EP2209776A1 - Aminoacyl-prodrugs als arzneimittelwirkstoff für thromboembolische erkrankungen - Google Patents

Aminoacyl-prodrugs als arzneimittelwirkstoff für thromboembolische erkrankungen

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Publication number
EP2209776A1
EP2209776A1 EP08773744A EP08773744A EP2209776A1 EP 2209776 A1 EP2209776 A1 EP 2209776A1 EP 08773744 A EP08773744 A EP 08773744A EP 08773744 A EP08773744 A EP 08773744A EP 2209776 A1 EP2209776 A1 EP 2209776A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
meaning given
salts
acid
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Withdrawn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
EP08773744A
Other languages
German (de)
English (en)
French (fr)
Inventor
Hans-Georg Lerchen
Ursula Krenz
Michael Härter
Mark Jean Gnoth
Georges Von Degenfeld
Elke Dittrich-Wengenroth
Anja BUCHMÜLLER
Susanne Röhrig
Swen Allerheiligen
Elisabeth Perzborn
Christoph Gerdes
Karl-Heinz Schlemmer
Metin Akbaba
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 Pharma AG
Original Assignee
Bayer Schering Pharma AG
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Filing date
Publication date
Application filed by Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Publication of EP2209776A1 publication Critical patent/EP2209776A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present application relates to prodrug derivatives of 5-chloro-N - ( ⁇ (5 ⁇ S) -2-oxo-3- [2-fluoro-4- (3-oxomorpholin-4-yl) -phenyl] -l, 3 -oxazolidin-5-yl ⁇ methyl) thiophene-2-carboxamide, process for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular thromboembolic diseases ,
  • Prodrugs are derivatives of an active substance which undergo a single or multistage biotransformation of enzymatic and / or chemical nature in vivo before the actual active substance is released.
  • a prodrug residue is usually used to improve the property profile of the underlying active ingredient [P. Ettmayer et al., J. Med. Chem. 47, 2393 (2004)].
  • the design of the prodrug residue as well as the desired release mechanism must be tailored very precisely to the individual drug, the indication, the site of action and the route of administration.
  • a large number of drugs are administered as prodrugs which have improved bioavailability over the underlying drug, for example, by improving physicochemical profile, especially solubility, active or passive absorption properties or tissue-specific distribution. Examples of the extensive literature on prodrugs are: H. Bundgaard (Ed.), Design of Prodrugs: Bioreversible Derivatives for Various Functional Groups and Chemical Entities, Elsevier Science Publishers B.V., 1985.
  • Compound (A) is an orally active, direct inhibitor of serine protease factor Xa, which exerts an essential function in the regulation of blood coagulation.
  • An oxazolidinone is! is currently undergoing in-depth clinical trials as a potential new drug for the prevention and treatment of thromboembolic disease [p. Roehrig et al., J. Med. Chem. 48, 5900 (2005)].
  • compound (A) has only a limited solubility in water and physiological media, which makes it difficult, for example, an intravenous administration of the drug.
  • the object of the present invention was therefore the identification of derivatives or prodrugs of compound (A), which have an improved solubility in said media and at the same time after application allow a controlled release of the active ingredient (A) in the body of the patient.
  • WO 2005/028473 describes acyloxymethylcarbamate prodrugs of oxazolidinones which serve to increase oral bioavailability.
  • WO 01/00622 discloses acyl prodrugs of carbamate inhibitors of inosine 5'-monophosphate dehydrogenase.
  • Another type of amide prodrugs for oxazolidinones, which release the underlying active ingredient via a multi-stage activation mechanism, is described in WO 03/006440.
  • the present invention relates to compounds of the general formula (I)
  • n is the number 1 or 2
  • X is an oxygen atom, sulfur atom or NH
  • R 1 is the side group of a natural ⁇ -amino acid or its homologs or isomers
  • R is hydrogen or methyl
  • R is hydrogen
  • R 1 and R 3 are linked via a (CH 2 ) 3 or (CH 2 ) 4 group and together with the nitrogen or carbon atom to which they are attached form a 5- or 6-membered ring,
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.
