WO1997041103A1 - Esters d'amide de 3-alcoxypyridine-2-acide carboxylique, leur preparation et leur utilisation comme medicaments - Google Patents

Esters d'amide de 3-alcoxypyridine-2-acide carboxylique, leur preparation et leur utilisation comme medicaments Download PDF

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Publication number
WO1997041103A1
WO1997041103A1 PCT/EP1996/001793 EP9601793W WO9741103A1 WO 1997041103 A1 WO1997041103 A1 WO 1997041103A1 EP 9601793 W EP9601793 W EP 9601793W WO 9741103 A1 WO9741103 A1 WO 9741103A1
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Prior art keywords
formula
compounds
radical
alkyl
hydrogen
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PCT/EP1996/001793
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German (de)
English (en)
Inventor
Klaus Weidmann
Karl-Heinz Baringhaus
Georg Tschank
Martin Bickel
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Hoechst Aktiengesellschaft
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Priority to PL96329770A priority Critical patent/PL329770A1/xx
Priority to PCT/EP1996/001793 priority patent/WO1997041103A1/fr
Priority to KR1019980708679A priority patent/KR20000065090A/ko
Priority to JP09538479A priority patent/JP2000509047A/ja
Priority to CA002253282A priority patent/CA2253282A1/fr
Priority to NZ332524A priority patent/NZ332524A/xx
Priority to EP96914152A priority patent/EP0900202A1/fr
Priority to AU57628/96A priority patent/AU5762896A/en
Publication of WO1997041103A1 publication Critical patent/WO1997041103A1/fr
Priority to NO984878A priority patent/NO984878L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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

