+

WO1999058519A1 - Acides phenyl-oxo-acetiques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie - Google Patents

Acides phenyl-oxo-acetiques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie Download PDF

Info

Publication number
WO1999058519A1
WO1999058519A1 PCT/US1999/010211 US9910211W WO9958519A1 WO 1999058519 A1 WO1999058519 A1 WO 1999058519A1 US 9910211 W US9910211 W US 9910211W WO 9958519 A1 WO9958519 A1 WO 9958519A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
alkyl
hydrogen
compound
pharmaceutically acceptable
Prior art date
Application number
PCT/US1999/010211
Other languages
English (en)
Inventor
Michael Sotirios Malamas
Jay Edward Wrobel
Arlene Joan Dietrich
Zenan Li
Iwan Gunawan
Original Assignee
American Home Products Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to JP2000548323A priority Critical patent/JP2002514636A/ja
Priority to CA002331120A priority patent/CA2331120A1/fr
Priority to AU37917/99A priority patent/AU3791799A/en
Priority to EP99920419A priority patent/EP1077965A1/fr
Publication of WO1999058519A1 publication Critical patent/WO1999058519A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen 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
    • A61P3/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms

Definitions

  • Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in IDDM subjects, as a consequence of over injection of insulin compared with normal physiological release of the hormone by the endocrine pancreas.
  • NIDDM diabetic diabetic
  • hyperinsulinemia with obesity and with ischemic diseases of the large blood vessels (e.g. atherosclerosis) has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout, Metabolism 1985, 34, 7, and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987, 3, 463).
  • the independent risk factors obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance.
  • insulin resistance is located in peripheral tissues (principally muscle) and correlates directly with the severity of hypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173).
  • insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit further weight gain via thermogenesis, but insulin also increases renal sodium reabsorption and stimulates the sympathetic nervous system in kidneys, heart, and vasculature, creating hypertension.
  • insulin resistance is usually the result of a defect in the insulin receptor signaling system, at a site post binding of insulin to the receptor.
  • Accumulated scientific evidence demonstrating insulin resistance in the major tissues which respond to insulin strongly suggests that a defect in insulin signal transduction resides at an early step in this cascade, specifically at the insulin receptor kinase activity, which appears to be diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).
  • Protein-tyrosine phosphatases (PTPases) play an important role in the regulation of phosphorylation of proteins.
  • PTPases dephosphorylate the activated insulin receptor, attenuating the tyrosine kinase activity. PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase.
  • the enzymes that appear most likely to closely associate with the insulin receptor and therefore, most likely to regulate the insulin receptor kinase activity, include PTP1B, LAR, PTPa and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry 1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B. J. Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).
  • Eur. Pat. Appl. 425359 Al discloses the preparation of 3-benzoylbenzofuran derivatives as cardiovascular drug intermediates.
  • Czech. Patent 265559 B 1 discloses a process for preparing 2-ethyl-3-(3,5-dibromo-4-hydroxybenzoyl) coumarone as an uricosuric agent.
  • Fodor discloses 2-Ethyl-3-(3,5-dibromo-4-hydroxybenzoyl)benzo- furan [HU 18236 (1980)].
  • This invention provides a compound of formula I having the structure
  • A is O, S, or N;
  • B is -(CH2) m - , -CH(OH)-, or carbonyl
  • R 1 is hydrogen, nitro, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or trifluoromethyl
  • R 2 is alkyl of 1-18 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, Het-alkyl wherein the alkyl moiety is 1-6 carbon atoms;
  • R ⁇ a is alkylene of 1-3 carbon atoms
  • G is oxygen, sulfur, or nitrogen
  • R3, R4 are each, independently, hydrogen, halogen, alkyl of 1-3 carbon atoms, aryl of 6-10 carbon atoms or a heterocyclic ring of 5 to 7 ring atom containing 1 to 3 heteroatoms selected from oxygen, nitrogen, sulfur;
  • R 5 is hydrogen, alkyl of 1-6 carbon atoms, -CH(R 7 )R 8 , -C(CH2) n CO 2 R 9 , -C(CH 3 ) 2 CO 2 R 9 . -CH(R7)(CH2)nCO 2 R 9 , or CH(R 7 )C 6 H 4 CO 2 R 9 ;