  • the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.
  • the present invention encompasses 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 themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of 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, naphthalene disulfonic 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, naphthalene disulfonic acid acetic acid, trifluoroacetic acid, propi
  • 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. Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
  • the side group of an ⁇ -amino acid in the meaning of R 1 comprises both the side groups of the naturally occurring ⁇ -amino acids and the side groups of homologues and isomers of these ⁇ -amino acids.
  • the ⁇ -amino acid can be present in both the L and the D configuration or else as a mixture of the L and D form.
  • side groups are exemplified: hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropane -l-yl (isoleucine), butan-1-yl (norleucine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (Histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl ( Methionine), carbamoylmethyl (asparagine),
  • Preferred ⁇ -amino acid side groups in the meaning of R 2 are hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), imidazol-4-ylmethyl (histidine), Hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoyl-ethyl (glutamine), 4-aminobutan-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 3 Guanidino-propan-1-yl (arginine).
  • the L configuration is preferred.
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one or two identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.
  • n is the number 1 or 2
  • X is an oxygen atom, sulfur atom or NH
  • R 1 is hydrogen, methyl, propan-2-yl, propan-1-yl, 2-methylpropan-1-yl, imidazol-4-yl-methyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2 Carbamoylethyl, 4-aminobutan-1-yl, 3-aminopropan-1-yl, 3-guanidinopropan-1-yl, benzyl or 4-hydroxybenzyl, R 2 is hydrogen or methyl,
  • R 3 is hydrogen
  • R 1 and R 3 are linked via a (CH 2 ) 3 or (CH 2 ) 4 group and together with the nitrogen or carbon atom to which they are attached form a 5- or 6-membered ring,
  • n is the number 1 or 2
  • X is NH
  • R 1 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutane-1 -yl, benzyl or 4-hydroxybenzyl,
  • R 2 is hydrogen
  • R 3 is hydrogen
  • R 1 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 2-carboxyethyl , Carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, 3-guanidinopropan-1-yl, benzyl or 4-hydroxybenzyl.
  • R 1 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl, imidazol-4-ylmethyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 2-carboxyethyl , Carbamoylmethyl, 2-carbamoylethyl, 4-aminobutan-1-yl, benzyl or 4-hydroxybenzyl.
  • Another object of the invention is a process for the preparation of the compounds of formula (I), characterized in that either
  • PG is an amino-protecting group such as ter ⁇ -butoxycarbonyl (Boc) or benzyloxycarbonyl (Z)
  • n, R 1 , R 2 , R 3 and PG have the abovementioned meaning
  • n, R, R and R have the abovementioned meaning
  • PG is an amino-protecting group such as tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z),
  • n, R 1 , R 2 , R 3 and PG have the abovementioned meaning, and subsequently the protective group PG by customary methods to obtain a compound of the formula
  • PG is an amino-protecting group such as, for example, tert-butoxy-carbonyl (Boc) or benzyloxycarbonyl (Z),
  • n, R, R, R and PG have the abovementioned meaning
  • the compounds of formula (I-A), (I-B) and (DC) may also be present in the form of their salts. These salts may optionally be converted to the free base with the appropriate (i) solvents and / or (ii) bases.
  • Protecting group PG is carried out by conventional methods known from peptide chemistry [see, e.g. T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York,
  • R 1 protecting groups can be removed simultaneously with the removal of PG or in a separate reaction step before or after the elimination of PG.
  • amino-protecting group PG tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Z) is preferably used in the above processes.
  • Boc tert-butoxycarbonyl
  • Z benzyloxycarbonyl
  • Methods preferably by reaction with a strong acid such as hydrogen chloride, bromine hydrogen or trifluoroacetic acid in an inert solvent such as dioxane, dichloromethane or acetic acid.
