WO2008003412A1 - Utilisation de dérivés de 1,4-diaryl-dihydropyrimidin-2-one pour le traitement de l'hypertension artérielle pulmonaire - Google Patents

Utilisation de dérivés de 1,4-diaryl-dihydropyrimidin-2-one pour le traitement de l'hypertension artérielle pulmonaire Download PDF

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Publication number
WO2008003412A1
WO2008003412A1 PCT/EP2007/005579 EP2007005579W WO2008003412A1 WO 2008003412 A1 WO2008003412 A1 WO 2008003412A1 EP 2007005579 W EP2007005579 W EP 2007005579W WO 2008003412 A1 WO2008003412 A1 WO 2008003412A1
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WO
WIPO (PCT)
Prior art keywords
pulmonary
formula
compound
salts
solvates
Prior art date
Application number
PCT/EP2007/005579
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German (de)
English (en)
Inventor
Franz Von Nussbaum
Heike Gielen-Haertwig
Martina Klein
Volkhart Min-Jian Li
Daniel Meibom
Peter Sandner
Klemens Lustig
Stefan Schäfer
Original Assignee
Bayer Healthcare 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 Healthcare Ag filed Critical Bayer Healthcare Ag
Priority to CA002656307A priority Critical patent/CA2656307A1/fr
Priority to US12/307,126 priority patent/US20100010024A1/en
Priority to EP07764815A priority patent/EP2037930A1/fr
Priority to JP2009516962A priority patent/JP2009541384A/ja
Publication of WO2008003412A1 publication Critical patent/WO2008003412A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present application relates to the use of l, 4-diaryl-dihydropyrimidin-2-one derivatives of the formula (I) for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension and their use for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.
  • elastase-mediated pathological processes underlie a shifted balance between free elastase and the body's elastase inhibitor protein (mainly alpha-1 antitrypsin, AAT) [Stockley, Neutrophils and protease / antiprotease imbalance, Am. J. Respir. Crit. Care Med. 160, 49-52 (1999)].
  • AAT alpha-1 antitrypsin
  • AAT alpha-1 antitrypsin
  • the membrane-bound elastase of the activated PMN cells is largely protected from inhibition by AAT.
  • AAT the membrane-bound elastase located in a difficult-to-access microcompartment between the neutrophil cell and the adjacent tissue cell (e.g., endothelial cell).
  • strongly oxidizing conditions prevail around activated leukocytes (English, oxidative burst), whereby AAT is oxidized and loses several orders of magnitude in its inhibitory effect.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having from 1 to 16 carbon atoms.
  • (CVCfi) -cycloalkyl in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 6 carbon atoms.
  • cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl By way of example and preferably mention may be made of: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the compounds according to the invention are therefore particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension including their subforms, such as idiopathic, familial and, for example, with portal hypertension, fibrotic disorders, HIV infection or improper medication or toxins associated pulmonary arterial hypertension.
  • Prostacyclin analogs such as by way of example and preferably iloprost, beraprost, treprostinil or epoprostenol;
  • the compounds according to the invention are administered in combination with a kinase inhibitor such as, for example and preferably, bortezomib, canertinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib, pelitinib, semaxanib, sorafenib, sunitinib, Tandutinib, tipifarnib, vatalanib, fasudil, lonidamine, leflunomide, BMS-3354825 or Y-27632.
  • a kinase inhibitor such as, for example and preferably, bortezomib, canertinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib, pelitin
  • the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.
  • the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • a factor Xa inhibitor such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982 , EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
  • the compounds according to the invention are administered in combination with
  • antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor Antagonists, Rho-kinase inhibitors and diuretics understood.
  • the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
  • the compounds according to the invention are administered in combination with an endothelialin antagonist, such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • an endothelialin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.
  • the compounds of the invention are administered in combination with a renin inhibitor, such as by way of example and preferably aliskiren, SPP-600 or SPP-800.
  • the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, such as by way of example and preferably spironolactone or eplerenone.
  • a mineralocorticoid receptor antagonist such as by way of example and preferably spironolactone or eplerenone.
  • the compounds of the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).
  • the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • an MTP inhibitor such as, for example and preferably, implitapide, BMS-201038, R-103757 or JTT-130.
