Classifications

• • 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
  • A61K31/42—Oxazoles
  • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
• • 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
  • A61K31/42—Oxazoles
  • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/16—Central respiratory analeptics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • 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
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
• • 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
• • 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
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • 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
• • 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 invention relates to the use of selective factor Xa inhibitors, in particular oxazolidinones of the formula (I), for the treatment and / or prophylaxis of pulmonary hypertension and their use for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary hypertension.
• Oxazolidinones of the formula (I) are known from WO 01/047919 and act in particular as selective inhibitors of the blood coagulation factor Xa and as anticoagulants.
• Oxazolidinones of formula (I) are selective factor Xa inhibitors and specifically inhibit only FXa.
• An antithrombotic effect of factor Xa inhibitors has been demonstrated in numerous animal models (see U. Sinha, P. Ku, J. Malinowskd, B. Yan Zhu, RM Scarborough, K.K. Marlowe, PW, Wong, P. Hua Lin, SJ Hollenbach, Antithrombotic and hemostatic capacity of factor Xa versus thrombin inhibitors in the mode of venous and arteriovenous thrombosis, European Journal of Pharmacology 2000, 395, 51-59, A. Betz, Recent Advances in Factor Xa inhibitors, Expert Opinion. Ther.
• factor Xa inhibitors can be preferably used in medicaments for the prophylaxis and / or treatment of thromboembolic disorders.
• Selective FXa inhibitors show a broad therapeutic window.
• FXa inhibitors have an antithrombotic effect in thrombosis models without, or only slightly, prolonging bleeding time (see RJ Leadly, Coagulation Factor Xa inhibition: biological background and rational, Curr Top Med Chem 2001, 1 , 151-159). An individual dosage in anticoagulation with selective FXa inhibitors is therefore not necessary.
• Pulmonary hypertension (Clinical Classification of Pulmonary Hypertension, Venice, 2003) is a progressive lung disease that may have multiple causes and lead to death if left untreated. This leads to an overload of the right heart withkherzinsuff ⁇ zienz up to the pump failure, which can lead to death.
• Defintionsmother is at a pulmonary arterial hypertension (mPAP) of> 25 mmHg at rest or> 30 mmHg during exercise (normal value ⁇ 20 mmHg).
• mPAP pulmonary arterial hypertension
• the pathophysiology of pulmonary hypertension often includes thrombosis of the pulmonary vessels.
• PAH primary pulmonary hypertension
• New combination therapies are one of the most promising future treatment options for the treatment of pulmonary arterial hypertension (Ghofrani et al., Herz 2005, 30, 296-302).
• P450 does not inhibit or inhibit CYP enzymes to a very limited extent (compare drug interactions in the combination therapy of bosentan and warfarin).
• WO 2006/045756 mentions the combination of dipyridamole with rivaroxaban for the treatment of pulmonary hypertension, but without mentioning any findings.
• dipyridamole has a variety of side effects, such as. Hypotension, cardiac arrest, cardiac arrhythmias, allergic reactions / aggravation of bronchial asthma (on tartrazine in hypersensitivity), bronchial asthma, hepatic enzyme elevation and liver failure.
• dipyridamole shows interactions with other drugs such.
• platelet aggregation inhibitors eg aspirin
• anticoagulants eg warfarin
• selective factor Xa inhibitors in particular oxazolidinones of the formula (I), are suitable for the treatment and prevention of pulmonary hypertension, in particular pulmonary arterial hypertension.
• the present invention is the use of selective factor Xa inhibitors for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary hypertension, in particular pulmonary arterial hypertension.
• the present invention particularly relates to the use of compounds of the formula (I)
• R 1 is 2-thiophene which is substituted in the 5-position by a radical selected from the group consisting of chlorine, bromine, methyl and trifluoromethyl,
• R 2 is DA-
• radical "A” is phenylene
• the group "A" in the meta position with respect to the linkage to the oxazolidinone may optionally be monosubstituted or disubstituted by a
• Radical selected from the group of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl and cyano
• radical "D” represents a saturated 5- or 6-membered heterocycle which is linked to "A” via a nitrogen atom and which is in direct proximity to the linking one
• Nitrogen atom has a carbonyl group and in which a ring carbon member may be replaced by a heteroatom from the series S, N and O,
• Oxazolidinones were originally described essentially only as antibiotics, occasionally also as MAO inhibitors and fibrinogen antagonists (review: Riedl, B., Endermann, R., Exp. Opin. Ther. Patents 1999, 9 (5), 625), a small 5- [acyl-aminomethyl] group (preferably 5- [acetylaminomethyl]) appears to be essential for antibacterial activity.