  • a strong acid such as hydrogen chloride, bromine hydrogen or trifluoroacetic acid in an inert solvent such as dioxane, dichloromethane or acetic acid.
  • the inert solvents used in process steps (A) + (H) -> (HI) and (A) + (VII) ⁇ (VTU) are preferably tetrahydrofuran, N, N-dimethylformamide or dimethyl sulfoxide; particularly preferred is N, N-dimethylformamide.
  • Particularly suitable bases in these reactions are sodium hydride.
  • the reactions mentioned are generally carried out in a temperature range of 0 0 C to +40 0 C at atmospheric pressure.
  • the process step (HI) + (IV) -> (V) is preferably carried out in N, N-dimethylformamide as a solvent.
  • the reaction in a temperature range of 0 0 C to +50 0 C, is forthcoming Trains t at +20 0 C to +50 0 C, at atmospheric pressure carried out.
  • the reaction can also be carried out advantageously under ultrasound treatment.
  • the compounds according to the invention and their salts are useful prodrugs of the active compound (A). On the one hand they have good stability, for example at pH 4, and on the other hand show efficient conversion to the active compound (A) in vivo. Moreover, the compounds according to the invention have good solubility in water and other physiologically compatible media, making them suitable for therapeutic use, especially in intravenous administration
  • Another object of the present invention is the use of the compounds according to the invention for the treatment and / or prophylaxis of diseases, preferably of thromboembolic diseases and / or thromboembolic complications
  • STEMI myocardial infarction with ST segment elevation
  • non-STEMI ST segment elevation
  • stable angina pectoris unstable angina pectories
  • reocclusions and pains in particular, pay particular attention to the "thromboembo disorders" in the sense of the present invention
  • coronary interventions such as angioplasty or aortocoronary bypass, peripheral arterial occlusive diseases, pulmonary embolism, deep venous thrombosis and renal vein thrombosis, transito-ischemic attacks as well as thrombotic and thromboembolic hemorrhages
  • the substances are therefore also useful in the prevention and treatment of cardiogenic thromboembolic events, such as brain ischemia, stroke and systemic thromboembolic and ischemia, in patients with acute, intermittent or persistent cardiac arrhythmias. such as atrial fibrillation, and those undergoing cardioversion, as well as patients with valvular heart disease or with artificial heart valves.
  • cardiogenic thromboembolic events such as brain ischemia, stroke and systemic thromboembolic and ischemia
  • patients with acute, intermittent or persistent cardiac arrhythmias. such as atrial fibrillation, and those undergoing cardioversion, as well as patients with valvular heart disease or with artificial heart valves.
  • the compounds of the invention are suitable for the treatment of disseminated intravascular coagulation (DIC).
  • DIC disseminated intravascular coagulation
  • Thromboembolic complications also occur in microangiopathic hemolytic anemias, extracorporeal blood circuits such as hemodialysis, and heart valve prostheses.
  • the compounds according to the invention are also suitable for the prophylaxis and / or treatment of atherosclerotic vascular diseases and inflammatory diseases such as rheumatic diseases of the musculoskeletal system, moreover also for the prophylaxis and / or treatment of Alzheimer's disease.
  • the compounds of the present invention can inhibit tumor growth and metastasis, microangiopathies, age-related macular degeneration, diabetic retinopathy, diabetic nephropathy and other microvascular diseases and for the prevention and treatment of thromboembolic complications such as venous thromboembolism in tumor patients, particularly those that undergo major surgery or chemo- or radiotherapy.
  • Another object of the present invention is the use of the inventive compounds for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.
  • Another object of the present invention is a method for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases, using PHg of the compounds of the invention.
