EP1937271A1 - Behandlung und prophylaxe von mikroangiopathien - Google Patents

Behandlung und prophylaxe von mikroangiopathien

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Publication number
EP1937271A1
EP1937271A1 EP06792284A EP06792284A EP1937271A1 EP 1937271 A1 EP1937271 A1 EP 1937271A1 EP 06792284 A EP06792284 A EP 06792284A EP 06792284 A EP06792284 A EP 06792284A EP 1937271 A1 EP1937271 A1 EP 1937271A1
Authority
EP
European Patent Office
Prior art keywords
oxo
chloro
methyl
phenyl
thiophenecarboxamide
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.)
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Application number
EP06792284A
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German (de)
English (en)
French (fr)
Inventor
Elisabeth Perzborn
Frank Misselwitz
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Bayer Pharma AG
Original Assignee
Bayer Healthcare AG
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Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1937271A1 publication Critical patent/EP1937271A1/de
Withdrawn legal-status Critical Current

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    • 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
    • A61K31/5355—Non-condensed oxazines 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
    • A61K31/41—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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • 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
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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

Definitions

  • the present invention relates to the use of selective factor Xa inhibitors, in particular oxazolidinones of the formula (T), for the treatment and / or prophylaxis of microangiopathies and their use for the production of medicaments for the treatment and / or prophylaxis of microangiopathies.
  • 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. Malinowski, 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. Patents 2001, 11, 1007; K.
  • 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.
  • Microangiopathies are a condition caused by stenosis and thrombosis of small and very small vessels. Common causes of microangiopathies are embolizing microthrombi from proximal vessels, endothelial damage with excessive activation of platelets and coagulation. So put in the pathogenesis of microangiopathy Endothelial defects are a crucial pathophysiological substrate. The normal, intact endothelial lining of the blood vessels is athrombogenic. In trauma thrombogenic properties of the endothelium come to the fore. Thrombi result in microangiopathic hemolysis, occlusion of small vessels and organic ischemia.
  • selective factor Xa inhibitors in particular oxazolidinones of the formula (I), are also suitable for the treatment and prevention of microangiopathies.
  • the present invention is the use of selective factor Xa inhibitors for the preparation of medicaments for the treatment and / or prophylaxis of microangiopathies.
  • the present invention particularly relates to the use of compounds of the formula (I)
  • R 1 is optionally benzo-fused thiophene (thienyl), which may optionally be mono- or polysubstituted;
  • R 2 is any organic radical
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same or different and are hydrogen or (C r C 6 ) alkyl
  • R 1 is optionally benzo-fused thiophene (thienyl), which may optionally be mono- or polysubstituted by a radical from the group of halogen;
  • R 2 is one of the following groups:
  • radical "A” is (C 6 -C 4) -aryl, preferably (C 6 -C 0) aryl, in particular phenyl or naphthyl, very particularly preferably phenyl;
  • the radical "B” is a 5- or 6-membered aromatic heterocycle containing up to 3 heteroatoms and / or hetero-chain members, in particular up to 2 heteroatoms and / or hetero-chain members, from the series S, N, NO ( N-oxide) and O;
  • radical "D” is a saturated or partially unsaturated, mono- or bicyclic, optionally benzo-fused 4- to 9-membered heterocycle containing up to three heteroatoms and / or hetero-chain members from the series S, SO, SO 2 , N , NO (N-oxide) and O;
  • v is either O or 1
  • R 27, R 28 and R 29 are identical or different and are independently hydrogen, (C r C4) alkyl, (C 3 -C 7) cycloalkyl, (C, -C 4) alkanoyl, carbamoyl, trifluoromethyl, Phenyl or pyridyl,
  • R 27 and R 28 or R 27 and R 29 together with the nitrogen atom to which they are attached, a saturated or partially unsaturated 5- to 7-membered heterocycle having up to three, preferably up to two identical or different hetero atoms from the group of N, O and S form, and
  • R 30 and R 31 are the same or different and are independently hydrogen
  • R 33 is (C 1 -C 6 ) -alkoxy, (C, -C 4) alkoxycarbonyl
  • R 1 is thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, amino,
  • R 2 is one of the following groups:
