WO2007085202A1 - Dérivés de l'acide oxamique, procédés de préparation et utilisations médicales de ces derniers - Google Patents

Dérivés de l'acide oxamique, procédés de préparation et utilisations médicales de ces derniers Download PDF

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Publication number
WO2007085202A1
WO2007085202A1 PCT/CN2007/000318 CN2007000318W WO2007085202A1 WO 2007085202 A1 WO2007085202 A1 WO 2007085202A1 CN 2007000318 W CN2007000318 W CN 2007000318W WO 2007085202 A1 WO2007085202 A1 WO 2007085202A1
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compound
formula
phenyl
methyl
methoxy
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PCT/CN2007/000318
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English (en)
Chinese (zh)
Inventor
Song Li
Jianlei Kang
Zhibing Zheng
Lili Wang
Dan Qin
Junhai Xiao
Wu Zhong
Hao Cui
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Beijing Molecule Science And Technology Co., Ltd ,
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Publication of WO2007085202A1 publication Critical patent/WO2007085202A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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 relates to novel compounds, and more particularly to a oxalic acid derivative capable of activating a human peroxisome proliferator-activated receptor (hPPAR), and a method for preparing the same, including A pharmaceutical composition of the compound, and the use of the compound in the manufacture of a medicament for the treatment and/or prevention of a hPPAR mediated disease or condition.
  • hPPAR human peroxisome proliferator-activated receptor
  • the peroxisome proliferator-activated receptor (abbreviated as PPAR) is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily equivalent to the glucocorticoid receptor, retinoic acid receptor, and thyroxine receptor.
  • PPAR peroxisome proliferator-activated receptor
  • ot three subtypes of PPARs have been found: ot, gamma and delta (also known as beta), which are encoded by different genes.
  • PPAR y is divided into two isoforms due to different promoters and splicing methods: V l , V 2 , which differ only in the N-terminal sequence (Vida l- Puig, J. Cl in. Inves t. , 97: 2553 -2561, 1996).
  • PPARs When activated by a specific small molecule, PPARs interact with the PPARs response element (PPRE) of the target gene promoter region to regulate expression of the gene. PPARs are important transcriptional regulators of glucose, lipids, and cholesterol metabolism in the body.
  • PPRE PPARs response element
  • PPAR alpha is expressed primarily in tissues with very high catabolic activity in lipids such as brown adipose tissue and liver, followed by kidney, heart, and skeletal muscle (Endocrinology, 1995, 137, 354). It can positively or negatively control genes involved in fatty acid metabolism and intracellular delivery (such as acyl-CoA synthetase, fatty acid-binding protein and lipoprotein lipase) and apolipoproteins (AI) involved in the metabolism of cholesterol and neutral lipids. , All, CI II) gene expression. PPAR ⁇ is mainly present in adipose tissue and is also present in small amounts in skeletal muscle, liver, colon, retina, and immune system.
  • Thiazolidinediones such as rosiglitazone, have been shown to enhance insulin action in patients with type 2 diabetes and reduce serum glucose. Thiazolidinediones have been reported to be potent and selective activators of PPARY and bind directly to PPARY (J. M. Lehmann et al, J. Biol. Chem. 12953-12956, 270 (1995)).
  • Fibrates have been widely used as therapeutic agents for hyperlipidemia, lowering serum triglycerides (20-50%) LDLc (10-15%) and increasing HDLc (10-15%).
  • PPAR alpha Activation of PPARa causes increased fatty acid catabolism and reduced re-synthesis of fatty acids in the liver (causing triglyceride synthesis and VLDL) Transcription of enzymes that produce/secretion is reduced.
  • PPARa activation reduces the production of apoC-III. Reduction of apoC-111 (inhibitor of LPL activity) increases clearance of VLDL (J. Arx et al, Atherosclerosis, J59-S37, 124 (Suppl), (1996))
  • PPAR PPAR involves many biological processes and disease states, including hypercholesterolemia, dyslipidemia, and diabetes. However, current drugs are not ideal because of toxic side effects, etc. Therefore, a safe and effective PPAR agonist is needed. Optionally activate a subtype or activate multiple subtypes simultaneously.