  • R 7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, or arylalkyl of 7-15 carbon atoms;
  • R 8 is -CO 2 R 10 , -CONHR 10 , tetrazole, or -PO 3 H 2 ;
  • R 9 and R 10 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, or arylalkyl of 7-15 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.
  • Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety.
  • organic and inorganic acids for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulf
  • Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains a carboxylate or phenolic moiety, or similar moiety capable of forming base addition salts.
  • alkali metal salts for example, sodium, lithium, or potassium
  • Alkyl includes both straight chain as well as branched moieties.
  • Halogen means bromine, chlorine, fluorine, and iodine.
  • the aryl portion of the aryl or aralkyl substituent is a phenyl, naphthyl or l,4-benzodioxan-5-yl group; with phenyl being most preferred.
  • the aryl moiety may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms, nitro, cyano, -CO 2 H, alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbon atoms.
  • the compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • Preferred compounds of this invention are those compounds of Formula I, wherein
  • R! is hydrogen or halogen
  • R2 is alkyl of 1-6 carbon atoms or aralkyl of 7-15 carbon atoms
  • R3 and R ⁇ are halogen
  • m 1; or a pharmaceutically acceptable salt thereof.
  • Ketones can be reduced to compounds (6) using the Wolff-Kishner protocol [ref. Org. Reactions, 1948, volume 4].
  • Compound (4) and (6) can be demethylated with BBr 3 [ref. J. Org. Chem. 1974, 39, 1427-1429] to produce phenols (5) and (7).
  • Phenols (5) and (7) can be brominated with bromine and potassium acetate in acetic acid or iodinated with iodine in the presence of sodium hydroxide to produce the brominated or iodinated compounds (9).
  • Compounds (9) can be coupled with aromatic or heteroaromatic boronic acids in the presence of palladium catalysts [ Suzuki protocol; ref. Syn. Comm.
  • compounds (5), (7), (9), and (10) can be used to produce the desired products (11-13).
  • compounds (5), (7), and (9) can be alkylated with methyl bromoacetate in the presence of sodium hydride, to produce oxo-acetic acids methyl esters, that can be saponified with sodium hydroxide to produce the oxo-acetic acids (11).
  • compounds (5), (7), and (9) can be alkylated with bromoacetonitrile to produce oxo-acetonitrile, that upon treatment with sodium azide and ammonium chloride produce tetarzoles (12).
  • compounds (5), (7), and (9) can be treated with 2-hydroxy carboxylates (for example 3-phenyllactic acid) using the Mitsunobu protocol [ref. Synthesis. 1981, 1-27] to produce oxo-acetates, that can be saponified with sodium hydroxide to afford oxo- acetic acids (13).
  • 2-hydroxy carboxylates for example 3-phenyllactic acid
  • the compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance.
  • the compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes.
  • the compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
  • This standard pharmacological test procedure assess the inhibition of rat hepatic microsomal PTPase activity using, as substrate, the phosphotyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase domain, phosphorylated on the
  • Rats (Male Sprague-Dawley rats (Charles River, Springfield, NY) weighing 100-150 g, maintained on standard rodent chow (Purina)) are sacrificed by asphyxiation with CO2 and bilateral thoracotomy. The liver is removed and washed in cold 0.85% (w/v) saline and weighed. The tissue is homogenized on ice in 10 volumes of Buffer A and the microsomes are isolated essentially as described by Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn CR. Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus.
  • liver homogenate is filtered through silk to remove any remaining tissue debris and then is centrifuged at 10,000xg for 20 minutes at 40C. The supernatant is decanted and centrifuged at 100,000xgfor 60 minutes at 40C.
  • the pellet, microsomes and small vesicles is resuspended and lightly homogenized in : 20 M TRIS-HC1 (pH 7.4), 50 mM 2-mercaptoethanol, 250 mM sucrose, 2 mM EDTA, 10 mM EGTA, 2 mM AEBSF, 0.1 mM TLCK, 0.1 mM TPCK, 0.5 mM benzamidine, 25 ug/ml leupeptin, 5 ug/ml pepstatin A, 5 ug/ml;H5B antipain, 5 ug/ml chymostatin, 10 ug/ml aprotinin (Buffer A), to a final concentration of approximately 850 ug protein/ml. Protein concentration is determined by the Pierce Coomassie Plus Protein Assay using crystalline bovine serum albumin as a standard (Pierce Chemical Co., Rockford, IL).
  • the microsomal fraction (83.25 ul) is preincubated for 10 min at 37deg.C with or without test compound (6.25ul) and 305.5 ul of the 81.83 mM HEPES reaction buffer, pH 7.4.