Definitions

  • the invention relates to 3-alkoxypyridine-2-carboxylic acid amide esters, their preparation and their use for inhibiting collagen biosynthesis and their use as medicaments for the treatment of fibrotic diseases.
  • Inhibitors of prolyl hydroxylase are therefore suitable substances in the therapy of diseases in which the deposition of collagens contributes significantly to the clinical picture. These include a. Fibrosis of the lungs, liver and skin (scleroderma and scarring after burns, injuries and surgical interventions) and atherosclerosis.
  • N-oxalylglycines as inhibitors of prolyl-4-hydroxylase are known from J. Med. Chem. 1 992, 35, 2652-2658 (Cunliffe et al.) And EP-A-0 457 1 63.
  • the object was therefore to provide compounds which are distinguished by a particularly high in vivo and / or in vitro activity, in particular when used systemically and / or locally.
  • 3-alkoxypyridine-2-carboxylic acid ester amides of the formula I are particularly potent inhibitors of collagen biosynthesis.
  • the compounds according to the invention represent a selection from the compounds described in EP-A-0 650 960. In comparison to the compounds mentioned in the European patent application, they are distinguished by a particularly high in vivo and in vitro activity, especially when used systemically and / or locally against fibrotic diseases. These include, for example, fibroids of the lungs, liver, kidney, heart, eye and skin, and in the case of atherosclerosis.
  • the compounds of the formula I lead to a strong inhibition of collagen biosynthesis in the most varied of cells (e.g. normal human skin fibroblasts, primary fat storage cells from rat liver, rat liver epithelial cells and in organ cultures of calvaria).
  • cells e.g. normal human skin fibroblasts, primary fat storage cells from rat liver, rat liver epithelial cells and in organ cultures of calvaria.
  • the compounds of the formula I are, for example, suitable for local use to prevent / reduce scarring after surgical interventions on the human body and for local use in the postoperative treatment of eye diseases, for example the postoperative treatment of glaucoma and in radiation-induced or chemotherapy-induced Fibrosis, especially on the lungs.
  • the compounds according to the invention are ester prodrugs of the corresponding carboxylic acids of the formula I, in which B denotes a carboxyl group.
  • the compounds of the formula I are cleaved in the living organism (in vivo) and in cell cultures (in vitro) to give compounds of the formula I in which B denotes a carboxyl group or its salts.
  • the compounds of the formula I After application of the compounds of the formula I, they inhibit collagen biosynthesis, which can be observed in vivo and in vitro, the compounds of the formula I in which B denotes a carboxyl group or its salts being formed. These compounds inhibit prolyl 4-hydroxylase and therefore lead to an inhibition of collagen biosynthesis.
  • R 1 , R 2 and R 3 are hydrogen, R 4 (C r C 6 ) alkyl,
  • A represents a -CH 2 group in which a hydrogen can be replaced by a methyl group
  • G represents the remainder of an alcohol GOH, including the physiologically active salts.
  • R ⁇ R 2 and R 3 are hydrogen
  • A represents a -CH 2 group in which a hydrogen can be replaced by a methyl group
  • G is a branched or unbranched or cyclic (C 1 -C 4 alkyl) radical, or a branched or unbranched or cyclic (C 2 -C 20 ) alkenyl radical, a corresponding (C 2 -C 20 ) alkynyl radical, means a corresponding (C 4 -C 20 ) alkeninyl residue or a retinyl residue, where the residues can each contain one or more multiple bonds, or denotes a phenylalkyl residue, the above residues in particular one or more substituents from the series Hydroxy, halogen, cyano, trifluoromethyl, carboxy, (C, -C 1 2 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 5 -C 8 ) cycloalkenyl, (C r C 1 2 ) alkoxy , (C r C 1 2 ) -alkoxy- (C r C 12 )
  • R 1 , R 2 and R 3 are hydrogen
  • A represents a -CH 2 group in which a hydrogen atom can be replaced by a methyl group
  • G is a branched or unbranched or cyclic aliphatic (C r C 18 ) alkyl radical, a (C 3 -C 8 ) cycloalkyl (C r C 8 ) alkyl radical, a branched or unbranched (C 2 -C 1 8 ) -Alkenyl radical, such as, for example, a geranyl, farnesyl or retinyl radical, or a corresponding (C 2 -C 18 ) -alkynyl radical, a benzyl, phenethyl, phenylpropyl or phenylbutyl radical,
  • radicals are a substituent from the series hydroxy, (C r C 4 ) alkoxy, (C r C 6 ) alkylcarbonyloxy, (C 3 -C 8 ) cycloalkylcarbonyloxy, benzoyloxy or phenyl (C r C 4 ) - alkylcarbonyloxy, including the physiologically active salts.
  • R 1 , R 2 and R 3 are hydrogen
  • A represents a -CH 2 group in which a hydrogen atom can be replaced by a methyl group
  • G is a branched or unbranched or cyclic aliphatic (C i "-C 8 ) alkyl radical, a (C 3 -C 8 ) cycloalkyl (C, -C 4 ) alkyl radical, a branched or unbranched (C 2 - C 18 ) alkenyl, benzyl, phenethyl, phenylpropyl or phenylbutyl the physiologically active salts.
  • R 1 , R 2 and R 3 are hydrogen
  • A represents a -CH 2 group in which a hydrogen is replaced by a
  • Methyl group can be replaced, and B means -CO 2 G, wherein
  • G is a branched or unbranched (C 1 -C 18 ) alkyl or
  • (C 2 -C 18 ) alkenyl radical means, including the physiologically active salts.
  • R 1 , R 2 and R 3 are hydrogen
  • A is a -CH 2 group
  • G is a branched or unbranched (C 1 -C l 8) alkyl or (C 2 -C 18) -
  • Alkenyl radical means, including the physiologically active salts.
  • R 1 , R 2 and R 3 are hydrogen
  • A is a -CH 2 group
  • G is a linear (C 1 -C l 8) -alkyl radical, including the physiologically active salts. Particularly preferred are those compounds of formula I in which G is a linear (C r C 1 6) alkyl radical, including the physiologically active salts.
  • the invention further comprises salts of the compounds of the general formula I.
  • Salt binding with acidic reagents can take place on the pyridine N atom.
  • Reagents used are, for example, toluenesulfonic acid, methanesulfonic acid, HCl, H 2 SO 4 , H 3 PO 4 and medicaments which contain an acidic group.