  • 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, especially ACE (angiotensin converting enzyme) inhibitors; AII (angiotensin II) receptor antagonists; beta-adrenoceptor antagonists; alpha 1 -adrenoceptor antagonists; diuretics; Calcium channel blockers; Substances that cause an increase in cyclic guanosine monophosphate (cGMP), such as soluble guanylate cyclase stimulators;
  • cGMP cyclic guanosine monophosphate
  • Plasminogen activators thrombolytics / fibrinolytics
  • thrombolysis / fibrinolysis enhancing compounds such as inhibitors of plasminogen activator inhibitor (P AI inhibitors) or inhibitors of thrombin-activated fibrinolysis inhibitor (TAFI inhibitors);
  • anticoagulant substances anticoagulants
  • platelet aggregation inhibiting substances platelet aggregation inhibitors, antiplatelet agents
  • Fibrinogen receptor antagonists (glycoprotein IIb / IIIa antagonists);
  • compositions containing at least one inventive compound are pharmaceutical compositions containing at least one inventive compound, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary or nasal. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.
  • the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such as tablets (uncoated or coated Tablets, for example with enteric or delayed-dissolving or insoluble coatings, which control the release of the compound of the invention), tablets or films / wafers, films / lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, rapidly disintegrating in the oral cavity Pellets, powders, emulsions, suspensions, aerosols or solutions.
  • parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar
  • suitable application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • inhalative dosage forms such as powder inhalers or nebulizers
  • nasally administrable dosage forms such as drops, solutions or sprays.
  • 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 for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecyl sulfate, polyoxysorbitanoleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • Stabilizers eg, antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous 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 dodecy
  • 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.
  • Method 1 Instrument: HP 1 100 with DAD Detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: 5 ml perchloric acid (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 6.5 min 90% B ⁇ 6.7 min 2% B ⁇ 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C .; UV detection: 210 nm.
  • Method 2 Instrument: HP 1 100 with DAD Detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 ⁇ m; Eluent A: 5 ml perchloric acid (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 9 min 0% B ⁇ 9.2 min 2% B ⁇ 10 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C; UV detection: 210 nm.
  • Method 3 Device Type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 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; Gradient: 0.0 min 90% A - »2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; 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.
  • Method 4 Instrument: Micromass GCT, GC6890; Column: Restek RTX-35MS, 30 m ⁇ 250 ⁇ m ⁇ 0.25 ⁇ m; constant flow with helium: 0.88 ml / min; Oven: 60 ° C; Inlet: 250 ° C; Gradient: 60 0 C (0.30 min hold), (1.7 min hold) 50 ° C / min ⁇ 120 0 C, 16 ° C / min ⁇ 250 0 C, 30 ° C / min ⁇ 300 0C.
  • Method 5 Column: GROM-SIL 120 ODS-4 HE, 10 ⁇ M, 250 mm x 30 mm; Flow: 50 ml / min; Mobile phase and gradient program: acetonitrile / 0.1% aqueous formic acid 10:90 (0-3 min), acetonitrile / 0.1% aqueous formic acid 10:90 -> 95: 5 (3-27 min), acetonitrile / 0.1% aqueous formic acid 95: 5 (27-34 min), acetonitrile / 0.1% aqueous formic acid 10:90 (34-38 min); Temperature: 22 ° C; UV detection: 254 nm.
  • Method 6 Instrument: Micromass ZQ; Device type HPLC: HP 1 100 Series; UV DAD; Column: Phenomenex Gemini 3 ⁇ 30 mm x 3.00 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; Gradient: 0.0 min 90% A -> 2.5 min 30% A ⁇ 3.0 min 5% A ⁇ 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min; Temperature: 50 ° C .; UV detection: 210 nm.
  • Method 7 Device Type MS: Waters (Micromass) Quattro Micro; Device type HPLC: Agilent 1 100 series; Column: Thermo Hypersil GOLD 3 ⁇ 20mm x 4mm; 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; Gradient: 0.0 min 100% A ⁇ 3.0 min 10% A ⁇ 4.0 min 10% A ⁇ 4.01 min 100% A (flow: 2.5 ml) ⁇ 5.00 min 100% A; Oven: 50 ° C .; Flow: 2 ml / min; UV detection: 210 nm.
