EP1148879A2 - Utilisation d'amides d'acides pyrazol-carboxyliques - Google Patents

Utilisation d'amides d'acides pyrazol-carboxyliques

Info

Publication number
EP1148879A2
EP1148879A2 EP00909096A EP00909096A EP1148879A2 EP 1148879 A2 EP1148879 A2 EP 1148879A2 EP 00909096 A EP00909096 A EP 00909096A EP 00909096 A EP00909096 A EP 00909096A EP 1148879 A2 EP1148879 A2 EP 1148879A2
Authority
EP
European Patent Office
Prior art keywords
general formula
anemia
compounds
treatment
optionally
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00909096A
Other languages
German (de)
English (en)
Inventor
Jürgen Stoltefuss
Gabriele Bräunlich
Berthold Hinzen
Thomas Krämer
Josef Pernerstorfer
Thomas STÜDEMANN
Ulrich Nielsch
Martin Bechem
Emanuel Lohrmann
Christoph Gerdes
Michael Sperzel
Klemens Lustig
Lorenz Mayr
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
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 Bayer AG filed Critical Bayer AG
Publication of EP1148879A2 publication Critical patent/EP1148879A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the use of pyrazolecarboxamides for the production of medicaments for the prophylaxis and / or treatment of anemias, new pyrazolecarboxamides and processes for their preparation.
  • EPO Erythropoietin
  • the EPO levels in the blood are usually low, but if the O 2 content in the blood drops, there is an increase in EPO synthesis and therefore an increase in EPO levels in the blood. As a result, the hematopoiesis is stimulated and the hematocrit increases. This leads to an increase in the O 2 transport capacity in the blood. If the number of erythrocytes is sufficient to transport enough O 2 , the EPO blood concentration drops again.
  • a lack of oxygen supply can have a number of causes, such as excessive blood loss, long stays at high altitudes, but also kidney failure or bone marrow suppression.
  • Rh EPO recombinant human (rh) EPO stimulates erythropoiesis and has therefore been used in the treatment of severe anemias. Rh EPO is also used to increase the body's own blood cells in order to reduce the need for foreign blood transfusions.
  • rh EPO is not available orally and must therefore i.p., i.v. or subcutaneously, which limits its use to the treatment of severe anemia.
  • Substituted pyrazoles are known from publication WO 97/19039.
  • the pyrazole derivatives are synthesized on the solid phase. After cleavage, pyrazole phenyl carboxamides are obtained. The use as a medicine is not described.
  • the present invention now relates to the use of pyrazolecarboxamides of the general formula (I),
  • A, D, E and G are the same or different and stand for hydrogen, halogen, trifluoromethyl, hydroxy or for (C, -C 6 ) -alkyl or for (C, -C 6 ) -alkoxy,
  • R 1 represents hydrogen or (C, -C 6 ) alkyl
  • R 2 represents (C 6 -C ) 0 ) aryl or a 5- to 6-membered aromatic, optionally benzo-fused heterocycle with up to 3 heteroatoms from the series S, N and / or O, the aromatic ring systems listed above optionally up to 3 times the same or different due to halogen, tri- fluoromethyl, trifluoromethoxy, (C, -C 6 ) alkyl, (C, -C 6 ) alkoxy or (C, -C 6 ) alkoxycarbonyl may be substituted,
  • medicinal products which are suitable for the prophylaxis and / or treatment of diseases, for example anemia.
  • the compounds can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
  • the invention relates to both the enantiomers or diastereomers or their respective mixtures.
  • the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • Physiologically acceptable salts of the compounds can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpipe
  • (C 6 -C 10 ) aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • (C, -C 6 ) alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms.
  • a straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. Examples include: methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • a straight-chain or branched alkyl radical having 1 to 3 carbon atoms is particularly preferred.
  • (C r C 6 ) alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms.
  • a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms is preferred. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
  • a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is particularly preferred.
  • (C i -C fi ) - Alkoxycarbonyl stands for a straight-chain or branched alkoxycarbonyl radical with 1 to 6 carbon atoms.
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred. Examples include: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 3 carbon atoms is particularly preferred.
  • Row S, O and / or N stands for example for pyridyl, pyrimidyl, pyridazinyl, Thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Pyridyl, pyrimidyl, pyridazinyl, furyl and thienyl are preferred.
  • a 5- to 6-membered aromatic benzocondensed heterocycle with up to 3 heteroatoms from the series S, O and / or N represents, for example, benzothiophene
