage fat cell transformation [Chawla A., Schwarz EJ., Dimaculangan DD, et al. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology.
  • PPAR- ⁇ knockout mice die early in embryonic development.
  • activation of PPAR- ⁇ can promote glucose uptake and transport by adipocytes and skeletal muscle cells, regulate signal transduction of adipocytes, induce differentiation of brown adipose tissue, and increase uncoupling Expression of proteins UCP1 and UCP2, which in turn increases energy expenditure, lowers blood sugar and blood lipids, and improves insulin resistance in people with type 2 diabetes [Motojima K., Passilly P., Peters JM, et al.
  • PPAR-gamma agonists currently used in the treatment of type 2 diabetes are in preclinical or clinical research, including Darglitazone in the TZD category and Farglitazar in the non-TZD category. They all showed good hypoglycemic effects without obvious side effects.
  • these drugs are ubiquitous, including side effects leading to obesity and edema [Lebovitz HE Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev. 2002 , 18 (Suppl 2): S23-9] limits their widespread use [Gershell L. Type 2 diabetes market. Nature Reviews Drug Discovery 2005, 4(5): 367-368]. Therefore, the use of PPAR- ⁇ as a target to find insulin sensitizers with less toxic side effects has become a hot spot for major multinational pharmaceutical companies.
  • the present invention discovers and synthesizes a series of small molecule compounds of substituted thiazol-4-one derivatives by applying various PPAR- ⁇ -based high-throughput drug screening models and structure-activity relationships of active samples.
  • Receptor binding viability assays, reporter gene assays, and adipocyte-induced differentiation assays have demonstrated that these compounds bind specifically to PPAR- ⁇ and are agonists of PPAR- ⁇ , suggesting their potential to be further developed into novel insulin sensitizers. Summary of the invention
  • Another object of the invention is to provide a process for the preparation of a compound of formula I.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula I.
  • a further object of the present invention is to provide the use of a compound of formula I for the treatment or prevention of a peroxisome proliferator-activated receptor gamma agonist of diabetes and its complications.
  • the present invention provides a peroxisome proliferator-activated receptor gamma agonist that increases the membership of an insulin sensitizer.
  • the present invention relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof:
  • Ar is any one of the following substituents: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing fluorenyl, nitro, including d- Any one, two or three substituted aryl groups such as a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group.
  • X is 0, S, leg or H.
  • ⁇ is: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl, nitro, carboxyl, ester, aldehyde, halogen, Any one, two or three substituted aryl groups including a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; a thiol group including CrC 4 , Any one, two or three of nitrate, carboxyl, ester, aldehyde, halogen, hydroxy, decyloxy, 'amine, amide, carboxamide, thiol, methylthio, ethylthio Substituted 2-, 3-, or 4-position pyridyl; containing alkyl, nitro, carboxy, ester, al, al
  • such a compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the present invention also provides a kit comprising the above compound for use in the treatment or prevention of diabetes and its complications.
  • the invention is implemented by the following steps:
  • the compounds of the present invention can be prepared in the form of their pharmaceutically acceptable salts with any suitable acid.
  • suitable acid for example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.; A sulfonic acid such as methanesulfonic acid or ethylsulfonic acid; an arylsulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acid or the like can be used.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid
  • Figure 1 Schematic representation of the protein domain of PPAR- ⁇ . '
  • diabetes refers to a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function.
  • the metabolic disorders in the body are not well controlled, leading to chronic complications of tissues such as the eyes, kidneys, nerves, blood vessels and heart, resulting in blindness and gangrene in the lower limbs. Uremic, stroke or myocardial infarction, even life-threatening.
  • plication refers to the pathological symptoms of related tissues and organs that occur with some major diseases.
  • an "effective amount" of a compound for treating a particular disease as used herein refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease.
  • This dose can be administered in a single dose or in accordance with a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable.
  • pharmaceutically acceptable salts, esters or other derivatives includes any salt, ester or derivative that is readily prepared by those skilled in the art by known methods.
  • the compounds thus derived and produced can be administered to animals and humans without toxic effects.
  • the compound is either pharmaceutically active or a prodrug.
  • treatment means that the disease and symptoms are improved in any way, or other beneficial changes. Treatment also includes the use of the compounds of the invention in medicine. As used herein, administration of a particular pharmaceutical composition "improves" a particular disease 3 ⁇ 4] symptom means any relief, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition Related to the application.
  • substantially pure means sufficiently uniform that no impurities can be detected by standard analytical methods used by those skilled in the art to evaluate purity, such as thin layer chromatography (TLC), gel electrophoresis, and High performance liquid chromatography (HPLC). Or sufficiently pure also means that even further purification does not alter the physicochemical properties detectable by the substance, such as enzymatic activity and biological activity.
  • Methods for producing substantially chemically pure compounds for purification are well known to those skilled in the art. However, a substantially chemically pure compound can be a stereoisomer or a mixture of isomers. In this case, further purification may increase the specific activity of the compound.
  • prodrug refers to a compound that is administered in vivo and which can be metabolized or converted into a biological, pharmacologically or therapeutically active form.