  • Peptide substrate, 10.5 ul at a final concentration of 50 uM, is equilibrated to 37deg.C in a LABLINE Multi-Blok heater equipped with a titerplate adapter.
  • the preincubated microsomal preparation (39.5 ul) with or without drug is added to initiate the dephosphorylation reaction, which proceeds at 37deg.C for 30 min.
  • the reaction is terminated by the addition of 200 ul of the malachite green- ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw).
  • the stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HC1 and 0.5% Tween 20.
  • Sample blanks are prepared by the addition of 200 ul MG/AM/Tw to substrate and followed by 39.5 ul of the preincubated membrane with or without drug.
  • sample absorbances are determined at 650 nm using a platereader (Molecular Devices). Samples and blanks are prepared in quadruplicates. Screening activity of 50 uM (final) drug is accessed for inhibition of microsomal PTPases.
  • PTPase activities based on a potassium phosphate standard curve, are expressed as nmoles of phosphate released/min/mg protein. Test compound PTPase inhibition is calculated as percent of control. A four parameter non-linear logistic regression of PTPase activities using SAS release 6.08, PROC NLIN, is used for determining IC50 values of test compounds. All compounds were administered at a concentration of 50 ⁇ M. The following results were obtained using representative compounds of this invention.
  • This standard pharmacological test procedure assess the inhibition of recombinant rat protein tyrosine phosphatase, PTPIB, activity using, as substrate, the phosphotyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase domain, phosphorylated on the 1146, 1150 and 1151 tyrosine residues.
  • the procedure used and results obtained are briefly described below.
  • Human recombinant PTPIB was prepared as described by Goldstein (see Goldstein et al. Mol. Cell. Biochem. 109, 107, 1992). The enzyme preparation used was in microtubes containing 500-700 ⁇ g/ml protein in 33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.
  • the malachite green-ammonium molybdate method as described (Lanzetta et al. Anal. Biochem. 100, 95, 1979) and adapted for a platereader, is used for the nanomolar detection of liberated phosphate by recombinant PTPIB.
  • the test procedure uses, as substrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc. (San Jose, CA).
  • the peptide, TRDIYETDYYRK corresponding to the 1142-1153 catalytic domain of the insulin receptor, is tyrosine phosphorylated on the 1146, 1150, and 1151 tyrosine residues.
  • the recombinant rPTPlB is diluted with buffer (pH 7.4, containing 33 mM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain an approximate activity of 1000-2000 nmoles/min/mg protein.
  • the diluted enzyme (83.25 mL) is preincubated for 10 min at
  • the reaction is terminated by the addition of 200 mL of the malachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw).
  • the stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HC1 and 0.5% Tween 20.
  • Sample blanks are prepared by the addition of 200 mL MG/AM/Tw to substrate and followed by 39.5 ml of the preincubated recombinant enzyme with or without drug. The color is allowed to develop at room temperature for 30 min. and the sample absorbances are determined at 650 nm using a platereader (Molecular Devices). Sample and blanks are prepared in quadruplicates.
  • PTPase activities based on a potassium phosphate standard curve, are expressed as nmoles of phosphate released/min/mg protein. Inhibition of recombinant PTPIB by test compounds is calculated as percent of phosphatase control.
  • the blood glucose lowering activity of representative compounds of this invention were demonstrated in an jn vivo standard procedure using diabetic (ob/ob) mice. The procedures used and results obtained are briefly described below.
  • the non-insulin dependent diabetic (NIDDM) syndrome can be typically characterizes by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia and insulin resistance.
  • the genetically obese-hyperglycemic ob/ob mouse exhibits many of these metabolic abnormalities and is thought to be a useful model to search for hypoglycemic agents to treat NIDDM [Coleman, D.: Diabetologia 14: 141-148, 1978].
  • mice [Male or female ob/ob (C57 B1/6J) and their lean litermates (ob/+ or +/+, Jackson Laboratories) ages 2 to 5 months (10 to 65 g)] of a similar age were randomized according to body weight into 4 groups of 10 mice. The mice were housed 5 per cage and are maintained on normal rodent chow with water ad libitum. Mice received test compound daily by gavage (suspended in 0.5 ml of 0.5% methyl cellulose); dissolved in the drinking water; or admixed in the diet. The dose of compounds given ranges from 2.5 to 200 mg/kg body weight/day. The dose is calculated based on the fed weekly body weight and is expressed as active moiety.