  • Indole, quinoline or benzofuran, benzothiophene and quinoline are preferred.
  • A, D, E and G are the same or different and represent hydrogen, fluorine, chlorine, bromine or trifluoromethyl,
  • R 1 represents hydrogen or methyl
  • R 2 represents phenyl, furyl, thienyl, benzothiophene or pyridyl, the aromatic ring systems listed above optionally being up to 2 times identical or different by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy,
  • (C, -C 4 ) alkyl or (C, -C 4 ) alkoxy or (C, -C 4 ) alkoxycarbonyl may be substituted
  • A, D, E and G stand for hydrogen and
  • R 1 represents hydrogen or methyl
  • R 2 represents phenyl, benzothiophene or pyridyl, where the aromatic ring systems listed above may optionally be substituted by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, methyl or methoxy
  • the invention also relates to new substances of the general formula (Ia) in which
  • a ', D', E ', G' and R 1 have the meaning of A, D, E, G and R 1 given above,
  • R 3 represents a (C, -C 4 ) alkyl radical
  • R 1 has the meaning given above, reacted, the compounds then split off from the resin and optionally (ie for R 1 ⁇ H) separated into the isomers,
  • carboxylic acid derivative e.g. carboxylic acid halide, anhydride or imidazolide
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents for the processes described above.
  • halogenated hydrocarbons such as dichloromethane, trichloromethane,
  • Tetrachloromethane 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloro- ethylene or trichlorethylene, hydrocarbon such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethylacetamide, acetonitrile or DMSO as well as ethers such as diethyl ether, dioxane or tetrahydrofuran. It is also possible to use mixtures of the solvents. Dimethylformamide and dichloromethane are particularly preferred.
  • the reactions described above generally take place in a temperature range from -78 ° C. to the reflux temperature, preferably from 0 ° C. to the boiling point of the solvent used.
  • the reactions described above can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • Suitable dehydrating reagents for process [B] are carbodiimides such as, for example, diisopropylcarbodiimide, dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1, 2-oxazolyl compounds such as 2-ethazolium compounds such as 2-ethazolium compounds 5-phenyl-l, 2-oxazolium-3-sulfonate or propanephosphoric anhydride or isobutylchloroformate or benzotriazolyloxy-tris- (dimethylamino) phosphonium hexyfluorophosphate or phosphonic acid diphenyl ester amide or methanesulfonyl chloride, optionally in the presence of base or methylamine aminoline triethene such as triethylamine or ethy
  • amino-functionalized polystyrenes are used as the solid phase.
  • Amino-functionalized polystyrene-polyethylene copolymers which are modified with a polyethylene glycol chain are preferred.
  • So-called SAM resins (abbreviation for standard amide resin) and RAM resins (abbreviation for Rink amide resin) are particularly preferred. Examples of amino functional, usable according to the invention ,
  • Resized resins are Tentagel SAM (S 30022) and Tentagel R RAM (R 28 023), both from Rapp Polymer GmbH.
  • the compounds of formula (V) are new and can be prepared, for example, by
  • R 3 represents a (C, -C 4 ) alkyl radical
  • R 1 has the meaning given above, reacted in inert solvents and the esters of the general formula (VIII) obtained
  • R 1 is H
  • N-alkylation isomeric mixtures with R 1 ⁇ H are prepared, which are separated by suitable separation methods in compounds of the formula (V) with R 1 for (C, -C 6 ) -alkyl which are then saponified,
  • R 2 has the meaning given above
  • R 4 represents a (C, -C 4 ) alkyl chain
  • R 2 and R 4 have the meaning given above
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents for processes [C] and [D]. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acetylene methanol, tetrahydrofuran, tetrahydrofuran Ethanol, 2-propanol or DMSO. It is also possible to use mixtures of the solvents. Ethanol and DMSO are particularly preferred.
  • the usual acidic and basic catalysts preferably acid (e.g. para-toluenesulfonic acid chloride), are suitable as catalysts.
  • the reactions described above generally take place in a temperature range from -78 ° C. to the reflux temperature, preferably from 0 ° C. to the boiling point of the solvent used.
  • the reactions described above can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • the saponification of the carboxylic acid esters is carried out by customary methods by treating the esters in inert solvents with customary bases or acids, the salts initially formed in the case of basic saponification being treated with
  • Acid can be converted into the free carboxylic acids.
  • the usual inorganic bases are suitable as bases for the saponification. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or Alkali carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate. Sodium hydroxide or lithium hydroxide are particularly preferably used.