  • the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • a lipoprotein (a) antagonist such as by way of example and preferably gemcabene calcium (CI-1027) or nicotinic acid.
  • the present invention further provides for the use of the compounds according to the invention, alone or in combination with one or more of the abovementioned active compounds, for the production of a medicament for the treatment and / or prophylaxis of the idiopathic, familial or pulmonary arterial hypertension associated with drugs, toxins or other disorders, for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases, left-sided heart valve diseases, chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness, pulmonary developmental disorders, chronic thrombotic and / or embolic diseases such as thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism, or in conjunction with sarcoidosis, histiocytosis X or Lymphangioleiomyomatose, as well as for the treatment and / or
  • Another object of the present invention is a method for the treatment and / or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension in humans and animals by administering an effective amount of at least one of the compounds of the invention or a drug containing at least one of the compounds of the invention.
  • the compounds according to the invention can act systemically and / or locally.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.
  • Device type MS Micromass ZQ
  • Device type HPLC HP 1100 Series
  • UV DAD Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.0 mm
  • Eluent A 1 l of water + 0.5 ml of 50% formic acid
  • eluent B 1 l of acetonitrile + 0.5 ml of 50% formic acid
  • Flow 0.0 min 1 ml / min -> 2.5 min / 3.0 min / 4.5 min 2 ml / min
  • Oven 50 ° C .
  • UV detection 210 nm.
  • Instrument Abimed Gilson Pump 305/306, Manometric Module 806; Column: GromSil 120 ODS-4HE, 10 ⁇ m, 250 mm x 30 mm; Eluent A: water, eluent B: acetonitrile; Gradient: 0.0 min 30% B ⁇ 3 min 30% B ⁇ 31 min 95% B ⁇ 44 min 95% B ⁇ 45 min 30% B; Flow: 50 ml / min; Column temperature: RT; UV detection: 210 nm.
  • Enantiomer separation on a chiral silica gel phase based on the selector poly (N-methacryloyl-L-leucine-D-menthylamide); Column: 250 mm x 30 mm; Eluent: Step gradient 100% ethyl acetate ⁇ 100% methanol; Flow: 30 ml / min; Temperature: 24 ° C; UV detection: 260 nm.
  • 5-fluoro-3- (trifluoromethyl) aniline 34 g (189 819 mmol) are dissolved in 227 ml of 2-propanol and added dropwise over a period of 10 minutes with 32,803 g (284 728 mmol) trimethyl silyl isocyanate are added at 50 0 C. The mixture is stirred overnight at 50 ° C and then concentrated on a rotary evaporator. The residue is stirred with dichloromethane, the solid is filtered off with suction and dried under high vacuum. 25.0 g (59% of theory) of the target compound are obtained.
  • the reaction mixture is concentrated in vacuo and the residue taken up in ethyl acetate (200 ml).
  • the organic phase is then washed with water (2 x 50 ml each) and then with saturated aqueous sodium chloride solution (50 ml), dried over sodium sulfate, filtered and concentrated.
  • the Crude product is flash chromatographed on silica gel (eluent: gradient cyclohexane ⁇ cyclohexane / ethyl acetate 6: 4). There are obtained 12.5 g (91% of theory) of the title compound as a solid.
  • the batch is concentrated in vacuo and the residue directly chromatographies (Biotage medium pressure system, silica gel column, eluent: cyclohexane / ethyl acetate 5: 1 ⁇ 3: 1 ⁇ 2: 1 ⁇ 1: 1). 188 mg (50% of theory) of the racemic title compound are obtained.
  • the racemate is then separated into the enantiomers by chromatography (Method 16). From 65 mg of the racemate, 28 mg of the enantiomerically pure title compound (> 99.5% ee) are obtained.
  • Example 24 The preparation of the title compound is carried out as described in WO 2005/082863 (Example 15A).
  • Example 24 The preparation of the title compound is carried out as described in WO 2005/082863 (Example 15A).
  • Example 24 The preparation of the title compound is carried out as described in WO 2005/082863 (Example 15A).
  • the potency of the compounds of the invention is determined in an in vitro inhibition test.
  • the HNE-mediated amidolytic cleavage of a suitable peptide substrate in this case leads to a fluorescence light increase.
  • the signal intensity of the fluorescent light is directly proportional to the enzyme activity.
  • the effective concentration of a test compound in which half of the enzyme is inhibited (50% signal intensity of the fluorescent light) is given as an IC 50 value.
  • test buffer 0.1 M HEPES pH 7.4, 0.5 M NaCl, 0.1% w / v BSA, 1% v / v DMSO
  • enzyme 80 pM HNE, Serva , Heidelberg
  • substrate 20 ⁇ M MeOSuc-Ala-Ala-Pro-Val-AMC, Fa. Bachern, Weil am Rhein
  • the fluorescent light intensity of the test mixtures is measured (ex. 380 nm, em. 460 nm).
  • the IC 50 values are determined by plotting the fluorescent light intensity versus the drug concentration.
  • Rat monocrotaline-induced pulmonary hypertension is a widely used animal model of pulmonary arterial hypertension.
  • the pyrrolizidine alkaloid monocrotaline is metabolized to the toxic monocrotaline pyrrole after subcutaneous injection in the liver and leads to endothelial damage in the pulmonary circulation within a few days, followed by remodeling of the small pulmonary arteries (medial hypertrophy, de novo muscularization).