  • mice received vehicle only.
  • representative compounds of this invention have been shown to inhibit PTPase activity and lower blood glucose levels in diabetic mice, and are therefore useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. More particularly, the compounds of this invention useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges. Effective administration of these compounds may be given at a daily dosage of from about 1 mg/kg to about 250 mg/kg, and may given in a single dose or in two or more divided doses.
  • Such doses may be administered in any manner useful in directing the active compounds herein to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
  • transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues.
  • Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
  • Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
  • Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, , xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar.
  • pharmaceutically acceptable diluents including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, micro
  • Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s).
  • Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
  • the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.
  • Example 2 f2.6-dibromo-4-(2-ethyl-benzofuran-3-carbonyl)-phenoxy1-acetic acid tert-Butyl bromoacetate (0.57 mL, 3.54 mmol) was added dropwise into a mixture of (2-ethyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone (1.0 g, 2.36 mmol), potassium carbonate (0.98 g, 7.08 mmol), and N,N-dimethylformamide (10 mL). The mixture was stirred at 80 °C for 3 hours, poured into water and extracted with ethyl acetate.
  • Example 4 (3.5-Dibromo-2.4-dihydroxy-phenyD-(2-ethyl-benzofuran-3-y -methanone A soultion of bromine (0.73 mL, 14.2 mmol) in acetic acid (3 mL) was added to a solution of the known compound (2,4-dihydroxy-phenyl)-(2-ethyl-benzofuran-3-yl)- methanone (CA reg. no. 90908-66-0) (2.0 g, 7.08 mmol) in 6:1 acetic acid: water (14 mL).
  • This compound was prepared from (2-ethyl-benzofuran-3-yl)-(3-hydroxy-phenyl)- methanone and bromine in substantially the same manner, as described in Example 6, and was obtained as a white solid, mp 153-154 °C; MS m/e 517 (M-H) + ;
  • Example 12 [4-(2-Benzyl- benzo[b]thiophen -3-carbonyl)-2.6-dibromo-phenoxy1-acetic acid This compound was prepared from (2-benzyl-benzo[b]thiophen-3-yl)-(3,5-dibromo-4- hydroxy-phenyl)-methanone and methyl bromoacetate in substantially the same manner, as described in Example 20, and was obtained as an off-white solid, mp 162-163 °C; MS m/e 558 (M) + ; Analysis for: C 24 H 16 Br 2 O 4 S Calc'd: C, 51.45; H, 2.88 Found: C, 51.15; H, 2.71
  • This compound was prepared from (5-chloro-2ethyl-benzofuran-3-yl)-(4-hydroxy- phenyl)-methanone and bromine in substantially the same manner, as described in Example 6, and was obtained as a white solid, mp 126-128 °C; MS m/e 454.9 (M-H) + ; Analysis for: C 17 H ⁇ Br 2 ClO 3 Calc'd: C, 44.53; H, 2.42 Found: C, 44.35; H, 2.13
  • Example 14 (2-Benzyl-benzofuran-3-yl)-(3.5-dibromo-4-hydroxy-phenyl -methanone This compound was prepared from (2-benzyl-benzofuran-3-yl)-(4-hydroxy-phenyl)- methanone and bromine in substantially the same manner, as described in Example 6 , and was obtained as an off-white solid, mp 156-158 °C; MS m/e 484 (M + );
  • This compound was prepared from (2-phenethyl-benzofuran-3-yl)-(3,5-dibromo-4- hydroxy-phenyl)-methanone in substantially the same manner, as described in Example 20, and was obtained as a white solid, mp 163-164 °C; MS m/e 556 (M + ); Analysis for: C 25 H 18 Br 2 O 5 Calc'd: C, 53.79; H, 3.25 Found: C, 53.91; H, 3.14
  • Methyl bromoacetate was added dropwise into a mixture of (4-chloro-2-ethyl- benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone (2.81 g, 6.13 mmol), potassium carbonate (0.93 g) and N,N-dimethylformamide (28 mL). The mixture was stirred for 15 hours poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO 4 .
  • This compound was prepared from 2,6-dibromo-4-(2-ethyl-benzofuran-3-yl-methyl)- phenol and (S)-(-)-3-phenyllactic acid methyl ester in substantially the same manner, as described in Example 21, and was obtained as an oil (0.11 g 91% yield).
  • the product was treated with IN sodium hydroxide (0.19 mL) in methyl alcohol for 30 minutes. Evaporation gave a white solid (0.1 g, 84% yield): mp 225-226 °C ; MS m/e 583 (M-H) + ;