  • radical "A” is (C ⁇ -C-O-aryl, preferably (C 6 -C 0) aryl, in particular phenyl or naphthyl, very particularly preferably phenyl;
  • the radical "B” is a 5- or 6-membered aromatic heterocycle containing up to 3 heteroatoms and / or hetero-chain members, in particular up to 2 heteroatoms and / or hetero-chain members, from the series S, N, NO ( N-oxide) and O;
  • the radical "D” is a saturated or partially unsaturated 4- to 7-membered heterocycle containing up to three heteroatoms and / or hetero-chain members from the series S, SO, SO 2 , N, NO (N-oxide) and Contains O;
  • v is either O or 1
  • R 27 , R 28 and R 29 are identical or different and independently of one another are hydrogen, (C 1 -C 4 ) -alkyl or (C 3 -C 7 ) -cycloalkyl,
  • R 27 and R 28 or R 27 and R 29 together with the nitrogen atom to which they are attached, a saturated or partially unsaturated 5- to 7-membered heterocycle having up to three, preferably up to two identical or different hetero atoms from the group of N, O and S form, and
  • R 30 and R 31 are the same or different and are independently hydrogen
  • R 1 is thiophene (thienyl), in particular 2-thiophene, which may optionally be mono- or polysubstituted by halogen, preferably chlorine or bromine, or (Ci-Cg) alkyl, preferably methyl, wherein the (Ci-Cg ) -Alkyl radical may optionally be monosubstituted or polysubstituted by halogen, preferably fluorine,
  • R 2 is one of the following groups:
  • radical "A” is phenyl or naphthyl, in particular phenyl;
  • radical "B” is a 5- or 6-membered aromatic heterocycle containing up to 2 heteroatoms from the series S, N, NO (N-oxide) and O;
  • the radical "D” is a saturated or partially unsaturated 5- or 6-membered heterocycle containing up to two heteroatoms and / or hetero-chain members from the series S, SO, SO 2 , N, NO (N-oxide) and Contains O;
  • the radical "M” for -NH-, -O-, -NH-CH 2 -, -CH 2 -NH-, -OCH 2 -, -CH 2 O-, -CONH-, -NHCO- or for a covalent Bond stands;
  • v is either O or 1, preferably O, and
  • R 27 , R 28 and R 29 are identical or different and independently of one another hydrogen
  • R 27 and R 28 or R 27 and R 29 together with the nitrogen atom to which they are bonded, a saturated or partially unsaturated 5- to 7-membered heterocycle having up to two identical or different heteroatoms from the group of N,
  • R 30 and R 31 are identical or different and are each independently hydrogen, (C 1 -C 4 ) -alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C 1 -C 4 ) -alkylsulfonyl, (C 1 -C 4 ) -hydroxyalkyl, (C r C 4) aminoalkyl, di-Cd-C ⁇ alkylamino-Cd-O-alkyl, (Ci-C mean 3) alkanoyl or phenylcarbonyl,
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same or different and are hydrogen or (C 1 -Q) -AIlCyI
  • R 1 is 2-thiophene, which may optionally be substituted in the 5-position by a radical from the group consisting of chlorine, bromine, methyl or trifluoromethyl,
  • R 2 is one of the following groups:
  • radical "A” is phenyl or naphthyl, in particular phenyl;
  • radical "B” is a 5- or 6-membered aromatic heterocycle containing up to 2 heteroatoms from the series S, N, NO (N-oxide) and O;
  • radical "D” is a saturated or partially unsaturated 5- or 6-membered heterocycle which is a nitrogen atom and optionally one further heteroatom and / or hetero-chain member from the series S, SO, SO 2 and O, or up to two
  • Heteroatoms and / or hetero-chain members from the series S, SO, SO 2 and O contains;
  • v is either 0 or 1, preferably 0, and
  • R 27 , R 28 and R 29 are identical or different and independently of one another are hydrogen, (C 1 -C 4 ) -alkyl or else cyclopropyl, cyclopentyl or cyclohexyl
  • R 27 and R 28 or R 27 and R 29 together with the nitrogen atom to which they are bonded, a saturated or partially unsaturated 5- to 7-membered heterocycle having up to two identical or different heteroatoms from the group of N, O. and S can form, and
  • R 30 and R 31 are identical or different and are each independently hydrogen, (QO-alkyl, cyclopropyl, cyclopentyl, cyclohexyl, (C 1 -C 4 ) -alkylsulfonyl, (C 1 -C 4 ) -hydroxyalkyl, (C 1 -C 4 ) -aminoalkyl, DHC 1 -C 4 ) -alkylamino- (C 1 -C 4 ) -alkyl J
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are the same or different and are hydrogen or (C 1 -Q) -AIlCyI
  • R 1 is 2-thiophene, which is substituted in the 5-position by a radical from the group chlorine, bromine, methyl or trifluoromethyl,
  • radical "A” is phenylene
  • radical "D” represents a saturated 5- or 6-membered heterocycle
  • a ring carbon member may be replaced by a heteroatom of the series S, N and O;
  • the previously defined group "A" in the meta position with respect to the linkage to the oxazolidinone may optionally be monosubstituted or disubstituted by a radical from the group of fluorine, chlorine, nitro, amino, trifluoromethyl, methyl or cyano,
  • R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are hydrogen
  • 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.