  • the object of the present invention is to find and develop small molecule compounds having hPPAR agonistic activity for the treatment of hPPAR mediated diseases, risk factors or conditions such as dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, Hyperglycemia, type 1 diabetes, type 2 diabetes, insulin resistance, diabetic complications, glucose insufficiency, X syndrome, heart failure, cardiovascular disease, and for suffering from diseases such as obesity, anorexia, bulimia and nerves Regulation of appetite and food absorption in patients with anorexia nervosa.
  • diseases such as dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, Hyperglycemia, type 1 diabetes, type 2 diabetes, insulin resistance, diabetic complications, glucose insufficiency, X syndrome, heart failure, cardiovascular disease, and for suffering from diseases such as obesity, anorexia, bulimia and nerves Regulation of appetite and food absorption in patients with anorexia nervosa.
  • the inventors have discovered that the compounds of formula I below can be used to treat or prevent a variety of diseases, risk factors or conditions mediated by hPPAR.
  • the invention provides a compound of formula I, as well as pharmaceutically acceptable salts and solvates thereof.
  • the invention provides a pharmaceutical composition comprising a compound of the invention.
  • the pharmaceutical composition of the present invention comprises at least one compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the invention provides a process for the preparation of a compound of formula I of the invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the invention provides a method of treating or preventing a hPPAR mediated disease, risk factor or disorder comprising administering to the subject a therapeutically or prophylactically effective amount of a compound of the invention.
  • hPPAR-mediated diseases risk factors or conditions including dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, hyperglycemia, type 1 diabetes, type II diabetes, insulin resistance, diabetic complications, and glucose tolerance Incomplete, X syndrome, heart failure, cardiovascular disease, obesity, anorexia, bulimia and anorexia nervosa.
  • the invention provides a compound of formula I, and pharmaceutically acceptable Salts and solvates,
  • a linear or branched alkyl group selected from H, ( ⁇ -, and a benzyl group optionally substituted by 1 to 5 substituents selected from the group consisting of: halogen, nitro, hydroxy, hydroxymethyl , trifluoromethyl, trifluoromethoxy, d-C 6 straight and branched alkyl, C 2 -C 6 straight and branched alkenyl, oxy, ( ⁇ 2 -( 4 alkenyloxy, Phenoxy, benzyloxy, nitrile, carboxyl and amino;
  • R 2 and R 3 are independently selected from H, ( ⁇ - alkyl, halogen, C 2 -C 6 straight and branched chain linear and branched (6 alkenyl, and C 3 -C 6 cycloalkyl alkyl;
  • R 4 is selected from the group consisting of linear and branched alkyl groups of d-C 4 , halogen, dC 3 alkoxy, trifluoromethyl, trifluoromethoxy, and nitrile;
  • n 0, 1, 2, 3 or 4;
  • X is selected from the group consisting of 0 and S atoms
  • n 1, 2, 3 or 4;
  • One of Y and Z is N and the other is S or 0;
  • Ar is selected from a monocyclic, bicyclic or tricyclic aromatic carbocyclic or heterocyclic group wherein each ring consists of 5 to 6 ring atoms, and the heterocyclic group includes 1 to 4 hetero atoms selected from the group consisting of : 0, S and ⁇ ; the ring may be unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, dC 6 straight and branched alkyl, C 2 -C 6 straight and branched alkenyl, d -C 4 alkoxy, C 2 -C 4 alkenoxy, phenoxy, benzyloxy, Nitrile group, carboxyl group and amino group.
  • the compounds of the invention activate hPPAR.