• Substituted aryl and heteroarylphenyloxazolidinones in which the monosubstituted or polysubstituted phenyl radical can be bonded to the N atom of the oxazolidinone ring and which can have an unsubstituted N-methyl-2-thiophenecarboxamide radical in the 5-position of the oxazolidinone ring, and Use as antibacterial substances are known from the US Patents 5,929,248, 5,801,246, 5,756,732, 5,654,435, 5,654,428 and 5,565,571.
• benzamidine-containing oxazolidinones are known as synthetic intermediates in the synthesis of factor Xa inhibitors or fibrinogen antagonists (WO 99/31092, EP 0 623 615).
• the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
• the invention therefore encompasses the use of the enantiomers or diastereomers and their respective mixtures. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses the use of all tautomeric forms.
• Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical applications themselves, but can be used, for example, for the isolation or purification of the compounds according to the invention.
• Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
• salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid acetic acid, trifluoroacetic acid, propionic acid
• 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.
• Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
• Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
• prodrugs include compounds which may themselves be biologically active or inactive, but which are converted during their residence time in the body into compounds of the invention (for example metabolically or hydrolytically).
• a saturated 5- or 6-membered heterocycle which is linked via a nitrogen atom and which has a carbonyl group in the direct vicinity of the linking nitrogen atom and in which a ring carbon member may be replaced by a heteroatom from the series S, N and O, is for example 2-oxo-pyrrolidin-1-yl , 2-oxopiperidin-1-yl, 2-oxopiperazin-1-yl, 2-oxomorpholin-1-yl, 3-oxothiornorpholin-4-yl, 2-oxo-1,3-oxazolidine 1-yl, 2-oxo-i, 3-oxazinan-1-yl, 2-oxo-imidazolidin-1-yl and 2-oxo-tetrahydropyrimidin-1-yl.
• Fig. 1 Maximum right-ventricular pressure
• Fig. 2 Maximum right ventricular pressure
• Fig. 3 Right ventricular hypertrophy
• Fig. 4 Right ventricular hypertrophy
• RVEDP right ventricular end-diastolic pressure
• RVEDP right ventricular end-diastolic pressure
• the compounds of formula (I) can be prepared by either
• R 2 has the meaning given above
• R 1 has the meaning given above
• R 1 has the meaning given above
• R 1 and R 2 have the abovementioned meaning
• Suitable solvents for the processes described above are organic solvents which are inert under the reaction conditions. These include halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethylene or trichlorethylene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane or cyclohexane, dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine, hexamethylphosphoric
• Suitable activating or coupling reagents for the processes described herein are the reagents customarily used therefor, for example N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide. HCl, NN'-dicyclohexylcarbodiimide, 1-hydroxy-1H-benzotriazole .H 2 O. and the same.
• Suitable bases are the customary inorganic or organic bases. These include preferably alkali metal hydroxides such as sodium or potassium hydroxide or alkali metal carbonates such as sodium or potassium carbonate or sodium or potassium or sodium or potassium or potassium tert-butoxide or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide or Amines such as triethylamine, diisopropylethylamine, diisopropylamine, 4-N, N-dimethylaminopyridine or pyridine.
• the base may in this case be used in an amount of 1 to 5 mol, preferably 1 to 2 mol, based on 1 mol of the compounds of the general formula (H).
• the reactions are generally carried out in a temperature range from -78 ° C to the reflux temperature, preferably in the range from 0 0 C to reflux temperature.
• the reactions may be carried out at normal, elevated or reduced pressure (e.g., in the range of 0.5 to 5 bar). In general, one works at atmospheric pressure.
• Suitable selective oxidizing agents for the preparation of the epoxides and for the optionally carried out oxidation to the sulfone, sulfoxide or N-oxide are m-chloroperbenzoic acid (MCPBA), sodium metaperiodate, N-methylmorpholine N-oxide (NMO), monoperoxyphthalic acid or osmium tetroxide into consideration.
• MCPBA m-chloroperbenzoic acid
• NMO N-methylmorpholine N-oxide
• monoperoxyphthalic acid or osmium tetroxide monoperoxyphthalic acid or osmium tetroxide into consideration.
• pulmonary hypertension encompasses certain forms of pulmonary hypertension, such as e.g. by the World Health Organization (WHO) (Clinical Classification of Pulmonary Hypertension, Venice 2003). Examples include pulmonary arterial hypertension, pulmonary hypertension in left heart disease, pulmonary hypertension in pulmonary disease and / or hypoxia, and pulmonary hypertension due to chronic thromboembolism (CTEPH).