  • Method 9 Analytical HPLC: Device: HP1090 Series II; Column: Waters XTerra C18-5, 3.9 mm x 150 mm WAT 186000478; Eluent A: 10 ml of 70% perchloric acid in 2.5 liters of water, eluent B: acetonitrile; Gradient: 0.0 min 20% B ⁇ 1 min 20% B ⁇ 4 min 90% B ⁇ 6 min 90% B ⁇ 8 min 20% B. Temperature: 40 ° C .; Flow: 1 ml / min.
  • Method 10 (analytical HPLC): Instrument: HP 1090 series ü; Column: Merck Chromolith Speed ROD RP-18e, 50 mm x 4.6 mm; Precolumn Chromolith Guard Cartridge Kit, RP-18e, 5-4.6mm; Eluent A: 5 ml perchloric acid (70%) / 1 water, eluent B: acetonitrile; Gradient: 0 min 20% B ⁇ 0.5 min 20% B ⁇ 3 min 90% B ⁇ 3.5 min 90% B ⁇ 3.51 min 20% B ⁇ 4 min 20% B; Flow: 5 ml / min; Column temperature: 40 ° C; UV detection: 210 nm.
  • Method 1 1 (preparative HPLC): Device: Gilson with UV detector, column: Kromasil Cl 8, 5 ⁇ m / 250 mm ⁇ 20 mm (flow: 25 ml / min); Eluent A: water (0.01% trifluoroacetic acid); Eluent B: acetonitrile (0.01% trifluoroacetic acid); Gradient: 0 min 5-20% B, 10 min-15 min 5-20% B, 45 min 90% B, 50 min 90% B; UV detection: 210 nm; Flow: 25 ml / min.
  • Method 12 (preparative HPLC): Device: Gilson with UV detector, column: YMC ODS AQ Cl 8, 10 ⁇ m / 250 mm x 30 mm (flow: 50 ml / min); Eluent A: water (0.01% trifluoroacetic acid), eluent B: acetonitrile (0.01% trifluoroacetic acid); Gradient: 0 min 5-20% B, 10 min-15 min 5-20% B, 45 min 90% B, 50 min 90% B; UV detection: 210 nm; Flow: 50 ml / min.
  • Method 13 Instrument: Micromass Quattro Premier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9 ⁇ , 50 mm x 1 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; Gradient: 0.0 min 90% A ⁇ 0.1 min 90% A ⁇ 1.5 min 10% A ⁇ 2.2 min 10% A; Oven: 50 ° C .; Flow: 0.33 ml / min; UV detection: 210 nm.
  • NMR measurements were carried out at a proton frequency of 400.13 MHz or 500.13 MHz.
  • the samples were usually dissolved in DMSO-dö; Temperature: 302 K.
  • the starting material was 5-chloro-N - ( ⁇ (55) -2-oxo-3- [2-fluoro-4- (3-oxomethyl-4-yl) -phenyl] -1,3-oxazolidin-5-yl ⁇ methyl) thiophene-2-carboxamide [compound (A)].
  • the title compound can be prepared analogously to Example 12A from compound (A) and the compound from Example 19A.
  • the title compound was prepared from Boc-glycine analogously to the literature-known specification [R. Michelot et al., Bioorg. Med. Chem. 1996, 4, 2201).
  • the title compound was prepared from bis-Boc-lysine analogously to the literature [R. Michelot et al., Bioorg. Med. Chem. 1996, 4, 2201).
  • the title compound was prepared from Boc-alanine analogously to the literature [R. Michelot et al., Bioorg. Med. Chem. 1996, 4, 2201).
  • the aqueous phase was adjusted to pH 2 with 4M hydrochloric acid and concentrated in vacuo.