  • the present invention relates to a compound represented by the formula II, and pharmaceutically acceptable salts and solvates thereof,
  • R 3 is selected from the group consisting of H, d-Cs straight and branched alkyl, halogen, C 2 -C 6 straight and branched alkenyl, and C 3 -C 6 cycloalkyl;
  • R 4 is selected from the group consisting of linear and branched alkyl groups of dC 4 , halogen, ( ⁇ -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, and nitrile groups;
  • n 0, 1, 2, 3 or 4;
  • X is selected from the group consisting of 0 and S atoms
  • n 1, 2, 3 or 4;
  • One of Y and Z is N and the other is S or 0;
  • Ar is selected from a monocyclic, bicyclic or tricyclic aromatic carbocyclic or heterocyclic group wherein each ring consists of 5 to 6 ring atoms, and the heterocyclic group includes 1 to 4 hetero atoms selected from the group consisting of : 0, S and N; the ring may be unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, nitro, hydroxy, hydroxymethyl, trifluoromethyl, trifluoromethoxy, -(: 6 straight-chain and branched alkyl groups, C 2 -C 6 straight-chain and branched alkenyl groups, d-( ⁇ alkoxy, C 2 -C 4 alkenyloxy, phenoxy, benzyloxy Base, nitrile group, carboxyl group and amino group.
  • Preferred compounds of the invention include:
  • the invention relates to the preparation of a compound of the above formula I or a medicament thereof
  • a compound of formula IV is reacted with a substituted p-nitrophenol or a substituted p-nitrophenylthiophenol in the presence of DEAD and PPh 3 to give a compound of formula V, Wherein W is halogen, and X, Y, Z, R 3 , , m, n and Ar are as defined above for formula I;
  • X, Y, Z, R 2 , R 3 , , m, n and Ar are as defined above for Formula I, and R! is as defined above for Formula I but not ⁇ ;
  • the compound of the formula I obtained in the above 3), which is not H, is hydrolyzed to obtain a ⁇ ! !
  • a compound of formula I which comprises hydrolyzing a compound of formula I wherein R 2 is H with a base such as sodium hydroxide or potassium hydroxide or an acid such as dilute hydrochloric acid or trifluoroacetic acid to provide a compound of formula II,
  • the compound of the formula III is added dropwise to a solution of the substituted p-nitrophenol or substituted p-nitrothiophenol in dry acetonitrile, using, for example, cesium carbonate as a base, stirring at room temperature overnight or refluxing for 5 to 8 hours.
  • the reaction mixture was filtered, and the filtrate was evaporated.
  • the silica gel used herein may be silica gel for conventional column chromatography, and has a particle size of 10 - 40 ⁇ m.
  • the compound of the formula VII was added dropwise to the Ot reaction solution of the compound of the formula VI and triethylamine in dichloromethane, and the reaction was terminated after stirring for 4 hours.
  • the reaction was concentrated column (eluent: n-hexane / ethyl acetate system), to give a compound of formula Gamma], i.e. a compound of formula wherein R 2 is I H.
  • Gamma i.e. a compound of formula wherein R 2 is I H.
  • the compound of formula I is hydrolyzed in the presence of a base such as a metal hydroxide or an acid such as dilute hydrochloric acid, trifluoroacetic acid or the like for 2 to 6 hours to give a compound of formula II.
  • a base such as a metal hydroxide or an acid such as dilute hydrochloric acid, trifluoroacetic acid or the like for 2 to 6 hours to give a compound of formula II.
  • the pharmaceutically acceptable salts of the compound of formula I or formula II include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts.
  • suitable salts with acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid.
  • citric acid citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene a salt of sulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, s teroic, citric acid or the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts.
  • Suitable salts with bases include sodium, lithium, potassium, rubidium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-methylglucamine and procaine salts.
  • a compound of the invention includes a compound of formula I or formula II, and pharmaceutically acceptable salts and solvates thereof.
  • the present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs.
  • prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula I.
  • suitable prodrug derivatives are described in "Des ign Of Prodrugs", H Bund Saard, El Sevier, ed., 1985. Regulation method.
  • the invention also includes active metabolites of the compounds of the invention.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient which is useful for in vivo treatment and is biocompatible.
  • the pharmaceutical composition can be prepared in various forms depending on the route of administration.