• WHO World Health Organization
• CTEPH chronic thromboembolism
• the "pulmonary arterial hypertension” includes the idiopathic pulmonary arterial hypertension (IPAH, formerly referred to as primary pulmonary hypertension), the familial Conditional Pulmonary Arterial Hypertension (FPAH) and Associated Pulmonary Arterial Hypertension (APAH) associated with collagenosis, congenital systemic pulmonary shunt veins, portal hypertension, HTV infections, the use of certain drugs and medications, with other disorders (thyroid disorders, Glycogen storage disorders, Gaucher's disease, hereditary telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy), with diseases with significant venous / capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, as well as persistent pulmonary hypertension of newborns.
• IPH idiopathic pulmonary arterial hypertension
• FPAH familial Conditional Pulmonary Arterial Hypertension
• APAH Associated Pulmonary Arterial Hypertension
• Pulmonary hypertension in left heart disease includes left atrial or ventricular disease and mitral or aortic valve failure.
• Pulmonary hypertension in lung disease and / or hypoxia includes chronic obstructive pulmonary disease, interstitial lung disease, sleep apnea syndrome, alveolar hypoventilation, chronic altitude sickness, and plant-related malformations.
• Pulmonary hypertension due to chronic thromboembolism includes thromboembolic occlusion of proximal pulmonary arteries, thromboembolic occlusion of distal pulmonary arteries, and non-thrombotic pulmonary embolisms (tumor, parasites, foreign bodies).
• Another object of the present invention is the use of selective factor Xa inhibitors for the preparation of medicaments for the treatment and / or prophylaxis of pulmonary hypertension in sarcoidosis, histiocytosis X and Lymphangiomatosis.
• compositions containing a compound of the invention and one or more other active ingredients are pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.
• suitable combination active ingredients may be mentioned by way of example and preferably:
• lipid-lowering agents in particular HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors
• Coronary / vasodilators in particular ACE (angiotensin converting enzymes)
• cGMP cyclic guanosine monophosphate
• Stimulators of soluble guanylate cyclase Plasminogen activators (thrombolytics / fibrinolytics) and thrombolysis / fibrinolysis-enhancing compounds such as inhibitors of the plasminogen activator inhibitor (P AI inhibitors) or inhibitors of the thrombin-activated fibrinolysis inhibitor (TAFI inhibitors);
• anticoagulant substances anticoagulants
• platelet aggregation inhibiting substances platelet aggregation inhibitors, antiplatelet agents
• Fibrinogen receptor antagonists (glycoprotein IIb / ⁇ ia antagonists);
• Another object of the present invention is a method for the treatment and / or prophylaxis of pulmonary hypertension in humans and animals by administering an effective amount of at least one selective factor Xa inhibitor or a drug containing at least one selective factor Xa-inhibitor in combination with an inert , non-toxic, pharmaceutically suitable excipient.
• Another object of the present invention is a method for the treatment and / or prophylaxis of pulmonary hypertension in humans and animals by administering an effective amount of at least one compound of the invention or a drug containing at least one compound of the invention in combination with an inert, non-toxic, pharmaceutically suitable excipient ,
• the medicaments to be produced according to the invention or to be used according to the invention comprise at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients.
• the compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
• the compounds according to the invention can be administered in suitable administration forms.
• the compounds of the invention which function and which rapidly and / or modify the delivery compounds according to the invention are those which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as, for example.
• Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention
• Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
• a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
• absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
• parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
• Inhalation medicines including powder inhalers, nebulizers
• nasal drops solutions or sprays
• lingual, sublingual or buccal tablets films / wafers or capsules
• suppositories ear or eye preparations
• vaginal capsules aqueous suspensions (lotions, shake mixtures)
• lipophilic suspensions ointments
• creams transdermal therapeutic systems (eg plasters)
• milk pastes, foams, powdered powders, implants or stents.
• the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
• excipients include, among others, excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl).
• binders for example polyvinylpyrrolidone
• synthetic and natural polymers for example albumin
• stabilizers for example antioxidants such as ascorbic acid
• dyes for example inorganic pigments such as, for example, iron oxides
• flavor and / or odoriferous agents for example polyvinylpyrrolidone
• synthetic and natural polymers for example albumin
• stabilizers for example antioxidants such as ascorbic acid
• dyes for example inorganic pigments such as, for example, iron oxides
• flavor and / or odoriferous agents for example polyvinylpyrrolidone
• synthetic and natural polymers for example albumin
• stabilizers for example antioxidants such as ascorbic acid
• dyes for example inorganic pigments such as, for example, iron oxides
• the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.
• the compounds of the formula (I) in particular act as selective inhibitors of the blood coagulation factor Xa and do not inhibit or only at significantly higher concentrations other serine proteases such as plasmin or trypsin.
• Selective refers to those coagulation factor Xa inhibitors in which the IC 50 values for factor Xa inhibition are at least 100-fold smaller than the IC 50 values for the inhibition of other serine proteases, in particular plasmin and trypsin in which, with regard to the selectivity test methods, reference is made to the test methods described in the following Examples Aal) and Aa2).