  • 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).
  • Solvates of the salts comprising the compounds of formula (I) of the following formulas and their salts, solvates and solvates of the salts and of 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) 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 encompasses the use of the enantiomers or diastereomers and their respective mixtures.
  • 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 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 according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethane sulfonic 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.
  • 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 1 to 16 carbon atoms, such as, by way of example and by way of illustration, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • 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
  • 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).
  • Halogen is fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • (C 1 -Cs) -AlkVl is a straight-chain or branched alkyl radical having 1 to 8 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. From this definition (6 C r C) alkyl and (C r C 4) -alkyl, are derived analogously the corresponding alkyl groups with fewer carbon atoms, such as from. In general, (C 1 -C 4 ) -alkyl is preferred.
  • C r C7VCvcloalk ⁇ l stands for a cyclic alkyl group having 3 to 7 carbon atoms, Examples which may be mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl From this definition, are derived analogously the corresponding cycloalkyl groups having fewer carbon atoms, such as, for example, (C 3 -Cs) - Cycloalkyl, cyclopentyl and cyclohexyl are preferred.
  • (C 2 -Cg) - alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms. Examples include: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.
  • (C 1 -Cs) -alkoxy represents a straight-chain or branched alkoxy radical having 1 to 8 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and n-octoxy. From this definition, the corresponding alkoxy groups with fewer carbon atoms, such as, for example, (C 1 -C 10) -alkoxy and (C 1 -C 4 ) -alkoxy, are derived analogously. In general, (C 1 -CI) -alkoxy is preferred.
  • Mono- or DHC-CaVAlkylaminocarbonyl represents an amino group which is linked via a carbonyl group and which has one straight-chain or branched or two identical or different straight-chain or branched alkyl substituents each having 1 to 4
  • (C 1 -C 6) -Alkanoyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms which carries a doubly bonded oxygen atom in the 1-position and is linked via the 1-position. Examples include: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl, n-hexanoyl. From this definition, (4 QC) alkanoyl and (Ci-C3) -alkanoyl, are derived analogously the corresponding alkanoyl groups with fewer carbon atoms, such as (C 1 -C 5) alkanoyl, from. In general, (C 1 -C 3 ) alkanoyl is preferred. From this definition, the meaning of the corresponding constituent of other more complex substituents such as cycloalkanoyl and Alkanoylalkvl derived.
  • (C 1 -C 7) -Calkloalkanoyl represents a cycloalkyl radical as defined above having 3 to 7 carbon atoms which is linked via a carbonyl group.
  • (C r Cfi) -alkanoyloxymethyloxy represents a straight-chain or branched alkanoyloxymethyloxy radical having 1 to 6 carbon atoms. Examples which may be mentioned are: acetoxymethyloxy, propionoxymethyloxy, n-butyroxymethyloxy, i-butyroxymethyloxy, pivaloyloxymethyloxy, n-hexanoyloxymethyloxy. From this definition, the corresponding alkanoyloxymethyloxy groups having fewer carbon atoms, such as (Q-C 3 ) -alkanoyloxymethyloxy, are derived analogously. In general, (C 1 -C 3 ) -alkanoyloxymethyloxy is preferred.
  • (Cfi-Cu) -aryl represents an aromatic radical having 6 to 14 carbon atoms. Examples include: phenyl, naphthyl, phenanthrenyl and anthracenyl. From this definition, (C 6 -C 0) are derived analogously the corresponding aryl groups with fewer carbon atoms, such as from aryl. In general, the (C 6 -C 0) - is preferred aryl.
  • Cs-CuO heteroaryl or a 5- to 10-membered aromatic Heterocvclus having up to 3 heteroatoms and / or heterokain members from the series S, O, N and / or NO (N-oxide) is a mono- or bicyclic heteroaromatic
  • N, NO (N-oxide) and / or O represents a heterocycle which may contain one or more double bonds, which may be mono- or bicyclic, in which a benzene ring may be fused to two adjacent ring carbon atoms and which may be fused via a ring carbon or a ring nitrogen atom is linked.