  • compositions of the present invention comprise an effective amount of a compound of formula I according to the invention, or a pharmaceutically acceptable salt or solvate thereof, such as a hydrate, and one or more suitable pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutically acceptable carrier, diluent or excipient includes, but is not limited to: ion exchangers, alumina, aluminum stearate, ovolipids, serum proteins such as human albumin, buffer substances such as phosphates, glycerol, Sorbic acid, potassium sorbate, partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, trisilicon Magnesium, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax, lanolin.
  • composition of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, Intraventricular, intrasternal, and intracranial injections or inputs, or by means of an explant reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the capsule preparation generally comprises lactose and dried corn starch.
  • Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If necessary, some sweeteners and aromatics may be added to the above oral preparations.
  • a fragrance or coloring agent may be added to the above oral preparations.
  • the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs, and the specific description is as follows: :
  • the compound of the present invention When applied topically to the eye, the compound of the present invention can be formulated into a micronized suspension or solution in a form of isotonic, sterile saline at a pH which may or may not be added with a preservative such as benzyl chloride. Alkoxide.
  • the compound can also be formulated into a bone form such as vaseline.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers for cartilage preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams may be used including but not Limited to: mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions.
  • a sterile injectable preparation including sterile aqueous or oily suspension or sterile injection solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the patient, the activity of the compound used, the time of administration, the rate of metabolism, the severity of the condition. And the subjective judgment of the doctor.
  • a preferred dosage is from 0.01 to 100 mg/kg body weight per day, and the most preferred dose is from 5 to 10 mg/kg body weight per day.
  • the melting point of the compound was determined by a YRT-3 type melting point apparatus, and the temperature was not corrected.
  • the ⁇ -NMR spectrum was measured by a Bruker ARX 400 type nuclear magnetic instrument.
  • FAB mass spectra were determined by a Zabspect high resolution magnetic mass spectrometer.
  • the title compound was prepared from benzamide as a crude material.
  • the title compound was prepared using p-bromobenzamide as a crude material.
  • step (iii) Dissolving the reaction product of step (ii) in 30 ml of hot absolute ethanol, adding a small spoon of Raney Ni, adding hydrazine hydrate (20 mmol) dropwise, heating and refluxing for 0.5-1 hour, cooling, filtering, and spinning the filtrate. Dry is 4-[(2-aryl-4-methyl-1,3-thiazol-5-yl)-methoxy]-phenylamine.
  • Example 2 Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 20 to give N-(4- ⁇ [4-methyl-2-(2,4-dichlorophenyl)- 1,3 -thiazole-5-yl]-methoxy ⁇ -phenyl)-oxalyl.
  • Example 2 Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 21 to give (4- ⁇ [4-methyl-2-(4-tert-butylphenyl)-1) as a pale yellow solid. 3-thiazole-5-yl]-methoxy ⁇ -phenyl)-oxalysine.
  • Example 2 Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 23 to give N-(4- ⁇ [4-methyl-2-(thiophen-3-yl)-1,3 as a pale yellow solid. -thiazol-5-yl]-decyloxy ⁇ -phenyl)-oxalysine.
  • Example 2 Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 24 to give N-(4- ⁇ [4-methyl-2-(Cai-2-yl)-1, 3 as a pale yellow solid. -thiazole-5-yl]-methoxy ⁇ -phenyl)-oxalysine.
  • Example 2 Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 25 to obtain N-(4- ⁇ [4-mercapto-2-(1,3-benzo)dioxole as a pale yellow solid. Cyclopentene-5-yl)-1,3-thiazole-5-yl]-methoxy ⁇ -phenyl)-oxaline.
  • Example 2 Using the preparation method of Example 1, the intermediate 14 was changed to the intermediate 26 to give N- ⁇ 4-[2-(5-methyl-2-phenyl-1, 3-oxazole) as a pale yellow solid. 4-yl)-ethoxy]-phenyl ⁇ -oxalysine.
  • the functional effects of transient transfection of compounds in 293-T cells were screened to determine their ability to activate PPAR subtypes.
  • the effect of the receptor subtype on the transcriptional activity of the same target gene was compared using a pre-established chimeric receptor system, and Rluc was used as an internal standard to reduce endogenous effects.