  • the invention relates to the compounds of the general formula I and the physiologically tolerable salts for use in inhibiting collagen biosynthesis, in particular in various cells.
  • the invention relates to the compounds of general formula I and the physiologically acceptable salts for use in inhibiting prolyl 4-hydroxylase in vivo and in vitro.
  • the invention further relates to the compounds of general formula I and the physiologically tolerable salts for use in fibrotic diseases of the lungs, liver, kidney, heart, eye and skin.
  • the compounds can also be used in atherosclerosis. Systemic and / or local applications are used here.
  • the invention relates to compounds of the general formula I and the physiologically tolerable salts for topical use, in particular as inhibitors of collagen biosynthesis, as antifibrotic active substances and in the case of disease forms which result from an increased formation of Connective tissue (collagen) are caused.
  • These include the applications for avoiding / reducing scarring after surgical interventions on the human body and in the postoperative treatment of eye surgery, for example in glaucoma surgery and in radiation-induced or chemotherapy-induced fibrosis, in particular on the lungs.
  • the invention relates to the compounds of general formula I for use as medicaments.
  • the invention relates to compounds of the formula I for topical use in fibroids of the skin, lungs and eyes, in particular for postoperative treatment of glaucoma.
  • the invention further relates to a process for the preparation of compounds of the general formula I.
  • the compounds of the formula IV are esterified with an alcohol GOH; or iii) the compounds of the formula V are alkylated with R 4 X, where X is a leaving group, in particular halogen, -OSO 2 Me, -OSO 2 phenyl and others.
  • reaction i1 Suitable methods for amide formation (reaction i1) are the methods of carbonyl activation and the condensation reactions known from peptide chemistry.
  • the substances known to the person skilled in the art can be used as reagents for carboxylic acid activation.
  • the activated derivatives of the compounds of the formula II are reacted in situ with the amide derivatives of the formula III.
  • a suitable condensing agent is, for example, the combination of N, N'-dicyclohexylcarbodiimide / N-hydroxy-1 H-benzotriazole and N-ethylmorpholine.
  • Suitable solvents are dichloromethane, carbon tetrachloride, butyl acetate, ethyl acetate, toluene, tetrahydrofuran, dimethoxyethane, 1,4-dioxane, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, nitromethane and / or pyridine.
  • the compounds of formula I according to the invention have valuable pharmacological properties and, in particular, show antifibrotic activity.
  • Collagen content of subcutaneously implanted "cotton pellets" or polyvinyl sponges e.g. Boyle, E., Mangan, F.R. , Br. J. Ep. Pathnol. 61: 351-60, 1980; and
  • Lung collagen content after radiation-induced or chemically induced fibrosis radiate. e.g. Ward, H.E. et al., Res., 1 36, 1 5-21, 1993, and Santana, A. et al. At the. J. Respir. Cell. Mol. Biol. 1 3: 34-44, 1995.
  • Calvaries are prepared from 1 5 day old chicken embryos and washed for 3 min at 37 ° C in Hanks' balanced salt solution minimum essential medium Eagle (HMEM, BioWhittaker, Walkersville, MD, USA). 4 calvaries each are incubated in glass vessels with 1.5 ml of HMEM with the addition of 2 mM glutamine and 1 ⁇ O [U- 14C] Prol ⁇ n and various inhibitor concentrations at 37 ° C. for 2.5 h. The incubation is ended by placing the sample vessels in ice. The medium is removed and the calvaries are briefly washed with 1 ml bidest H 2 O.
  • HMEM Hanks' balanced salt solution minimum essential medium Eagle
  • the amino acids are then derivatized for 20 min at room temperature in a solution of ethanol / triethylamine / phenyl isothiocyanate / H 2 O 7: 1: 1: 1 (v: v: v: v) and dried again.
  • the samples are dissolved in 1 50 ⁇ l of a phosphate buffer (5 mM Na 2 HPO 4 , pH 7.4 / acetonitrile 95: 5 (v: v)) and centrifuged at 10,000 g for 5 min. 50 ⁇ ⁇ are used for analysis.
  • HPLC chromatography is carried out on a C 1 8 reverse phase column Ultrasphere ODS 3 ⁇ m, 4.6 nim x 7.5 cm (Beckman) at 50 ° C with the following gradient system:
  • the compounds of the formula I can be used as medicaments in the form of pharmaceutical preparations which they may contain with compatible pharmaceutical carriers.
  • the compounds can be used as remedies e.g. find use in the form of pharmaceutical preparations which mix these compounds with a pharmaceutical, organic or inorganic carrier suitable for enteral, percutaneous, parenteral and inhalation administration, e.g. Contain water, gum arabic, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly etc.
  • they can be administered orally in doses of 0.1 to 25 mg / kg / day, preferably 1 to 5 mg / kg / day or parenterally in doses of 0.01 to 5 mg / kg / day, preferably 0.01 to 2.5 mg / kg / day, in particular 0.5 to 1.0 mg / kg / day.
  • the dosage can also be increased in severe cases. In many cases, however, lower doses are sufficient.
  • These figures refer to an adult weighing approximately 75 kg.
  • the 3-methoxypyridine-2-carboxylic acid used as starting compound in the following examples was obtained starting from 4-chloro-3-methoxy-2-methylpyridine, which was obtained from maltol ( cf. EP-A-0 208 452 and EP- A-0 304 732).
  • substituted pyridine-2-carboxylic acid (glycylester) amides are referred to as substituted pyridine-2-carboxylic acid (glycylester) amides.
  • Example 7 3-methoxypyridine-2-carboxylic acid N - (((1-nonyloxy) carbonyl) methyl) amide
  • Example 8 3-methoxypyridine-2-carboxylic acid N - (((1-decylox ⁇ ) carbonyl) methyl) amide
  • Example 1 3-methoxypyridine-2-carboxylic acid N - (((1-propyloxy) carbonyl) methyl) amide
  • Example 1 (3-Methoxypyridine-2-carboxylic acid N - (((2-propyloxy) carbonyl) methyl) amide
  • Example 13 3-methoxypyridine-2-carboxylic acid N - (((1-tridecyloxy) carbonyl) methyl) amide
  • Example 1 3-Methoxypyridine-2-carboxylic acid N - (((4-heptyloxy) carbonyl) methyl) amide