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Furan Compounds (AREA)

Abstract

L'invention concerne des composés de la formule structurelle (I) dans laquelle A représente O, S, ou N, B représente -(CH2)m-, -CH(OH)- ou carbonyle, R1 représente hydrogène, halogène, alkyle C¿1-6?, alcoxy C1-6, ou trifluorométhyle, R?2¿ représente alkyle C¿1-18?, aryle C6-10, arylalkyle C7-15, Het-alkyle où la fraction alkyle possède 1 à 6 atomes de carbone, Het représente un groupe (a) ou (b); R?2a¿ représente alkylène C¿1-3?, G représente oxygène, soufre ou azote, R?3 et R4¿ représentent chacun indépendamment hydrogène, halogène, alkyle C¿1-3?, aryle C6-10, ou un noyau hétérocyclique possédant 5 à 7 chaînons contenant 1 à 3 hétéroatomes choisis parmi oxygène azote, soufre; R?5¿ représente hydrogène, alkyle C¿1-6?, -CH(R?7)R8¿, -C(CH¿2?)nCO2R?9¿, -C(CH¿3?)2CO2R?9, -CH(R7)(CH¿2)nCO2R9, ou CH(R7)C6H4CO2R9; R6 représente hydrogène, halogène, alkyle C¿1-6?, ou OR?5¿; m vaut 1 à 6, n vaut 1 à 6 ; R7 représente hydrogène, alkyle C¿1-6?, aryle C6-10, ou arylalkyle C7-15; R?8¿ représente CO¿2R?10, -CONHR10, tétrazole ou PO¿3?; R?9 et R10¿ représentent chacun indépendamment hydrogène, alkyle C¿1-6?, aryle C6-10, ou arylalkyle C7-15. L'invention concerne également un sel de ces composés, acceptable sur le plan pharmacologique. Ces composés et ce sel sont utiles dans le traitement des troubles métaboliques associés à l'insulinorésistance ou à l'hyperglycémie.
PCT/US1999/010211 1998-05-12 1999-05-10 Acides phenyl-oxo-acetiques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie WO1999058519A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2000548323A JP2002514636A (ja) 1998-05-12 1999-05-10 インスリン抵抗性または高血糖症の治療に有用なフェニルオキソ−酢酸類
CA002331120A CA2331120A1 (fr) 1998-05-12 1999-05-10 Acides phenyl-oxo-acetiques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie
AU37917/99A AU3791799A (en) 1998-05-12 1999-05-10 Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
EP99920419A EP1077965A1 (fr) 1998-05-12 1999-05-10 Acides phenyl-oxo-acetiques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7659698A 1998-05-12 1998-05-12
US09/076,596 1998-05-12

Publications (1)

Publication Number Publication Date
WO1999058519A1 true WO1999058519A1 (fr) 1999-11-18

Family

ID=22133037

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/010211 WO1999058519A1 (fr) 1998-05-12 1999-05-10 Acides phenyl-oxo-acetiques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie

Country Status (6)

Country Link
EP (1) EP1077965A1 (fr)
JP (1) JP2002514636A (fr)
CN (1) CN1308621A (fr)
AU (1) AU3791799A (fr)
CA (1) CA2331120A1 (fr)
WO (1) WO1999058519A1 (fr)