  • Examples which may be mentioned are: tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, morpholinyl-N-oxide, thiomorpholinyl, azepinyl, 1,4-diazepinyl and cyclohexyl. Preference is given to piperidinyl, morpholinyl and pyrrolidinyl.
  • the compounds of formula (I) can be prepared by either following a process alternative
  • Carboxylic acid chlorides or else with the corresponding symmetrical or mixed carboxylic acid anhydrides of the previously defined carboxylic acids of the general formula (II) in inert solvents, if appropriate in the presence of an activating or coupling reagent and / or a base, to give compounds of the general formula (I)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the meanings given above,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the meanings given above,
  • R 2 is a 3- to 7-membered saturated or partially unsaturated cyclic hydrocarbon radical having one or more identical or different heteroatoms from the group of N and S may include oxidation with a selective oxidizing agent to the corresponding sulfone, sulfoxide or N-oxide
  • Carboxylic acid chlorides, isocyanates, sulfonyl chlorides or alkyl halides to the corresponding derivatives can connect
  • 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 methods described above are the reagents customarily used therefor, for example N '- (3
  • 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.
  • 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 or potassium tert-butoxide
  • amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide or Amines such as triethylamine, diisopropylethylamine, diisopropylamine
  • 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 general formula (II).
  • 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 can 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.
  • the customary production conditions are used.
  • a compound of the formula (I) which can preferably be used according to the invention is 5-chloro-N - ( ⁇ (5S) -2-oxo-3 - [4- (3-oxo-4-morpholinyl) -phenyl] -1,3-oxazolidine 5-yl ⁇ methyl) -2-thiophenecarboxamide, the compound of Example 44.
  • microangiopathies in the sense of the present invention encompasses closure syndromes that arise primarily on the skin and other organs.
  • microangiopathies further includes the primary forms of thrombotic microangiopathies (TMA), such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS).
  • TTP is characterized by the appearance of intravascular coagulation with the formation of microthrombi in the smallest vessels, which can affect all organs.
  • HUS is an acute disease characterized by aggregation of platelets, hemolysis, thrombosis in the microcirculation, and consecutive multi-organ failure.
  • TMA also includes secondary forms that occur particularly after infections, ingestion of drugs (ciclosporin, mitomycin, metamizol, etc.), endocarditis, collagenosis, malignancies, transplants and during pregnancy.
  • diabetic microangiopathies diabetic retinopathy, glomerulopathy, trophic disorders, diabetic gangrene
  • venous occlusive liver disease cerebral vasculitis
  • placental microthrombosis a recurrent miscarriage
  • Another object of the present invention is the use of selective factor Xa inhibitors for the manufacture of a medicament for the treatment and / or prophylaxis of occlusive syndromes, especially on the skin and other organs resulting occlusive syndromes of primary forms of thrombotic microangiopathies (TMA), in particular the thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), secondary forms of TMA, especially after infections, ingestion of drugs, endocarditis, collagenosis, malignancies, transplants, and secondary forms of TMA occurring in pregnancy, diabetic microangiopathies, especially diabetic Retinopathy, glomerulopathy, trophic disorders and diabetic gangrene, of venous occlusive diseases of the liver, cerebral vasculitis and placental microthrombosis and the resulting repeated miscarriages.
  • TMA thrombotic microangiopathies
  • TTP thrombotic thrombocytopenic purpura
  • the present invention further relates to the use of the compounds according to the invention for the preparation of a medicament for the treatment and / or prophylaxis of occlusive syndromes, in particular closure syndromes arising on the skin and other organs, of primary forms of thrombotic microangiopathies (TMA), in particular thrombotic thrombocytopenic purpura (TTP) and Hemolytic Uremic Syndrome (HUS), secondary forms of TMA, especially after infections, ingestion of medication, endocarditis, collagenosis, malignancies, transplants, and secondary forms of TMA occurring in pregnancy, diabetic microangiopathies, especially diabetic Retinopathy, glomerulopathy, trophic disorders and diabetic gangrene, of venous occlusive diseases of the liver, cerebral vasculitis and placental microthrombosis and the resulting repeated miscarriages.
  • TMA thrombotic microangiopathies
  • TTP thrombotic thrombocytopenic purpura
  • HUS
  • tissue thromboplastin tissue Factor; TF
  • proteases factor VIIa, TF-VIIa-Xa complex, factor FXa, thrombin
  • PARI proteases
  • PAR2 proteases
  • FXa inhibitors are also capable of reducing or preventing the harmful capillary sprouts arising in microangiopathies.