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pulmonology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne des esters d'amide de 3-alcoxypyridine-2-acide carboxylique de la formule (I) dans laquelle R?1, R2 et R3¿ désignent hydrogène, R4 désigne alkyle(C¿1?-C6), A désigne un groupe -CH2 dans lequel un hydrogène peut être remplacé par un groupe méthyle, et B désigne -CO2G, G désignant le reste d'un alcool GOH, y compris les sels à action physiologique. L'invention concerne leur préparation, leur utilisation pour inhiber la biosynthèse du collagène, ainsi que leur utilisation comme médicaments pour traiter des affections fibreuses.
PCT/EP1996/001793 1996-04-30 1996-04-30 Esters d'amide de 3-alcoxypyridine-2-acide carboxylique, leur preparation et leur utilisation comme medicaments WO1997041103A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
PL96329770A PL329770A1 (en) 1996-04-30 1996-04-30 3-alkoxypyridine-2-carboxylic amidoesters, method of obtaining them and their application as therapeutic agents
PCT/EP1996/001793 WO1997041103A1 (fr) 1996-04-30 1996-04-30 Esters d'amide de 3-alcoxypyridine-2-acide carboxylique, leur preparation et leur utilisation comme medicaments
KR1019980708679A KR20000065090A (ko) 1996-04-30 1996-04-30 3-알콕시피리딘-2-카복실산아미드에스테르,이의제조방법및약제로서의이의용도
JP09538479A JP2000509047A (ja) 1996-04-30 1996-04-30 ３―アルコキシピリジン―２―カルボキサミドエステル類、その製法および薬剤としてのその使用
CA002253282A CA2253282A1 (fr) 1996-04-30 1996-04-30 Esters d'amide de 3-alcoxypyridine-2-acide carboxylique, leur preparation et leur utilisation comme medicaments
NZ332524A NZ332524A (en) 1996-04-30 1996-04-30 3-alkoxypyridine-2-carboxylic acid amide esters as inhibitors of collagen biosynthesis
EP96914152A EP0900202A1 (fr) 1996-04-30 1996-04-30 Esters d'amide de 3-alcoxypyridine-2-acide carboxylique, leur preparation et leur utilisation comme medicaments
AU57628/96A AU5762896A (en) 1996-04-30 1996-04-30 3-alkoxypyridine-2-carboxylic acid amide esters, their preparation and the ir use as drugs
NO984878A NO984878L (no) 1996-04-30 1998-10-19 Fremstilling og anvendelse som medikamenter av 3-alkoksypyridin-2-karboksylsyreamidestere