  • Human PPAR ⁇ , PPAR ⁇ and PPAR ⁇ ligand binding domains are each The yeast transcription factor GAL4 DNA binding domain is fused. Then, the mammalian expression vector pM was ligated, and three plasmids pM-hPPAR ot /GAL4, pM-PPAR ⁇ /GAL4 and pM-PPAR 5 /GAL4 were constructed.
  • the GAL4 DNA binding region was ligated to pB4-tk-luc to constitute PB4-RES-tk-luc (a reporter gene for firefly luciferase containing a GAL4 DNA binding site). Transfection efficiency and endogenous effects were corrected using pRL-CMV-R luc as an internal standard.
  • 293-T cells were seeded into 48-well plates at a cell density of 2 - 4 ⁇ 10 4 /well, and the culture medium was 10% non-fat fetal bovine serum (FCS) in phenol red free antibiotic-free 1640 medium. After 48 hours, the culture medium was changed to 5% defatted FCS phenol red-free antibiotic-free 1640 medium, and then three subtypes of pM-hPPAR/GAL4, pB4-RES-tk-luc and pRL-CMV-, respectively. Three plasmids of Rluc were co-transfected into 293-T cells, and the test compound was added 24 hours later, and the intensity of luciferase was measured 24 hours after the addition of the compound. 0%. DMS0 was used as a blank control.
  • FCS non-fat fetal bovine serum

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Abstract

L'invention concerne des composés représentés par la formule générale 1, ainsi que leurs sels et solvates pharmaceutiquement acceptables. Les substituants de la formule 1 sont tels que définis dans la description. L'invention se rapporte à des compositions pharmaceutiques contenant les composés de la formule générale 1, à leurs procédés de préparation et à leurs utilisations dans la fabrication de médicaments pharmaceutiques destinés à traiter ou prévenir diverses maladies et facteurs dangereux liés au récepteur activé proliférateur du peroxysome humain ('human being's peroxisome proliferator-activating receptor' ou hPPAR).
PCT/CN2007/000318 2006-01-27 2007-01-29 Dérivés de l'acide oxamique, procédés de préparation et utilisations médicales de ces derniers WO2007085202A1 (fr)

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CN2006100023920A CN101007790B (zh) 2006-01-27 2006-01-27 草氨酸衍生物、其制备方法和医药用途
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CN1321152A (zh) * 1998-08-07 2001-11-07 葛兰素集团有限公司 作为hPPARγ和hPPARα激活剂的取代的噁唑和噻唑衍生物
CN1358179A (zh) * 1999-06-25 2002-07-10 葛兰素集团有限公司 噻唑和噁唑衍生物以及它们的药物应用
CN1527822A (zh) * 2000-12-20 2004-09-08 用于治疗与paar有关的疾病的噻唑衍生物
CN1633421A (zh) * 2001-05-31 2005-06-29 葛兰素集团有限公司 HPPAR－α受体的噁唑/噻唑衍生物活化剂
CN1668606A (zh) * 2002-07-03 2005-09-14 霍夫曼-拉罗奇有限公司 噁唑衍生物及其作为胰岛素敏化剂的应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4517196A (en) * 1981-09-05 1985-05-14 Basf Aktiengesellschaft Tricyclic thiazolyloxamic acids and their derivatives, their preparation, and therapeutic agents containing these compounds
CN1321152A (zh) * 1998-08-07 2001-11-07 葛兰素集团有限公司 作为hPPARγ和hPPARα激活剂的取代的噁唑和噻唑衍生物
CN1358179A (zh) * 1999-06-25 2002-07-10 葛兰素集团有限公司 噻唑和噁唑衍生物以及它们的药物应用
CN1527822A (zh) * 2000-12-20 2004-09-08 用于治疗与paar有关的疾病的噻唑衍生物
CN1633421A (zh) * 2001-05-31 2005-06-29 葛兰素集团有限公司 HPPAR－α受体的噁唑/噻唑衍生物活化剂
CN1668606A (zh) * 2002-07-03 2005-09-14 霍夫曼-拉罗奇有限公司 噁唑衍生物及其作为胰岛素敏化剂的应用

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