  • a single subcutaneous injection is sufficient to induce severe pulmonary hypertension in rats within 4 weeks [Cowan et al., Nature Med. 6, 698-702 (2000)].
  • the model uses male Sprague-Dawley rats. On day 0 the animals receive a subcutaneous injection of 60 mg / kg monocrotaline.
  • Systemic blood pressure is determined in the left carotid artery using a Millar microtip catheter.
  • a polyethylene catheter is advanced via the right jugular vein into the right ventricle to determine right ventricular pressure.
  • Cardiac output is determined by thermodilution.
  • the heart is removed and the ratio of right to left ventricles, including the septum, is determined.
  • plasma samples for the determination of biomarkers (for example, proBNP) and plasma substance levels are obtained.
  • the ability of substances to inhibit CYPl A2, CYP2C9, CYP2D6 and CYP3A4 in humans is investigated using pooled human liver microsomes as the enzyme source in the presence of standard substrates (see below) that form CYP-specific metabolites.
  • the inhibition effects are examined at six different concentrations of the test compounds (2.8, 5.6, 8.3, 16.7, 25 and 50 ⁇ M), compared with the extent of CYP-specific metabolite formation of the standard substrates in the absence of the test compounds and the corresponding IC 50 values calculated.
  • a standard inhibitor that specifically inhibits a single CYP isoform is always incubated to make results comparable between different series.
  • test compounds are preferably dissolved in acetonitrile.
  • 96-well plates are incubated for a defined time at 37 ° C with pooled human liver microsomes.
  • the reactions are by addition of 100 ⁇ l of acetonitrile, which is a suitable internal standard.
  • Precipitated proteins are separated by centrifugation, the supernatants are pooled and analyzed by LC-MS / MS.
  • the metabolic stability of test compounds to hepatocytes is determined by incubating the compounds at low concentrations (preferably below 1 ⁇ M) and at low numbers of cells (preferably at 1 ⁇ 10 6 cells / ml) in order to ensure the best possible linear kinetic conditions in the experiment. Seven samples from the incubation solution are taken at a fixed time interval for LC-MS analysis to determine the half life (ie degradation) of the compound. From this half-life, different "clearance” parameters (CL) and "F m1x " values are calculated (see below ).
  • the CL and F ⁇ sides are a measure of the phase I and phase 2 metabolism of the compound in the hepatocytes.
  • its concentration In order to minimize the influence of the organic solvent on the enzymes in the incubation mixtures, its concentration generally becomes limited to 1% (acetonitrile) and 0.1% (DMSO).
  • hepatocyte cell count in the liver 1.1 * 10 8 cells / g liver is expected.
  • CL parameters based on half-lives beyond the incubation period typically 90 minutes can only be considered as rough guidelines.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • the mixture of compound of the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water.
  • the granules are mixed after drying with the magnesium stearate for 5 minutes.
  • This mixture is compressed with a conventional tablet press (for the tablet format see above).
  • a pressing force of 15 kN is used as a guideline for the compression.
  • the rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h.
  • the compound of the invention is dissolved in a concentration below saturation solubility in a physiologically acceptable solvent (e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically acceptable solvent e.g., isotonic saline, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Heart & Thoracic Surgery (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente demande concerne l'utilisation de dérivés de 1,4-diaryl-dihydropyrimidin-2-one de formule (I) pour le traitement et/ou la prophylaxie de l'hypertension artérielle pulmonaire et d'autres formes d'hypertension pulmonaire ainsi que leur utilisation pour la fabrication de médicaments destinés au traitement et/ou à la prophylaxie de l'hypertension artérielle pulmonaire et d'autres formes d'hypertension pulmonaire.
PCT/EP2007/005579 2006-07-01 2007-06-25 Utilisation de dérivés de 1,4-diaryl-dihydropyrimidin-2-one pour le traitement de l'hypertension artérielle pulmonaire WO2008003412A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002656307A CA2656307A1 (fr) 2006-07-01 2007-06-25 Utilisation de 1,4-diaryldihydropyrimidin-2-one pour le traitement de l'hypertension arterielle pulmonaire
US12/307,126 US20100010024A1 (en) 2006-07-01 2007-06-25 Use of1,4-diaryl-dihydropyrimidine-2-on derivatives for treating pulmonary arterial hypertension
EP07764815A EP2037930A1 (fr) 2006-07-01 2007-06-25 Utilisation de dérivés de 1,4-diaryl-dihydropyrimidin-2-one pour le traitement de l'hypertension artérielle pulmonaire
JP2009516962A JP2009541384A (ja) 2006-07-01 2007-06-25 肺動脈高血圧の処置のための１，４−ジアリール−ジヒドロピリミジン−２−オン誘導体の使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006031314A DE102006031314A1 (de) 2006-07-01 2006-07-01 Verwendung von 1,4-Diaryl-dihydropyrimidin-2-on-Derivaten zur Behandlung der pulmonalen arteriellen Hyptertonie
DE102006031314.3 2006-07-01