  • the residue was purified by flash chromatography on silica gel with acetonitrile / water / acetic acid 5: 1: 0.1 as eluent. The appropriate fractions were concentrated and stirred with ethyl acetate and diethyl ether. The residue was then filtered off with suction and dried under high vacuum. 9.1 g (45% of theory) of the p-methoxybenzyl-protected amino acid were obtained.
  • Urethane-protected N-carboxyanhydrides of amino acid derivatives are either commercially available or can be prepared according to literature procedures: M. Johnston et al. J. Org. 1985, 50, 2200; W. D. Meder et al. J. Am. 1990, 112, 7414; S. Mobasheri et al. J. Org. 1992, 57, 2755.
  • N-hydroxysuccinimide Esters of amino acid derivatives are either commercially available or can be prepared by standard methods of peptide chemistry. example 1
  • the title compound can be prepared analogously to Examples 2 and 25 from the compound of Example 10A and Boc-glycine.
  • the title compound can be prepared in analogy to Examples 2 and 25 from the compound of Example 1 IA and Boc-valine.
  • the title compound was prepared by dissolving 7.4 mg of the compound of Example 26 in pH 3 adjusted aqueous hydrochloric acid and subsequent lyophilization. Yield: 6.4 mg (quant.)
  • Example 6 The title compound can be prepared in analogy to Examples 4 and 26 from the compounds of Examples 1 IA and 16A.
  • Example 6
  • the title compound can be prepared analogously to Examples 4 and 26 from the compounds of Examples IA and 17A.
  • Example 8 The title compound can be prepared analogously to Examples 4 and 26 from the compounds of Examples 1 IA and 18A.
  • Example 8
  • the Braverbind ⁇ ng can be prepared in analogy to Examples 4 and 26 from the compounds of Examples 10A and 15A.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 12A with Boc-glycine.
  • the deprotection can alternatively also be carried out as in Example 25, step b) described be carried out with trifluoroacetic acid and from the initially formed trifluoroacetate by salination with aqueous hydrochloric acid, the title compound can be generated.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-glycine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-proline.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with bis-Boc histidine.
  • the deprotection may alternatively be carried out as described in Example 25, step b) with trifluoroacetic acid and from the first formed trifluoroacetate by salting with aqueous hydrochloric acid, the title compound can be generated.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-valine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with bis-Boc-lysine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • Example 16 The title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-threonine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • Example 16
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-tyrosine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-asparagine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-phenylalanine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-glutamine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • the title compound can be prepared in analogy to Example 23 from the compound of Example 13A with Boc-glutamic acid tert-butyl ester.
  • the deprotection may alternatively be carried out as described in Example 25, step b) with trifluoroacetic acid and from initially formed trifluoroacetate by salting with aqueous hydrochloric acid, the title compound can be generated.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-serine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • the title compound can be prepared analogously to Example 23 from the compound of Example 13A with Boc-leucine.
  • the deprotection can alternatively also be carried out as described in Example 25, step b) with trifluoroacetic acid and the title compound can be generated from the initially formed trifluoroacetate by salification with aqueous hydrochloric acid.
  • the title compound can be prepared in analogy to Example 23 from the corresponding starting compounds.
  • test substance is suspended in water or dilute hydrochloric acid (pH 4). This suspension is shaken for 24 h at room temperature. After ultra-centrifugation at 224000g for 30 min, the supernatant is diluted with DMSO and analyzed by HPLC. Quantification is via a two-point calibration curve of the test compound in DMSO.
  • test substance weigh 0.25 mg of the test substance in a 2 ml HPLC vial and add 0.5 ml of acetonitrile. To dissolve the substance, the sample vessel is placed in the ultrasonic bath for approx. 10 seconds. Subsequently, 0.5 ml of the respective buffer solution is added and the sample is again treated in an ultrasonic bath.