  • Suitable solvents for the saponification are water or the organic solvents customary for saponification. These preferably include alcohols such as methanol,
  • Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned. Water / tetrahydrofuran or water / ethanol is preferred.
  • the saponification is generally carried out in a temperature range from 0 ° C. to + 100 ° C., preferably from 0 ° C. to + 80 ° C.
  • the saponification is generally carried out at normal pressure. But it is also possible to work under negative pressure or overpressure (e.g. from 0.5 to 5 bar).
  • the base or the acid is generally used in an amount of 1 to 3 mol, preferably 1 to 2.5 mol, based on 1 mol of the ester.
  • Molar amounts of the reactants are particularly preferably used.
  • the compounds of the general formulas (VI) and (XI) are known per se or can be prepared by customary methods [cf. Erne, D. et al., Helv. Chim. Acta 62: 994-1006 (1979); Hasegawa, E. et al. J. Org. Chem. 56 (1991), 1631-1635; Watanabe, Kenichi et al., Bull. Chem. Soc. Jpn. 55 (1988) 3208-3211].
  • the compounds of the general formula (VII), (VIII), (IX), (X) and (XII) are partly new or known and can be prepared as described above.
  • the compounds of the general formula (I) used according to the invention and the new substances of the general formula (Ia) have an unforeseeable, valuable pharmacological activity spectrum and are therefore suitable for the treatment and prophylaxis of diseases.
  • anemia such as, for example, premature anemia, anemia in chronic renal failure, anemia after chemotherapy and anemia in HIV patients, and thus also for the treatment of severe anemia.
  • the application is preferably oral, transdermal or parenteral. Oral application is very particularly preferred, which is a further advantage over the therapy of anemias with rh-EPO known from the prior art.
  • the compounds according to the invention act in particular as erythropoietin sensitizers.
  • Erythropoiesis is increased, in particular that the oxygen supply is improved. Surprisingly, they are orally active, which significantly improves and at the same time simplifies the therapeutic use with the exclusion or reduction of the known side effects.
  • the present invention thus also relates to the use of EPO sensitizers for stimulating erythropoiesis, in particular for the prophylaxis and / or treatment of anemia, preferably severe anemia such as premature anemia, anemia in the case of chronic renal failure, anemia after chemotherapy or anemia in HIV -Patients. Besides that comes the
  • EPO sensitizers in the case of completely intact endogenous EPO production for additional stimulation of erythropoiesis, which can be used in particular with autologous blood donors.
  • the compounds according to the invention thus enable efficient stimulation of erythropoiesis and consequently prophylaxis or therapy of anemias which intervenes before the stage in which the conventional treatment methods with EPO are used. This is because the compounds according to the invention allow an effective influence on the body's own EPO, whereby the direct administration of EPO with the associated disadvantages can be avoided.
  • the present invention therefore furthermore relates to medicaments and pharmaceutical compositions which contain at least one compound of the general formula (I) together with one or more pharmacologically acceptable auxiliaries or excipients, and to their use for stimulating erythropoiesis, in particular for the purposes of prophylaxis and / or or treatment of anemia, such as premature anemia, anemia with chronic kidney failure, anemia after chemotherapy or anemia in HIV patients.
  • anemia such as premature anemia, anemia with chronic kidney failure, anemia after chemotherapy or anemia in HIV patients.
  • CD34 positive cells from this cell fraction were isolated by means of a commercial purification method (CD34 multisort kit from Miyltenyi).
  • CD34-positive cells (6000-10000 cells / ml) were in stem cell medium (0.9%
  • mice Normal mice are treated with test substances over several days. The application takes place intraperitoneally, subcutaneously or by os.
  • Preferred solvents are Solutol / DMSO / sucrose / NaCl solution or glycofurol.
  • the new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents, if appropriate
  • Auxiliary solvents can be used.
  • the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously.
  • it has proven to be advantageous to administer amounts of approximately 0.01 to 10 mg / kg, preferably approximately 0.1 to 10 mg / kg, of body weight in the case of intravenous administration in order to achieve effective results.
  • the resin (100 mg, 0.2 mmol) is suspended in dimethylacetamide and 2 ml of a 1.5 M solution of methylhydrazine in dimethylacetamide are added. The mixture is stirred at 70 ° C. for 48 hours. Then the liquid