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1996/001793 WO1997041103A1 (fr) 1996-04-30 1996-04-30 Esters d'amide de 3-alcoxypyridine-2-acide carboxylique, leur preparation et leur utilisation comme medicaments

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WO1997041103A1 true WO1997041103A1 (fr) 1997-11-06

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PCT/EP1996/001793 WO1997041103A1 (fr) 1996-04-30 1996-04-30 Esters d'amide de 3-alcoxypyridine-2-acide carboxylique, leur preparation et leur utilisation comme medicaments

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EP (1) EP0900202A1 (fr)
JP (1) JP2000509047A (fr)
KR (1) KR20000065090A (fr)
AU (1) AU5762896A (fr)
CA (1) CA2253282A1 (fr)
NO (1) NO984878L (fr)
WO (1) WO1997041103A1 (fr)

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EP1379630A2 (fr) * 2001-03-21 2004-01-14 Isis Innovation Limited Procedes, methodes et dispositifs concernant l'hydroxylase de l'hif
US7811595B2 (en) 2006-06-26 2010-10-12 Warner Chilcott Company, Llc Prolyl hydroxylase inhibitors and methods of use
US8050873B2 (en) 2006-03-07 2011-11-01 Warner Chilcott Company Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US8309537B2 (en) 2009-11-06 2012-11-13 Aerpio Therapeutics Inc. Compositions and methods for treating colitis
US8865748B2 (en) 2011-06-06 2014-10-21 Akebia Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
US9145366B2 (en) 2011-06-06 2015-09-29 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
CN107105649A (zh) * 2014-12-30 2017-08-29 美国陶氏益农公司 具有杀真菌活性的吡啶酰胺
US9987262B2 (en) 2013-11-15 2018-06-05 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
EP2289531B1 (fr) * 2001-12-06 2018-07-04 Fibrogen, Inc. Médicaments pour le traitement ou la prévention de l'anémie
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
US10173981B2 (en) 2014-12-30 2019-01-08 Dow Agrosciences Llc Picolinamides as fungicides
US10172354B2 (en) 2012-12-28 2019-01-08 Dow Agrosciences Llc Synergistic fungicidal mixtures for fungal control in cereals
US10182568B2 (en) 2014-12-30 2019-01-22 Dow Agrosciences Llc Use of picolinamide compounds as fungicides
US10188109B2 (en) 2014-12-30 2019-01-29 Dow Agrosciences Llc Picolinamide compounds with fungicidal activity
US10433555B2 (en) 2014-12-30 2019-10-08 Dow Agrosciences Llc Picolinamide compounds with fungicidal activity
US11155520B2 (en) 2018-03-08 2021-10-26 Dow Agrosciences Llc Picolinamides as fungicides
US11191269B2 (en) 2017-05-02 2021-12-07 Dow Agrosciences Llc Use of an acyclic picolinamide compound as a fungicide for fungal diseases on turfgrasses
US11206828B2 (en) 2017-05-02 2021-12-28 Corteva Agriscience Llc Synergistic mixtures for fungal controls in cereals
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
US11639334B2 (en) 2018-10-15 2023-05-02 Corteva Agriscience Llc Methods for synthesis of oxypicolinamides
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US11771085B2 (en) 2017-05-02 2023-10-03 Corteva Agriscience Llc Synergistic mixtures for fungal control in cereals
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia

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FR2803592A1 (fr) * 2000-01-06 2001-07-13 Aventis Cropscience Sa Nouveaux derives de l'acide 3-hydroxypicolinique, leur procede de preparation et compositions fongicides les contenant.
JP6814134B2 (ja) * 2015-05-28 2021-01-13 日本たばこ産業株式会社 糖尿病性腎症を治療又は予防する方法

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EP0650960A1 (fr) * 1993-11-02 1995-05-03 Hoechst Aktiengesellschaft Esters de carboxamide hétérocycliques substitués, leur préparation et leur utilisation comme médicaments

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EP0650960A1 (fr) * 1993-11-02 1995-05-03 Hoechst Aktiengesellschaft Esters de carboxamide hétérocycliques substitués, leur préparation et leur utilisation comme médicaments

Cited By (67)

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US8535899B2 (en) 2001-03-21 2013-09-17 Isis Innovation Limited Assay for identifying a modulator of HIF hydroxylase
EP1379630B1 (fr) * 2001-03-21 2012-09-26 Isis Innovation Limited Procedes, methodes et dispositifs concernant l'hydroxylase de l'hif
US9844546B2 (en) 2001-03-21 2017-12-19 Oxford University Innovation Limited Antibody against human HIF hydroxylase
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CA2253282A1 (fr) 1997-11-06
AU5762896A (en) 1997-11-19
JP2000509047A (ja) 2000-07-18
EP0900202A1 (fr) 1999-03-10
NO984878D0 (no) 1998-10-19
NO984878L (no) 1998-12-29
KR20000065090A (ko) 2000-11-06

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