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2186063C1 (ru) * 2001-06-18 2002-07-27 Федеральное государственное унитарное предприятие "Новокузнецкий научно-исследовательский химико-фармацевтический институт" Способ получения 2-бутил-3-(3,5-дийод-4-оксибензоил)бензофурана
US6498182B2 (en) 2000-09-26 2002-12-24 Biovitrum Ab Compounds
WO2003009839A1 (fr) * 2001-07-20 2003-02-06 Karo Bio Ab Benzofuranes et leur utilisation dans le traitement de la fibrillation atriale
FR2862646A1 (fr) * 2003-11-20 2005-05-27 Merck Sante Sas Nouveaux composes antidiabetiques contenant des derives benzofuranes, benzothiophenes
EP1534264A2 (fr) * 2002-03-01 2005-06-01 Sunesis Pharmaceuticals, Inc. Composes modulant l'activite de ptp-1b et de tc-ptp
FR2864536A1 (fr) * 2003-12-24 2005-07-01 Clariant France Sa Procede de preparation de n-alkyl-2 (hydroxy-4-benzoyl)-3 benzofurannes et intermediaires pour sa mise en oeuvre
US7056943B2 (en) 2002-12-10 2006-06-06 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7091230B2 (en) 2001-02-09 2006-08-15 Merck & Co., Inc. 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
US7101903B2 (en) 2002-12-10 2006-09-05 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7186749B2 (en) 2004-08-23 2007-03-06 Wyeth Pyrrolo-naphthyl acids and methods for using them
JP2007511552A (ja) * 2003-11-20 2007-05-10 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング ベンゾフランおよびベンゾチオフェン誘導体を含む抗糖尿病化合物
US7259182B2 (en) 2002-12-10 2007-08-21 Wyeth Aryl, aryloxy, and aklyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7291639B2 (en) 2001-06-20 2007-11-06 Wyeth Aryloxy-acetic acid compounds useful as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7348351B2 (en) 2002-12-10 2008-03-25 Wyeth Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7351730B2 (en) 2001-06-20 2008-04-01 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7605172B2 (en) 2004-08-23 2009-10-20 Wyeth Thiazolo-naphthyl acids
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
US8877801B2 (en) 2013-02-19 2014-11-04 Novartis Ag Compounds and compositions as selective estrogen receptor degraders
KR20190077083A (ko) * 2016-11-16 2019-07-02 쟝쑤 애텀 바이오사이언스 앤드 파머수티컬 컴퍼니 리미티드 Urat1 억제제 및 그의 응용

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10005750B2 (en) * 2010-10-06 2018-06-26 J-Pharma Co., Ltd. Developing potent urate transporter inhibitors: compounds designed for their uricosuric action
CN102718735B (zh) * 2012-05-28 2014-04-23 沈阳药科大学 2-乙基-3-（4-羟基）苯甲酰基苯并呋喃类化合物、组合物及其制备方法
WO2023149549A1 (fr) * 2022-02-03 2023-08-10 国立大学法人富山大学 Nouvelle composition pharmaceutique

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3012042A (en) * 1956-12-21 1961-12-05 Belge Produits Chimiques Sa Benzofurans
DE3342624A1 (de) * 1983-11-25 1984-03-29 Heinfried Dr. 4019 Monheim Grote Benzaronderivate, verfahren zu ihrer herstellung und diese derivate enthaltende arzneimittel
EP0425359A1 (fr) * 1989-10-23 1991-05-02 Sanofi Procédé de préparation de dérivés de benzoyl-3 benzofuranne
WO1991019702A1 (fr) * 1990-06-14 1991-12-26 Pfizer Inc. Derives d'acide 3-aryl-2-hydroxypropionique et leurs analogues utilises comme agents hypoglycemiques
WO1992020331A1 (fr) * 1991-05-17 1992-11-26 Karobio Aktiebolag Ligands de recepteurs
EP0599142A2 (fr) * 1992-11-24 1994-06-01 MERCK PATENT GmbH Méthode de fabrication d'immunoconjugués
WO1996005190A1 (fr) * 1994-08-11 1996-02-22 Karo Bio Ab Derives de 3-benzoyle benzofurane en tant qu'antagonistes de l'hormone thyroidienne
WO1997040017A2 (fr) * 1996-04-19 1997-10-30 Novo Nordisk A/S Modulateurs de molecules possedant des unites de reconnaissance de la phosphotyrosine
DE19624292A1 (de) * 1996-06-18 1998-01-02 Merckle Gmbh Verfahren und Zwischenprodukte zur Herstellung von 1'-Hydroxybenzbromaron

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3012042A (en) * 1956-12-21 1961-12-05 Belge Produits Chimiques Sa Benzofurans
DE3342624A1 (de) * 1983-11-25 1984-03-29 Heinfried Dr. 4019 Monheim Grote Benzaronderivate, verfahren zu ihrer herstellung und diese derivate enthaltende arzneimittel
EP0425359A1 (fr) * 1989-10-23 1991-05-02 Sanofi Procédé de préparation de dérivés de benzoyl-3 benzofuranne
WO1991019702A1 (fr) * 1990-06-14 1991-12-26 Pfizer Inc. Derives d'acide 3-aryl-2-hydroxypropionique et leurs analogues utilises comme agents hypoglycemiques
WO1992020331A1 (fr) * 1991-05-17 1992-11-26 Karobio Aktiebolag Ligands de recepteurs
EP0599142A2 (fr) * 1992-11-24 1994-06-01 MERCK PATENT GmbH Méthode de fabrication d'immunoconjugués
WO1996005190A1 (fr) * 1994-08-11 1996-02-22 Karo Bio Ab Derives de 3-benzoyle benzofurane en tant qu'antagonistes de l'hormone thyroidienne
WO1997040017A2 (fr) * 1996-04-19 1997-10-30 Novo Nordisk A/S Modulateurs de molecules possedant des unites de reconnaissance de la phosphotyrosine
DE19624292A1 (de) * 1996-06-18 1998-01-02 Merckle Gmbh Verfahren und Zwischenprodukte zur Herstellung von 1'-Hydroxybenzbromaron