  • Another object of the present invention is the use of selective factor Xa inhibitors for the manufacture of a medicament for the treatment and / or prophylaxis of harmful Kapillaraussprossungen resulting in microangiopathies.
  • 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 harmful Kapillaraussprossungen resulting in microangiopathies.
  • Another object of the present invention is a method for controlling microangiopahtien 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 controlling Mikroangiopahtien 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.
  • a further subject of the present invention is a method of combating harmful capillary sprouts in humans and animals resulting from microangiopathies by administering an effective amount of at least one selective factor Xa inhibitor or a medicament 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 combating harmful Kapillaraussssssssssss.
  • 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.
  • they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds according to the invention rapidly and / or modified donating application forms, the compounds of the invention in crystalline and / or amorphized and / or dissolved
  • Tablets uncoated or coated tablets, for example, with enteric or delayed-dissolving or insoluble coatings containing the
  • Soft gelatin capsules Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • 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 (in particular 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 ( For example, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.
  • excipients in particular for example microcrystalline cellulose, lactose, mannitol
  • solvents for example liquid polyethylene glycols
  • emulsifiers and dispersants or wetting agents
  • 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 of Examples Aa1) and Aa2) described below.
  • 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.
  • test substances are dissolved in different concentrations in DMSO and incubated for 10 minutes with human FXa (0.5 nmol / l dissolved in 50 mmol / l Tris buffer [C, C, C]).
  • 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 IC 50 values are calculated.
  • test substances are tested for their inhibition of other human serine proteases such as trypsin, plasmin.
  • trypsin 500 mU / ml
  • plasmin 3.2 nmol / 1
  • 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 the IC calculates 5 0- values.
  • 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 determined of varying concentrations of test substance or the corresponding solvent using a commercial test kit (Neoplastin ® from Boehringer Mannheim or Hemoliance ® RecombiPlastin, Fa from Instrumentation Laboratory.) In the presence , The 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.
  • This polyethylene tube was centered in another 3 cm polyethylene tube (PE 160) which contained a roughened and looped nylon thread to create a thrombogenic surface.
  • PE 160 3 cm 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. Results obtained in this way are shown in Table 1:
  • An extracorporeal shunt is placed between the two vessels by means of a 10 cm long polyethylene tube (PE 60) venous catheter.
  • This polyethylene tube catheter is center-wrapped in another 3-cm polyethylene tube (PE 160, Becton Dickenson) which includes a roughened and looped nylon thread to create a thrombogenic surface.
  • the extracorporeal circuit is maintained for 15 minutes.
  • 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 to an ear vein or orally by gavage to the conscious animals prior to application of the extracorporeal circuit.
  • the compounds according to the invention can be converted into pharmaceutical preparations as follows:
  • composition
  • the mixture of the compound according to 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 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.
  • iv solution The compound according to the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (eg isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%).
  • a physiologically tolerated solvent eg isotonic saline solution, glucose solution 5% and / or PEG 400 solution 30%.
  • the solution is sterile filtered and filled into sterile and pyrogen-free injection containers.
  • N- (2,3-epoxypropyl) phthalimide is described in J.-W. Chern et al. Tetrahedron Lett. 1998, 39, 8483.
  • the substituted anilines can be obtained by reacting, for example, 4-fluoronitrobenzene, 2,4-difluoronitrobenzene or 4-chloronitrobenzene with the corresponding amines or amides in the presence of a base.
  • Pd catalysts such as Pd (OAc) 2 / DPPF / NaOt-Bu (Tetrahedron Lett., 1999, 40, 2035) or copper (Renger, Synthesis 1985, 856, Aebischer et al., Heterocycles, 1998, 45 , 2225).
  • haloaromatics without a nitro group can first be converted into the corresponding amides in order to subsequently nitrate them in the 4-position (US3279880).
  • NMP N-methylpyrrolidone
  • MS (rI%) 222 (74, M + ), 193 (100), 164 (28), 150 (21), 136 (61), 117 (22), 106 (24), 90 (37), 76 (38), 63 (32), 50 (25)
  • Purification can also be carried out by chromatography on silica gel with hexane / ethyl acetate.
  • the nitro compound is dissolved in methanol, ethanol or ethanol / dichloromethane mixtures (0.01 M to 0.5 M solution), treated with palladium on carbon (10%) and stirred overnight under normal pressure hydrogen. Then it is filtered and concentrated.
  • the crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile / water mixtures).