  • pH 4.0 1 liter of Millipore water is adjusted to pH 4.0 with 1 N hydrochloric acid;
  • pH 7.4 90 g of sodium chloride, 13.61 g of potassium dihydrogen phosphate and 83.35 g of 1 M sodium hydroxide solution are made up to 1 liter with Millipore water and then diluted 1:10.
  • Agilent 1100 with DAD (G1314A), binary pump (G1312A), autosampler (G1329A), column oven (G1316A), thermostat (G1330A); Column: Kromasil 100 C18, 250 mm x 4.6 mm, 5 ⁇ m; Column temperature: 30 ° C .; Eluent A: water + 5 ml perchloric acid / liter, eluent B: acetonitrile.
  • a defined volume of plasma (e.g., 2.0 ml) is heated to 37 ° C in a closed test tube in a water bath. After reaching the target temperature, a defined amount of the test substance is added as a solution (volume of the solvent max 2% of the plasma volume). The plasma is shaken and a first sample (50-100 ⁇ l) taken immediately. In the period up to 2 h after the start of incubation, 4-6 further aliquots are subsequently taken.
  • test substance and optionally known cleavage products of the test substance are quantitatively determined in the supernatant with a suitable LC / MS-MS method.
  • test substance On the day of the test, a defined dose of the test substance is administered as a solution with a Hamilton ® glass syringe into the tail vein (bolus administration, application time ⁇ 10 s). Within 24 hours of substance administration, blood samples (8-12 times) are taken sequentially across the catheter. For plasma collection, the samples are centrifuged in heparinized tubes. At each point in time, a defined plasma volume for protein precipitation is mixed with acetonitrile. After centrifugation, test substance and optionally known cleavage products of the test substance are quantitatively determined in the supernatant with a suitable LC / MS-MS method.
  • the pharmacokinetic parameters of the test substance or of the active substance compound (A) released therefrom are calculated from the measured plasma concentrations.
  • the metabolic stability of the test compounds to hepatocytes is determined by incubating the compounds at low concentrations (preferably below 1 ⁇ M) and at low cell counts (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 max " values are calculated (see below).
  • the CL and F max values are a measure of the phase I and phase 2 metabolism of the compound in the hepatocytes.
  • its concentration generally becomes limited to 1% (acetonitrile) and 0.1% (DMSO).
  • Fasting male rats (strain: HSD CPB: WU) are anesthetized by intraperitoneal administration of a Rompun / Ketavet solution (12 mg / kg / 50 mg / kg). Thrombus formation is performed in an arteriovenous shunt following the procedure described by PC Wong et al. described method [Thrombosis Research 82 (2), 117-126 (1996)]. For this purpose, the left jugular vein and the right carotid artery are dissected free.
  • An 8 cm long polyethylene catheter (PE60, Becton-Dickinson) is inserted into the artery, followed by a 6 cm long Tygon tube (R-3606, ID 3.2 mm, from Kronlab), which is roughened to produce a thrombogenic surface and to a double loop nylon thread (60 x 0.26 mm, Berkley Trilene) included.
  • a 2 cm long polyethylene catheter (PE60, Becton-Dickinson) is integrated and connected to the Tygon tube via a 6 cm long polyethylene catheter (PEI 60, Becton-Dickinson).
  • the tubes are filled with saline before opening the shunt.
  • the extracorporeal circuit is kept for 15 min. get right.
  • test substance as a solution in physiological saline adjusted to pH 4 with 0.1N hydrochloric acid
  • the test substance is administered as a bolus injection prior to application of the extracorporeal circuit.
  • the compounds according to the invention can be converted, for example, into pharmaceutical preparations as follows:
  • the compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically acceptable solvent (eg isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%, which are each adjusted to a pH of 3-5) ,
  • a physiologically acceptable solvent eg isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%, which are each adjusted to a pH of 3-5
  • the solution is optionally filtered sterile and / or filled into sterile and pyrogen-free injection containers.

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