WO2000046207A1 - Alkylamides de pyrazol - Google Patents

Alkylamides de pyrazol Download PDF

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Publication number
WO2000046207A1
WO2000046207A1 PCT/EP2000/000504 EP0000504W WO0046207A1 WO 2000046207 A1 WO2000046207 A1 WO 2000046207A1 EP 0000504 W EP0000504 W EP 0000504W WO 0046207 A1 WO0046207 A1 WO 0046207A1
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WO
WIPO (PCT)
Prior art keywords
anemia
general formula
pyrazole
alkylamides
compounds
Prior art date
Application number
PCT/EP2000/000504
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
Original Assignee
Bayer Aktiengesellschaft
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 Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Priority to AU34211/00A priority Critical patent/AU3421100A/en
Publication of WO2000046207A1 publication Critical patent/WO2000046207A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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

Definitions

  • the present invention relates to substituted pyrazole-alkylamides, processes for their preparation and their use as medicaments, in particular for the prophylaxis and / or control of anemias.
  • EPO Erythropoietin
  • EPO produced is secreted into the blood.
  • the primary physiological function of EPO is the regulation of erythropoiesis in the bone marrow. There EPO stimulates the
  • 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, e.g. severe blood loss, longer stays at high altitudes, but also
  • 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
  • rh EPO Convulsions and cerebral or myocardial infarction due to thrombosis. Furthermore, rh EPO is not available orally and must therefore be administered ip, iv or subcutaneously, which limits its use to the therapy of severe anemia.
  • the present invention now relates to pyrazole alkylamides 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 10 ) aryl or a 5- to 6-membered aromatic, optionally benzocondensed heterocycle having up to 3 heteroatoms from the series S, N and / or O which, in the case of phenyl, preferably in para position for ring attachment - can be substituted by halogen, (C, -C 6 ) -alkyl, (C r C 6 ) -alkoxy, trifluoromethyl or trifluoromethoxy,
  • R 3 represents (C 3 -C 8 ) cycloalkyl or (C, -C 6 ) alkyl
  • A, D, E, G, R 2 and R 3 have the meaning given above.
  • A, D, E, G, R 2 and R 3 have the meaning given above.
  • the compounds according to the invention 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.
  • Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids are particularly preferred.
  • Salts which can be mentioned are salts with conventional bases, for example
  • Alkali metal salts e.g. sodium or potassium salts
  • alkaline earth salts e.g. calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, or 1-ephenylamine - piperidine.
  • (C 6 -C 10 ) aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • (C r C fi ) alkyl represents a straight-chain or branched
  • Alkyl radical with 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 ] -C 6 ) -alkoxy stands for 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 3 -C 8 ) cycloalkyl stands for cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl. May be mentioned:
  • Cyclopropyl, cyclopentyl and cyclohexyl In the context of the invention, a 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms from the series S, O and / or N is, for example, pyridyl, pyrimidyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl.
  • Pyridyl are preferred; Pyrimidyl, pyridazinyl, furyl and thienyl.
  • a 5- to 6-membered aromatic benzocondensed heterocycle with up to 3 heteroatoms from the S, O and / or N series is, for example, benzothiophene, quinoline, indole or benzofuran in the context of the invention. 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 or pyridyl optionally substituted by halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy, in the case of phenyl the phenyl ring may preferably be substituted in the para position to the ring attachment,
  • R 3 represents cyclopropyl, cyclopentyl, cyclohexyl or (C, -C 4 ) -alkyl
  • A, D, E and G stand for hydrogen
  • R 1 represents methyl
  • R 2 represents phenyl, thienyl or pyridyl which is optionally substituted by halogen, methyl, methoxy, trifluoromethyl or trifluoromethoxy, where in the case of phenyl the phenyl ring can preferably be substituted in the para position,
  • R 3 represents methyl or cyclopropyl
  • X represents chlorine, bromine or iodine
  • Carboxylic acid derivative e.g. carboxylic acid halide, anhydride or imidazolide
  • compounds of the formula (V) e.g. carboxylic acid halide, anhydride or imidazolide
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents for [A] and [B].
  • solvents for [A] and [B] include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichlorethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acetonitrile, acetonitrile. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred.
  • bases include, for example, alkali metal hydrides and alkaline earth metal hydrides such as sodium hydride and calcium hydride or alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide, sodium hydride or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyl lithium or phenyllithium. NaHMDS, lithium diisopropylamide and lithium bis (trimethylsilyl) amide are preferred.
  • the base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compounds of the general formula (II).
  • the reaction generally takes 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 reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
  • R 2 has the meaning given above
  • R 4 represents a (C, -C 4 ) alkyl radical
  • R 1 has the meaning given above
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents for process [C]. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, carbon tetrachloroethane, 1,2-dichloroethylene or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane or