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WO2008003412A1 true WO2008003412A1 (fr) 2008-01-10

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PCT/EP2007/005579 WO2008003412A1 (fr) 2006-07-01 2007-06-25 Utilisation de dérivés de 1,4-diaryl-dihydropyrimidin-2-one pour le traitement de l'hypertension artérielle pulmonaire

Country Status (5)

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EP (1) EP2037930A1 (fr)
JP (1) JP2009541384A (fr)
CA (1) CA2656307A1 (fr)
DE (1) DE102006031314A1 (fr)
WO (1) WO2008003412A1 (fr)

Cited By (7)

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DE102008022521A1 (de) 2008-05-07 2009-11-12 Bayer Schering Pharma Aktiengesellschaft 1,4-Diaryl-pyrimidopyridazin-2,5-dione und ihre Verwendung
DE102008052013A1 (de) 2008-10-17 2010-04-22 Bayer Schering Pharma Aktiengesellschaft 4-(4-Cyano-2-thioaryl)-dihydropyrimidinone und ihre Verwendung
DE102009004197A1 (de) 2009-01-09 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Heterocyclisch anellierte Diaryldihydropyrimidin-Derivate und ihre Verwendung
DE102009016553A1 (de) 2009-04-06 2010-10-07 Bayer Schering Pharma Aktiengesellschaft Sulfonamid- und Sulfoximin-substituierte Diaryldihydropyrimidinone und ihre Verwendung
DE102010030187A1 (de) 2010-06-16 2011-12-22 Bayer Schering Pharma Aktiengesellschaft 4-Cyan-2-sulfonylphenyl)pyrazolyl-substituierte Pyridinone und Pyrazinone und ihre Verwendung
TWI690515B (zh) * 2014-12-12 2020-04-11 日商日本煙草產業股份有限公司 二氫嘧啶-２-酮化合物及其醫藥用途
US10899717B2 (en) 2018-02-28 2021-01-26 Japan Tobacco Inc. 4-methyldihydropyrimidinone compounds and pharmaceutical use thereof