  • the pharmaceutically active compound will be modified to reproduce the active compound by metabolic processes.
  • Prodrugs can be designed to alter their metabolic stability, or precursors of transport properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties.
  • substantially are the same or are either hooked or similar, and the understanding of the relevant art may vary in the context, and is generally at least 70%, preferably at least 80%, more preferably at least 90%, The optimal is at least 95% identical.
  • composition refers to any mixture. It may be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof. '
  • object as used herein includes humans and animals; for example, dogs, cats, cows, pigs, rodents, and the like. Experienced practitioners should understand that the subject is suitable and willing to treat and prevent diabetes and its complications.
  • Peroxisome proliferator-activated receptor gamma agonist Peroxisome proliferator-activated receptor gamma agonist
  • the present invention provides an agonist of peroxisome proliferator-activated receptor gamma, which increases the membership of insulin sensitizers.
  • the present invention relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof -
  • Ar is any one of the following substituents: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl group containing -( 4 , nitro , carboxyl group, ester group, aldehyde group, 'halogen, hydroxyl group, decyloxy group, amine Group, one of the two amide groups, carboxamide, mercapto, methylthio, ethylthio, including three or substituted aryl; ⁇ contains include - (: 4 alkyl, nitro, carboxyl, ester Any one, two or three substituted 2-, 3- groups including an aldehyde group, an aldehy
  • X is 0, S, NH or H. .
  • a ri is '. aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing dC 4 1 ⁇ 2 alkyl, exact, carboxyl, thiol Any one, two or three substituted aryl groups, an aldehyde group, a hydroxy group, a methoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; ⁇ -C 4 alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio One, two or three substituted 2-, 3-, or 4-position pyridyl groups; containing ( ⁇ -( ⁇ thiol, nitro, carboxyl,
  • the compound of the present invention may be a specific stereoisomer, such as the R- or S-configuration, or a mixture thereof, for example, a racemic mixture.
  • Compounds contemplated herein include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are hydration types thereof, such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain varying amounts of bound water molecules.
  • the compounds of the invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.
  • a sulfonic acid such as methanesulfonic acid or ethylsulfonic acid
  • an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid can be used.
  • the pharmaceutical composition of the present invention comprises a therapeutically effective amount of a selective I substituted thiazol-4-one compound or a pharmaceutically acceptable salt thereof, and one or more diabetes therapeutic agents including insulin sensitizers, excipients And a pharmaceutical composition composed of an auxiliary material.
  • the compounds of the invention are formulated for any suitable route of administration, for example, intraluminal, subcutaneous, intravenous, intramuscular, intradermal Injection, oral or topical.
  • the method can be administered by injection in a single dose in an ampoule, or in a multi-dose container with an additional buffer.
  • the formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles.
  • the formulations may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in the form of a powder in the form of a suitable carrier, sterile non-pyrogenic water or other solvent.
  • the topical medicament of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.
  • Dosage forms include tablets, lozenges, lenticular capsules, dispersing agents, suspending agents, solutions, capsules, films and the like.
  • the compound of the present invention may be in accordance with a general pharmaceutical mixing technique with a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxy-propyl- ⁇ -cyclodextrin. Finely blended'.
  • a pharmaceutical carrier or excipient such as ⁇ -cyclodextrin and 2-hydroxy-propyl- ⁇ -cyclodextrin. Finely blended'.
  • a special carrier a special carrier for the local or parenteral route can be used.
  • parenteral dosage forms such as compositions for intravenous injection or infusion
  • similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. .
  • parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions.
  • the total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 ml to about 2000 ml. The amount of diluent will vary depending on the total dose administered.
  • the invention also provides a kit for achieving a therapeutic regimen.
  • the kit comprises an effective amount of a compound of the invention in a pharmaceutically acceptable form, alone or in combination with other agents, in one or more containers.
  • a preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffered solution, or other pharmaceutically acceptable sterile liquid.
  • the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably a sterile solution, in a container to reconstitute the complex A solution for injection purposes is formed.
  • Typical pharmaceutically acceptable The solution is saline and dextrose solution.
  • the kit of the present invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in a sterile form. Instructions for use by a doctor or patient may optionally be included.
  • HP1100 HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector.
  • the melting point was measured by a IA6304 melting point apparatus; the iHNMR was measured by a Varian Mercury-300 nuclear magnetic resonance spectrometer (solvent CDC1 3 with internal standard TMS or CD 3 OD or DMSO-d 6 ); ESI-MS by AB Mariner mass spectrometry The instrument was measured by EI by a Finnigan MAT95 mass spectrometer. The raw materials used in the synthesis are all commercially available products.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • the human PPAR- ⁇ expression plasmid and the human RXR expression plasmid were added to the American Addgene company (Add gene. MA, USA); the African green monkey kidney cell CV-1 and the mouse pre-adipocyte 3T3-L1 were purchased from the American model strain. Collection center (American Type Culture Collection, ATCC); Luciferase reporter vector containing PPAR-gamma response elements was purchased from Panomics, USA (Panomics, USA).