• the enzymatic activity of human factor Xa is measured by the reaction of a FXa-specific chromogenic substrate.
• the factor Xa cleaves from the chromogenic substrate p-nitroaniline. The determinations are carried out in microtiter plates as follows.
• the control is pure DMSO.
• the chromogenic substrate 150 .mu.mol / 1 Pefachrome® FXa from Pentapharm
• the absorbance at 405 nm is determined.
• the extinctions of the test mixtures with test substance are compared with the control batches without test substance and from this the
• test substances are tested for their inhibition of other human serine proteases such as trypsin, plasmin.
• trypsin 500 mU / ml
• plasmin 3.2 nmol / l
• the enzymatic reaction is then started by addition of the corresponding specific chromogenic substrates (Chromozym Trypsin® and Chromozym Plasmin®, from Roche Diagnostics) and the extinction is determined after 20 minutes at 405 nm. All determinations are carried out at 37 ° C.
• the extinctions of the test mixtures with test substance are compared with the control samples without test substance and from this the IC 50 values are calculated.
• the anticoagulant effect of the test substances is determined in vitro in human and rabbit plasma.
• blood is taken using a 0.11 molar sodium citrate solution as a template in a mixing ratio of sodium citrate / blood 1/9.
• the blood is mixed well immediately after collection and centrifuged for 10 minutes at about 2500 g. The supernatant is pipetted off.
• the prothrombin time (PT, synonyms: thromboplastin time, quick-test) is home or in the presence of varying concentrations of test substance or the corresponding solvent using a commercial test kit (Neoplastin ® from Boehringer Man Hemoliance ® RecombiPlastin, Fa from Instrumentation Laboratory. ) certainly.
• test compounds are incubated for 3 minutes at 37 ° C with the plasma. Subsequently, coagulation is triggered by the addition of thromboplastin and the time of coagulation is determined. The concentration of test substance is determined which causes a doubling of the prothrombin time.
• the shunt is closed in the middle by a 3 cm polyethylene tube (PE 160) containing a roughened and looped nylon thread to create a thrombogenic surface.
• PE 160 polyethylene tube
• the extracorporeal circuit is maintained for 15 minutes. Then the shunt is removed and the nylon thread with the thrombus weighed immediately. The net weight of the nylon thread was determined before the start of the test.
• the Test substances are administered either intravenously via the tail vein or animals monitored by gavage prior to application of the extracorporeal circuit.
• Rat monocrotaline-induced pulmonary hypertension is a widely used animal model of pulmonary arterial hypertension.
• the pyrrolizidine alkaloid monocrotalin becomes subcutaneous
• the model uses male Sprague-Dawley rats. On day 0 the animals receive a subcutaneous injection of monocrotaline 60 mg / kg. The treatment of the animals begins before the monocrotaline injection and extends over a period of at least 28 days. At the end of the study hemodynamic examinations of the animals as well as a determination of arterial and central venous oxygen saturation are carried out. For hemodynamic measurement, the rats are initially anesthetized with pentobarbital 60 mg / kg.
• the animals are then tracheotomized and artificially ventilated (frequency: 60 breaths / min, inspiration to expiration ratio: 50:50, positive end-expiratory pressure: 1 cm H 2 O, tidal volume: 10 ml / kg bw, FIO 2 : 0.5).
• the anesthesia is maintained by isoflurane inhalation anesthesia.
• 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. Following hemodynamics, the heart is removed and the ratio of right to left ventricles including the septum is determined.
• Example 1 shows both better efficacy and lower side effects compared to enoxaparin and warfarin.
• Rats e.g., Rats or mice performed.
• Rats e.g., Sprague-Dawley, body weight 200-25Og
• mice e.g., C57 / BL6N; body weight 18-2Og
• Appropriate control rats or mice are kept under normoxic conditions.
• Chronic hypoxia of at least 14 days leads to the development of functionally and morphologically detectable rat and mouse pulmonary hypertension (literature: Dumitrascu et al, Circulation 2006, Koulmann et al, Am J Respir Crit Care Med 2006, Earley et al, Am J Physiol 2002).
• Treatment of the animals begins before or at the beginning of the keeping in a controlled hypoxic atmosphere and extends over a period of at least 14 days.
• the compounds according to the invention can be converted into pharmaceutical preparations as follows:
• composition
• 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.
• a single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.
• 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.
• a single dose of 100 mg of the compound according to the invention corresponds to 20 g of oral solution.
• the compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.
• i.v. solution The compound of the invention is dissolved in a concentration below the 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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• Plural Heterocyclic Compounds (AREA)

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• 2007
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  • 2008-04-10 WO PCT/EP2008/002829 patent/WO2008128653A1/de active Application Filing
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