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GB201004179D0 (en) * 2010-03-12 2010-04-28 Pulmagen Therapeutics Inflamma Enzyme inhibitors
GB201004178D0 (en) * 2010-03-12 2010-04-28 Pulmagen Therapeutics Inflamma Enzyme inhibitors
US20140221335A1 (en) 2013-02-06 2014-08-07 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9115093B2 (en) 2013-03-04 2015-08-25 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
WO2015091281A1 (fr) * 2013-12-16 2015-06-25 Chiesi Farmaceutici S.P.A. Dérivés de tétrahydrotriazolopyrimidine en tant qu'inhibiteurs de l'élastase neutrophile humaine
USRE47493E1 (en) 2014-02-20 2019-07-09 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9290457B2 (en) 2014-07-31 2016-03-22 Boehringer Ingelheim International Gmbh Substituted dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9475779B2 (en) 2014-07-31 2016-10-25 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9458113B2 (en) 2014-07-31 2016-10-04 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9440930B2 (en) 2014-07-31 2016-09-13 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity
US9657015B2 (en) 2014-07-31 2017-05-23 Boehringer Ingelheim International Gmbh Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity

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WO2006136857A1 (fr) * 2005-06-24 2006-12-28 Argenta Discovery Limited Multimères dihydropyrimidone et leur utilisation en tant qu’inhibiteurs de l’élastase neutrophile humaine

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Cited By (11)

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DE102008052013A1 (de) 2008-10-17 2010-04-22 Bayer Schering Pharma Aktiengesellschaft 4-(4-Cyano-2-thioaryl)-dihydropyrimidinone und ihre Verwendung
DE102009004197A1 (de) 2009-01-09 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Heterocyclisch anellierte Diaryldihydropyrimidin-Derivate und ihre Verwendung
WO2010078953A1 (fr) 2009-01-09 2010-07-15 Bayer Schering Pharma Aktiengesellschaft Dérivés de triazolo- et tétrazolopyrimidine en tant qu'inhibiteurs de l'élastase neutrophile humaine (hne) pour le traitement de la maladie pulmonaire obstructive chronique (copd)
JP2012514615A (ja) * 2009-01-09 2012-06-28 バイエル・ファルマ・アクチェンゲゼルシャフト Ｃｏｐｄの処置用のｈｎｅ阻害剤としてのトリアゾロおよびテトラゾロピリミジン誘導体
DE102009016553A1 (de) 2009-04-06 2010-10-07 Bayer Schering Pharma Aktiengesellschaft Sulfonamid- und Sulfoximin-substituierte Diaryldihydropyrimidinone und ihre Verwendung
WO2010115548A1 (fr) 2009-04-06 2010-10-14 Bayer Schering Pharma Aktiengesellschaft Diaryldihydropyrimidinones à substitution sulfonamide et sulfoximine et leur utilisation
DE102010030187A1 (de) 2010-06-16 2011-12-22 Bayer Schering Pharma Aktiengesellschaft 4-Cyan-2-sulfonylphenyl)pyrazolyl-substituierte Pyridinone und Pyrazinone und ihre Verwendung
TWI690515B (zh) * 2014-12-12 2020-04-11 日商日本煙草產業股份有限公司 二氫嘧啶-２-酮化合物及其醫藥用途
TWI739206B (zh) * 2014-12-12 2021-09-11 日商日本煙草產業股份有限公司 二氫嘧啶-２-酮化合物及其醫藥用途
US10899717B2 (en) 2018-02-28 2021-01-26 Japan Tobacco Inc. 4-methyldihydropyrimidinone compounds and pharmaceutical use thereof

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