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des amides d'acides pyrazol-carboxyliques, de formules générales (I) et (Ia), dont certains sont nouveaux et d'autres connus, ainsi que la fabrication desdits amides soit par la chimie en phase solide, soit par l'intermédiaire des nouveaux acides pyrazol-carboxyliques. Ces amides peuvent être utilisés comme médicaments, notamment pour le traitement de l'anémie.
EP00909096A 1999-02-04 2000-01-24 Utilisation d'amides d'acides pyrazol-carboxyliques Withdrawn EP1148879A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19904397 1999-02-04
DE19904397A DE19904397A1 (de) 1999-02-04 1999-02-04 Verwendung von Pyrazol-Carbonsäureamiden
PCT/EP2000/000519 WO2000045894A2 (fr) 1999-02-04 2000-01-24 Utilisation d'amides d'acides pyrazol-carboxyliques

Publications (1)

Publication Number Publication Date
EP1148879A2 true EP1148879A2 (fr) 2001-10-31

Family

ID=7896339

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00909096A Withdrawn EP1148879A2 (fr) 1999-02-04 2000-01-24 Utilisation d'amides d'acides pyrazol-carboxyliques

Country Status (8)

Country Link
EP (1) EP1148879A2 (fr)
JP (1) JP2002536348A (fr)
AR (1) AR022470A1 (fr)
AU (1) AU3150300A (fr)
CA (1) CA2361636A1 (fr)
DE (1) DE19904397A1 (fr)
GT (1) GT200000009A (fr)
WO (1) WO2000045894A2 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6878729B2 (en) 2001-05-04 2005-04-12 The Procter & Gamble Company Medicinal uses of dihydropyrazoles
AU2005287170B2 (en) * 2004-09-17 2012-03-29 Exelixis, Inc Pyrazole kinase modulators and methods of use
UY30892A1 (es) 2007-02-07 2008-09-02 Smithkline Beckman Corp Inhibidores de la actividad akt
PE20120003A1 (es) 2009-01-30 2012-02-12 Glaxosmithkline Llc Hidrocloruro de n-{(1s)-2-amino-1-[(3-fluorofenil)metil)etil}-5-cloro-4-(4-cloro-1-metil-1h-pirazol-5-il)-2-tiofenocarboxamida cristalino
EP4173485A1 (fr) * 2021-10-27 2023-05-03 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Composés inhibant l'agrégation de protéine pour la lutte contre les maladies des plantes

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH27357A (en) * 1989-09-22 1993-06-21 Fujisawa Pharmaceutical Co Pyrazole derivatives and pharmaceutical compositions comprising the same
US5434178A (en) * 1993-11-30 1995-07-18 G.D. Searle & Co. 1,3,5 trisubstituted pyrazole compounds for treatment of inflammation
WO1997019039A1 (fr) * 1995-11-17 1997-05-29 Novartis Ag Synthese en phase solide de composes heterocycliques et d'une banque combinatoire de composes
DE19904396A1 (de) * 1999-02-04 2000-08-10 Bayer Ag Substituierte Pyrazolbenzylamin-Derivate
DE19904406A1 (de) * 1999-02-04 2000-08-10 Bayer Ag Substituierte Pyrazolcarbonsäuren

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0045894A2 *

Also Published As

Publication number Publication date
WO2000045894A3 (fr) 2001-04-19
GT200000009A (es) 2001-07-27
CA2361636A1 (fr) 2000-08-10
JP2002536348A (ja) 2002-10-29
AR022470A1 (es) 2002-09-04
AU3150300A (en) 2000-08-25
WO2000045894A2 (fr) 2000-08-10
DE19904397A1 (de) 2000-08-10

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