  • Cyclohexane dimethylformamide, acetonitrile, tetrahydrofuran or DMSO. It is also possible to use mixtures of the solvents. Dichloromethane is particularly preferred.
  • the reaction generally takes place in a temperature range from -78 ° C to
  • Reflux temperature preferably from 0 ° C to the boiling point of the solvent used.
  • the reaction 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 compounds of formula (IV) are new and can be prepared, for example, by
  • R 5 represents a (C, -C 4 ) alkyl radical
  • R 1 has the meaning given above
  • R 1 is a (C, -C 6 ) alkyl radical
  • 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 (IV) with R 1 for (C, -C 6 ) -alkyl which are then saponified, or
  • R 2 has the meaning given above
  • R 6 represents a (C r C 4 ) alkyl chain
  • Inert organic solvents which do not change under the reaction conditions are suitable as solvents for processes [D] and [E].
  • halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene or trichlorethylene
  • hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, acoleitrile methanol, acetonitrile, acetonitrile Ethanol, 2-propanol or DMSO. It is also possible to use mixtures of the solvents mentioned. Ethanol and DMSO 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.
  • acidic catalysts e.g. para-toluenesulfonic acid.
  • Amino-functionalized polystyrene-polyethylene copolymers which are modified with a polyethylene glycol chain are preferred. So-called are particularly preferred
  • SAM resins (abbreviation for standard amide resins) and RAM resins (abbreviation for Rink amide resins).
  • RAM resins (abbreviation for Rink amide resins).
  • resins which can be used according to the invention are Tentagel SAM (S 30022) and Tentagel R RAM (R 28 023) from Rapp Polymer GmbH.
  • the compounds of the general formula (I) according to the invention 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, in which there 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 comprise at least one compound of the general Formula (I) together with one or more pharmacologically acceptable auxiliaries or carriers, and their use for stimulating erythropoiesis, in particular for the purposes of prophylaxis and / or treatment of anemias, such as prematurity anemia, anemia with chronic renal insufficiency, anemia after chemotherapy or anemia in HIV patients.
  • anemias such as prematurity anemia, anemia with chronic renal insufficiency, 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 resuspended in stem cell medium (0.9% methyl cellulose, 30% calf serum, 1% albumin (bovine), 100 ⁇ M 2-mercaptoethanol and 2 mM L-glutamine) from StemCell Technologies Inc. 10 mU / ml human erythropoietin, 10 ng / ml human IL-3 and 0-1 O ⁇ M test substance were added. 500 ul deep well (24-well plates) were in 14% at 37 ° C in 5%
  • Cultures were diluted with 20 ml 0.9% w / v ⁇ aCl solution, centrifuged for 15 min at 600xg and resuspended in 200 ⁇ l 0.9% w / v ⁇ aCl. To determine the number of erythroid cells, 50 ⁇ l of the cell suspension was made into 10 ⁇ l benzidine stain. solution (20 ⁇ g benzidine in 500 ⁇ l DMSO, 30 ⁇ l H2O2 and 60 ⁇ l conc. acetic acid). The number of blue cells was counted microscopically.
  • 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 Glyco colrol.
  • the parameter is the hematocrit increase compared to the baseline value of the treated animals compared to the change in the hematocrit in the placebo control (double-standardized value).
  • the new active compounds 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, ie in amounts which are sufficient to achieve the dosage range indicated.
  • the formulations are prepared, for example, by stretching the active compounds with solvents and / or carriers, if appropriate using emulsifiers and / or dispersants, it being possible, for example if organic solvents to be used as diluents, to use organic solvents as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously.
  • the resin (100 mg, 0.21 mmol) is suspended under argon in dimethylacetamide (10 ml), 4-trifluoromethyl-benzoic acid methyl ester (771 mg, 3.78 mmol) is added and the mixture is shaken for 10 min at room temperature. Then NaH (disp. In mineral oil, 60%, 96.6 mg, 2.52 mmol) is added and the mixture is shaken at 90 ° C. for 1 h. The liquid phase is then suctioned off and the resin is washed with dimethylformamide, methanol, methylene chloride and diethyl ether (2 times 5 ml each).
  • 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 h. Then the aspirated liquid phase and the resin washed with dimethylformamide, methanol, methylene chloride and diethyl ether (2 times 5 ml).
  • the resin (100 mg “0.2 mmol) is suspended in 1.1 ml of tetrahydrofuran, and NaHMDS (1 M solution in tetrahydrofuran, 5.5 ml, 5.5 mmol) is added. The mixture is stirred at room temperature for 30 min, in which case methyl iodide (1.05 g, 7.38 mmol, dissolved in 4 ml of tetrahydrofuran) is then added. The mixture is stirred at 50 ° C. for 6 h, then the liquid phase is separated off and the resin is washed with dimethylformamide, methanol, methylene chloride and ether (5 ml each twice).
  • the resin (100 mg) is mixed with 2 ml of a 1: 1 (v: v) mixture of methylene chloride and trifluoroacetic acid and shaken for 1 h at room temperature.
  • the liquid phase is separated off, the solid phase is washed with methylene chloride and the combined liquid phases are evaporated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouveaux alkylamides de pyrazol de formule générale (I), ainsi que des procédés pour leur préparation. L'étape-clé de leur préparation est soit l'alkylation d'amides primaires soit l'amidation d'acides carboxyliques avec des alkylamides. Ces alkylamides de pyrazol s'utilisent comme médicaments, notamment pour le traitement et la prophylaxie d'anémies.
PCT/EP2000/000504 1999-02-04 2000-01-24 Alkylamides de pyrazol WO2000046207A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34211/00A AU3421100A (en) 1999-02-04 2000-01-24 Pyrazole alkylamides