  • iron powder may be used as the reducing agent.
  • the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and at 90 ° C six equivalents of iron powder and water (0.3 to 0.5 times the volume of acetic acid) are added portionwise over 10-15 min. After a further 30 min at 9O 0 C is filtered and the filtrate is concentrated. The residue is worked up by extraction with ethyl acetate and 2N sodium hydroxide solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile / water mixtures).
  • the amide is dissolved in DMF and treated with 1.5 equivalents of potassium tert-butoxide. The mixture is stirred at RT for 1 h, then 1.2 equivalents of the l-fluoro-4-nitrobenzene are added in portions. The reaction mixture is stirred overnight at RT, diluted with ether or ethyl acetate and washed with sat. aq. Washed sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures).
  • the nitro compound is dissolved in ethanol (0.01 M to 0.5 M solution), treated with palladium on carbon (10%) and stirred overnight under normal pressure hydrogen. Then it is filtered and concentrated.
  • the crude product can be purified by chromatography on silica gel (dichloromethane / ethanol mixtures) or preparative reversed-phase HPLC (acetonitrile / water mixtures).
  • iron powder can also be used as a reducing agent.
  • the nitro compound is dissolved in acetic acid (0.1 M to 0.5 M solution) and at 90 0 C, six equivalents of iron powder and water (0.3 to 0.5 times the volume of acetic acid) are added portionwise over 10-15 min.
  • Example 12 is obtained by reacting Example 12 with trifluoroacetic acid in methylene chloride.
  • ICso value 140 nM; 1 H NMR [de-DMSO]: 3.01-3.25 (m, 8H), 3.5-3.65 (m, 2H), 3.7-3.9 (m, IH), 4.05-4.2 (m, IH), 4.75-4.9 ( m, IH), 7.05-7.25 (m, 3H), 7.5 (dd, IH), 7.7 (d, IH), 8.4 (broads, IH), 9.0 (t, IH).
  • Example 17 1 H-NMR (d ö -DMSO, 300 MHz): 2.05 (m, 2H), 2.45 (m, 2H), 3.6 (t, 2H), 3.77-3.85 (m, 3H), 4.15 (t, lH) , 4.75 ⁇ .85 (m, 1H), 7.2 (d, 1H), 7.5 (d, 2H), 7.65 (d, 2H), 7.69 (d, 1H), 8.96 (t, 1H).
  • the individual stages of the above-described synthesis of Example 17 with the respective precursors are as follows:
  • the final step which is 5-chloro-N - ( ⁇ (5S) -2-oxo-3- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1,3-oxazolidin-5-yl ⁇ methyl) - 2-thiophenecarboxamide is prepared by adding 0.32 g (1.16 mmol) of the (5S) -5- (aminomethyl) -3- [4- (2-oxo-1-pyrrolidinyl) phenyl] -1,3-oxazolidine shown above -2-ons, 5 -
  • EDCI Dimethylaminopropyl) -N-ethylcarbodiimide
  • DIEA diisopropylethylamine
  • IC 50 90 nM
  • Example 45 (1.0 eq.) And absolute pyridine (about 6 eq) in absolute dichloromethane.
  • the reaction suspension is stirred at 60 ° C for 12 h (the precipitate goes into solution, after some time re-formation of a precipitate), with a second portion of N, N'-carbonyldiimidazole (2.94 g, 18.1 mmol) and added for a further 12 h 60 0 C stirred.
  • Examples 20 to 30 and 58 to 139 relate to the process variant [B], wherein Examples 20 and 21 describe the preparation of precursors.
  • the product can be isolated by chromatography on silica gel (cyclohexane-ethyl acetate mixtures, dichloromethane-methanol mixtures or dichloromethane-methanol-triethylamine mixtures).
  • Examples 14 to 16 are exemplary embodiments of the optional, ie optionally occurring oxidation process step.
  • the batch After stirring for another night, the batch is added to 50 ml of water and extracted three times with ethyl acetate. After drying and evaporation, 23 mg of the organic phase and, after aspiration of the insoluble solid, 19 mg (in total 39% of theory) of the target compound of the aqueous phase are obtained.
  • IC 50 210 nM
  • Examples 31 to 35 and 140 to 147 refer to the optional, i. optionally taking place amidination process step.
  • the crude product is dissolved in acetone (0.01-0.1 mol / l) and treated with methyl iodide (40 eq.). The reaction mixture is stirred for 2 to 5 h at room temperature (RT) and then concentrated in vacuo.

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