  • - Fetal bovine serum FBS, GIBCO/BRL, USA
  • Activated carbon and dextran treatment of fetal bovine serum CD-FBS, Hyclone, USA
  • DMEM medium GIBCO/BRL, USA
  • PPAR- ⁇ protein is a PPAR- ⁇ gene transfected insect cell expression product; positive control drug rosiglitazone (BRL 4965, Cayman, USA); 1H]BRL49653 (53 Ci/mmol, American Radiolabeled Chemicals, Inc., USA); Biotin-binding protein-coated SPA microspheres
  • Wallac 1420 Plate Reader PerkinElmer, USA; Carbon Dioxide Incubator (Forma, USA); Wallac MicroBeta® Liquid Flash Counter (TriLux 1450, PerkinElmer, USA)
  • Biotin-PPRE biotin-labeled PPAR- ⁇ response element
  • reaction buffer 25 mM NaH 2 P0 4 , 80 mM KCL, 0.5 mM MgCl 2 and 10% glycerol, adjusted to pH 7.4 at 4 ° C
  • FlashPlate 200 ⁇ per well, incubate overnight at 4 ° C, aspirate the solution in the well the next day, add 200 buffer The solution was washed twice. After the buffer in the well was removed, 5 positive control drugs or samples to be sieved were added to each well, and the FlashPlateTM was placed at 4 ° C for use.
  • the compound concentration was set to 0, 0.003 ⁇ , 0.016 ⁇ , 0.08 ⁇ , 0.4 ⁇ , 2 ⁇ , 10 ⁇ , 100 ⁇ eight gradients, and the positive drug concentration was set to 0, 0.3 ⁇ , 1.6 ⁇ , 8 ⁇ , 40 ⁇ , 200 ⁇ , 1000 ⁇ , 10000 ⁇ eight gradients.
  • the experimental results are shown in Table 1.
  • the compounds mww7008, 7012, 7018, 7020, 7022 and mww7023 have better receptor binding activities with IC 5Q values of less than 300 nM.
  • HeLa cells were cultured in DMEM medium containing 10% FBS and 2 mM L-type glutamate. The day before transfection, the cells were replaced with DMEM medium containing 10% CD-FBS, and transfected with Fugene6 transfection reagent.
  • the human PPAR- ⁇ expression plasmid, the RXR expression plasmid and the luciferase reporter gene plasmid were mixed at a ratio of 1:1:10, and the ratio of the plasmid to Fugene6 was 1:3, and the cells were uniformly mixed and added to the cells. Incubation was carried out for 6 hours at 37 ° C and 5% CO 2 .
  • the cells were inserted into a 96-well culture plate at 5000 cells/100 ⁇ M/well, and cultured in DMEM medium containing 10% CD-FBS at 37 ° C for 2 hours.
  • the test compound was added, and after 24 hours of culture, the luciferase assay kit was used to detect the enzyme activity, thereby evaluating the pharmacological activity of the compound against PPAR- ⁇ .
  • the concentration of the positive drug and the compound were set to 50 ⁇ , ⁇ , 2 ⁇ , 0.4 ⁇ , 0.08 ⁇ , 0.016 ⁇ , 0.0032 ⁇ , and the results are shown in Table 2.
  • 3T3-L1 cells were inserted into 24-well plates. After 2 days, they were cultured in DMEM medium containing 10% fetal bovine serum, and ⁇ dexamethasone, 1 g/mL insulin and different concentrations of test compounds were added. Incubate for 3 days at 37 ° C and 10% CO 2 , continue to culture for the same culture medium and compound for two days, discard the culture solution, and culture for 2 days in DMEM medium containing 10% fetal bovine serum and 1 g/inL insulin. Discard the culture solution and wash it with PBS. Cell samples were tested as described in the Triglyceride Assay Kit. The absorption wavelength is 505 nM and the reference wavelength is 690 nM.
  • Compounds mww7008, 7012, 7018, 7020, 7022 and 7023 can compete with rosiglitazone for binding to PPAR- ⁇ receptors, wherein compounds mwW 7008, 7012, 7018 have good binding activity and IC 5 o values are less than 50. ⁇ ;

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
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  • Obesity (AREA)
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  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule générale suivante, leurs procédés de fabrication, et leur utilisation en tant que nouvel agoniste du récepteur Ϝ activé par les proliférateurs des peroxisomes (PPAR-Ϝ) dans le traitement du diabète, ainsi que leur deutéropathie. (formule)
PCT/CN2006/001657 2005-07-15 2006-07-13 Composes thiazol-4-one substitues, leurs procedes de fabrication et leur utilisation WO2007009353A1 (fr)

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YANG D.-H. ET AL.: "Organic Reactions in Ionic Liquids; Ionic Liquid-Accelerated Three-Component Reaction: A Rapid One-Pot Synthesis of 3-Alkyl-5-[(Z)-arylmethylidene]-1,3-hiazolidine-2,4-diones", SYNTHESIS, no. 12, 2003, pages 1891 - 1894, XP003007885 *

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