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19904391A DE19904391A1 (de) 1999-02-04 1999-02-04 Pyrazol-Alkylamide
DE19904391.4 1999-02-04

Publications (1)

Publication Number Publication Date
WO2000046207A1 true WO2000046207A1 (fr) 2000-08-10

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AU (1) AU3421100A (fr)
DE (1) DE19904391A1 (fr)
GT (1) GT200000008A (fr)
WO (1) WO2000046207A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19929785A1 (de) * 1999-06-29 2001-01-04 Bayer Ag Tetrahydrochinolinyl-6-methyldihydrothiadiazinon-Derivate und ihre Verwendung
US6878729B2 (en) 2001-05-04 2005-04-12 The Procter & Gamble Company Medicinal uses of dihydropyrazoles

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0417449A1 (fr) * 1989-07-31 1991-03-20 Bristol-Myers Squibb Company Dérivés d'arylpyrazole comme agents antiagrégants plaquettaires
EP0554829A2 (fr) * 1992-02-05 1993-08-11 Fujisawa Pharmaceutical Co., Ltd. Dérivés du pyrazole à activité anti-inflammatoire, analgésique et antithrombotique
WO1997024120A1 (fr) * 1995-12-29 1997-07-10 Smithkline Beecham Corporation THIENO(2,3-b)PYRAZOLO(3,4-d)PYRIDIN-3-ONES SERVANT A FAVORISER L'ERYTHROPOIESE

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0417449A1 (fr) * 1989-07-31 1991-03-20 Bristol-Myers Squibb Company Dérivés d'arylpyrazole comme agents antiagrégants plaquettaires
EP0554829A2 (fr) * 1992-02-05 1993-08-11 Fujisawa Pharmaceutical Co., Ltd. Dérivés du pyrazole à activité anti-inflammatoire, analgésique et antithrombotique
WO1997024120A1 (fr) * 1995-12-29 1997-07-10 Smithkline Beecham Corporation THIENO(2,3-b)PYRAZOLO(3,4-d)PYRIDIN-3-ONES SERVANT A FAVORISER L'ERYTHROPOIESE

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
F. BONDAVALLI ET AL.: "3,5-Diphenyl-1H-Pyrazole Derivatives", IL FARMACO, vol. 43, no. 9, 1988, pages 725 - 743, XP002140614 *

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GT200000008A (es) 2001-07-27
AU3421100A (en) 2000-08-25
DE19904391A1 (de) 2000-08-10

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