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6498182B2 (en) 2000-09-26 2002-12-24 Biovitrum Ab Compounds
US7495020B2 (en) 2001-02-09 2009-02-24 Merck & Co., Inc. 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
US7091230B2 (en) 2001-02-09 2006-08-15 Merck & Co., Inc. 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
RU2186063C1 (ru) * 2001-06-18 2002-07-27 Федеральное государственное унитарное предприятие "Новокузнецкий научно-исследовательский химико-фармацевтический институт" Способ получения 2-бутил-3-(3,5-дийод-4-оксибензоил)бензофурана
US7629377B2 (en) 2001-06-20 2009-12-08 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7351730B2 (en) 2001-06-20 2008-04-01 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7368471B2 (en) 2001-06-20 2008-05-06 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7291639B2 (en) 2001-06-20 2007-11-06 Wyeth Aryloxy-acetic acid compounds useful as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
WO2003009839A1 (fr) * 2001-07-20 2003-02-06 Karo Bio Ab Benzofuranes et leur utilisation dans le traitement de la fibrillation atriale
EP1534264A4 (fr) * 2002-03-01 2007-06-13 Sunesis Pharmaceuticals Inc Composes modulant l'activite de ptp-1b et de tc-ptp
EP1534264A2 (fr) * 2002-03-01 2005-06-01 Sunesis Pharmaceuticals, Inc. Composes modulant l'activite de ptp-1b et de tc-ptp
US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7101903B2 (en) 2002-12-10 2006-09-05 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
US7459478B2 (en) 2002-12-10 2008-12-02 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7160918B2 (en) 2002-12-10 2007-01-09 Hassan Mahmoud Elokdah Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor (PAI-1)
US7056943B2 (en) 2002-12-10 2006-06-06 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7566791B2 (en) 2002-12-10 2009-07-28 Wyeth Substituted 3-carbonyl-1h-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7348351B2 (en) 2002-12-10 2008-03-25 Wyeth Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7674818B2 (en) 2002-12-10 2010-03-09 Wyeth Llc Aryl, aryloxy, alkyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7259182B2 (en) 2002-12-10 2007-08-21 Wyeth Aryl, aryloxy, and aklyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7803835B2 (en) 2003-09-25 2010-09-28 Wyeth Llc Substituted acetic acid derivatives
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7534894B2 (en) 2003-09-25 2009-05-19 Wyeth Biphenyloxy-acids
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7141596B2 (en) 2003-10-08 2006-11-28 Incyte Corporation Inhibitors of proteins that bind phosphorylated molecules
JP4819692B2 (ja) * 2003-11-20 2011-11-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング ベンゾフラン類およびベンゾチオフェン類
US7375130B2 (en) * 2003-11-20 2008-05-20 Merck Patent Gesellschaft Mit Beschrankter Haftung Antidiabetic compounds comprising benzofuran and benzothiophene derivatives
US7371774B2 (en) 2003-11-20 2008-05-13 Merck Patent Gmbh Benzofurans and benzothiophenes
WO2005054226A1 (fr) * 2003-11-20 2005-06-16 Merck Patent Gmbh Benzofuranes et benzothiophenes
FR2862646A1 (fr) * 2003-11-20 2005-05-27 Merck Sante Sas Nouveaux composes antidiabetiques contenant des derives benzofuranes, benzothiophenes
JP2007511552A (ja) * 2003-11-20 2007-05-10 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング ベンゾフランおよびベンゾチオフェン誘導体を含む抗糖尿病化合物
JP4786545B2 (ja) * 2003-11-20 2011-10-05 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング ベンゾチオフェン誘導体を含む抗糖尿病化合物
WO2005066149A1 (fr) * 2003-12-24 2005-07-21 Clariant (France) Procede d'elaboration de n-alkyle-2(hydroxy-4 benzoyle)-3 benzofuranes, et intermediaires correspondants
US7544817B2 (en) 2003-12-24 2009-06-09 Clariant (France) Process for the preparation of n-alkyl-2(hydroxy-4benzoyl)-3 benzofurans and intermediates thereof
FR2864536A1 (fr) * 2003-12-24 2005-07-01 Clariant France Sa Procede de preparation de n-alkyl-2 (hydroxy-4-benzoyl)-3 benzofurannes et intermediaires pour sa mise en oeuvre
KR101150627B1 (ko) 2003-12-24 2012-06-01 클라리언트 스페셜티 파인 케미칼스 (프랑스) Ｎ-알킬-2(하이드록시-4 벤조일)-3 벤조퓨란의 제조 방법및 이의 중간 생성물
US7186749B2 (en) 2004-08-23 2007-03-06 Wyeth Pyrrolo-naphthyl acids and methods for using them
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
US7605172B2 (en) 2004-08-23 2009-10-20 Wyeth Thiazolo-naphthyl acids
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
US8877801B2 (en) 2013-02-19 2014-11-04 Novartis Ag Compounds and compositions as selective estrogen receptor degraders
US9321746B2 (en) 2013-02-19 2016-04-26 Novartis Ag Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders
US9561211B2 (en) 2013-02-19 2017-02-07 Novartis Ag Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders
US9931317B2 (en) 2013-02-19 2018-04-03 Novartis Ag Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders
US10058534B2 (en) 2013-02-19 2018-08-28 Novartis Ag Benzothiophene derivatives and compositions thereof as selective estrogen receptor degraders
KR20190077083A (ko) * 2016-11-16 2019-07-02 쟝쑤 애텀 바이오사이언스 앤드 파머수티컬 컴퍼니 리미티드 Urat1 억제제 및 그의 응용
EP3543240A4 (fr) * 2016-11-16 2020-05-06 Jiangsu Atom Bioscience And Pharmaceutical Co., Ltd. Inhibiteur de l'urat1 et son utilisation
KR102263441B1 (ko) * 2016-11-16 2021-06-09 쟝쑤 애텀 바이오사이언스 앤드 파머수티컬 컴퍼니 리미티드 Urat1 억제제 및 그의 응용

Also Published As

Publication number Publication date
JP2002514636A (ja) 2002-05-21
EP1077965A1 (fr) 2001-02-28
CA2331120A1 (fr) 1999-11-18
AU3791799A (en) 1999-11-29
CN1308621A (zh) 2001-08-15

Similar Documents

Publication Publication Date Title
US6166069A (en) Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
EP1077965A1 (fr) Acides phenyl-oxo-acetiques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie
US6110963A (en) Aryl-oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
EP1077967B1 (fr) Acides biphenyl-oxo-acetiques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie
AU756337B2 (en) Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia
US6369072B2 (en) Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
WO1999058521A1 (fr) 11-ARYL-BENZO[B]NAPHTO[2,3-D]FURANES ET 11-ARYL-BENZO[b]NAPHTO[2,3-d]THIOPHENES UTILES DANS LES TRAITEMENTS DE LA RESISTANCE INSULINIQUE ET DE L'HYPERGLYCEMIE
US6699896B1 (en) Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6310081B1 (en) Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6057316A (en) 4-aryl-1-oxa-9-thia-cyclopenta[b]fluorenes
US6221902B1 (en) Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
US6110962A (en) 11-aryl-benzo[B]naphtho[2,3-D]furans and 11-aryl-benzo[B]naphtho[2,3-D]thiophenes useful in the treatment of insulin resistance and hyperglycemia
WO1999058511A1 (fr) Acides oxazol-aryl-carboxyliques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie
EP1077966B1 (fr) Acides biphenyl-sulfonyl-aryl-carboxyliques utiles dans le traitement de l'insulinoresistance et de l'hyperglycemie
US6340676B2 (en) 4-aryl-1-oxa-9-thia-cyclopenta (b) fluorenes
MXPA00011083A (en) Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
MXPA00011090A (en) Oxazole-aryl-carboxylic acids useful in the treatment of insulin resistance and hyperglycemia
CZ20004182A3 (cs) Deriváty benzothiofenu, benzofuranu a indolu
MXPA00011086A (en) Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 99808361.5

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1999920419

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2331120

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2000 548323

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/2000/011083

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: KR

WWP Wipo information: published in national office

Ref document number: 1999920419

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 1999920419

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载