EP1309549A1 - Acetamidderivate und ihre verwendung als inhibitoren des koagulationsfaktors xa und viia - Google Patents

Acetamidderivate und ihre verwendung als inhibitoren des koagulationsfaktors xa und viia

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Publication number
EP1309549A1
EP1309549A1 EP01960449A EP01960449A EP1309549A1 EP 1309549 A1 EP1309549 A1 EP 1309549A1 EP 01960449 A EP01960449 A EP 01960449A EP 01960449 A EP01960449 A EP 01960449A EP 1309549 A1 EP1309549 A1 EP 1309549A1
Authority
EP
European Patent Office
Prior art keywords
benzyl
acetamide
biphenyl
amidino
sulfamoyl
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Withdrawn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
EP01960449A
Other languages
German (de)
English (en)
French (fr)
Inventor
Werner Mederski
Horst Juraszyk
Dieter Dorsch
Christos Tsaklakidis
Johannes Gleitz
Christopher Barnes
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.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1309549A1 publication Critical patent/EP1309549A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/08—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton

Definitions

  • the invention relates to compounds of the formula
  • R 1 unbranched, branched or cyclic alkyl with 1-20 C-
  • R ⁇ simply phenyl substituted by S (0) p A, S (0) p NHA, CF 3 , COOA, CH 2 NHA, CN or OA,
  • a H unbranched, branched or cyclic alkyl with 1-20 C-
  • the invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. Alcohololates, these compounds.
  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability.
  • they show factor Xa inhibitory properties and can therefore be used to combat and prevent thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
  • the compounds of the formula I according to the invention can furthermore be inhibitors of the coagulation factors factor VIIa, factor IXa and thrombin of the blood coagulation cascade.
  • Aromatic amidine derivatives with antithrombotic activity are e.g. from EP 0 540 051 B1, WO 98/28269, WO 00/71508, WO 00/71511, WO 00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO 00/71515 or WO 00 / 71516 known.
  • Cyclic guanidines for the treatment of thromboembolic diseases are e.g. described in WO 97/08165.
  • Aromatic heterocycles with factor Xa inhibitory activity are e.g. known from WO 96/10022. Substituted N - [(aminoiminomethyl) phenylalkyl] azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.
  • the antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibitory effect against the activated coagulation protease, known under the name factor Xa, or to the inhibition of other activated serine proteases such as factor VIII, factor IXa or thrombin.
  • Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin cleaves fibrinogen into fibrin monomers which, after cross-linking, make an elementary contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders. However, inhibition of thrombin can inhibit fibrin formation involved in thrombus formation. The inhibition of thrombin can be measured, for example, by the method of GF Cousins et al. in Circulation 1996, 94, 1705-1712. Inhibition of factor Xa can thus prevent thrombin from being formed.
  • the compounds of formula I according to the invention and their salts interfere with the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.
  • the inhibition of factor Xa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods.
  • a suitable method is e.g. by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.
  • the measurement of the inhibition of factor Xa can e.g. using the method of T. Hara et al. in thromb. Haemostas. 1994, 71, 314-319.
  • the coagulation factor VIa initiates the extrinsic part of the coagulation cascade after binding to the tissue factor and contributes to the activation of factor X to factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and thus the subsequent formation of thrombin.
  • the inhibition of the factor VIIa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods.
  • a common method for measuring the inhibition of factor VIIa is e.g. by H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81.
  • Coagulation factor IXa is generated in the intrinsic coagulation cascade and is also involved in the activation of factor X to factor Xa. Inhibition of factor IXa can therefore otherwise prevent factor Xa from being formed.
  • the inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.
  • the compounds according to the invention can furthermore be used for the treatment of tumors, tumor diseases and / or tumor metastases. A relationship between the tissue factor TF / factor Vlla and the
  • the compounds of formula I can be used as active pharmaceutical ingredients in the
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudication intermittent, venous thrombosis, pulmonary embolism, arterial thrombosis , unstable angina and thrombosis-based stroke.
  • the compounds according to the invention are also used for the treatment or prophylaxis of atherosclerotic diseases such as coronary arterial disease, cerebral arterial disease or peripheral arterial pressure
  • the compounds are also used in combination with other thrombolytics for myocardial infarction, furthermore for prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary bypass surgery.
  • thrombolytics for myocardial infarction
  • prophylaxis for reocclusion after thrombolysis
  • percutaneous transluminal angioplasty PTCA
  • coronary bypass surgery percutaneous transluminal angioplasty
  • the compounds according to the invention are also used for the prevention of rethrombosis in microsurgery, also as anticoagulants in connection with artificial organs or in hemodialysis.
  • the compounds are also used in the purification of catheters and medical aids in patients in vivo, or as anticoagulants for the preservation of blood, plasma and other blood products in vitro.
  • the compounds according to the invention are also used in diseases in which blood coagulation makes a decisive contribution to the course of the disease or is a source of secondary pathology, such as, for example, cancer including metastasis, inflammatory diseases including arthritis, and diabetes.
  • the compounds according to the invention are also used in combination with other thrombolytically active compounds, such as, for example, the “tissue plasminogen activator” t-PA, modified t-PA, streptokinase or urokinase.
  • thrombolytically active compounds such as, for example, the “tissue plasminogen activator” t-PA, modified t-PA, streptokinase or urokinase.
  • the compounds according to the invention are administered with the other substances mentioned either simultaneously or before or after. Simultaneous administration with aspirin is particularly preferred in order to prevent recurrence of thrombus formation.
  • the compounds according to the invention are also used in combination with platelet glycoprotein receptor (IIb / IIla) antagonists which inhibit platelet aggregation.
  • IIb / IIla platelet glycoprotein receptor
  • the invention relates to the compounds of formula I and their
  • Trt trityl (triphenylmethyl).
  • radicals or parameters R, R 1 , R 2 , R 3 , Ar, Ar ', A, A ⁇ Het, X, Y, n, m and p have the meanings given in formula I, if not expressly stated otherwise.
  • A denotes H or alkyl, where alkyl is unbranched (linear), branched or cyclic and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1 -, 2-, 3- or 4-methylpentyl, 1, 1 -, 1, 2-, 1, 3-, 2,2-, 2 , 3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, more preferred eg Trifluoromethyl
  • A also means e.g. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexylmethyl.
  • a ' is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2 , 2-dimethylpropyl, 1-ethyl propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl,
  • Cyclic alkyl or cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Ar means unsubstituted or single, double or triple by A, OA, NAA ', N0 2 , CF 3) CN, shark, NHCOA, COOA, CONAA', S (0) p A, S (0) p NAA ' substituted phenyl or naphthyl.
  • Preferred substituents for phenyl or naphthyl are e.g. Methyl, ethyl, propyl, butyl, OH, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, diethylamino, nitro, trifluoromethyl, fluorine, chlorine, acetamido, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, suifonamido, Methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, tert.-butylsulfonamido, tert.-butylaminosulfonyl, dimethylsulfonamido, phenylsulfonamido, carboxy, dimethylaminocarbonyl, phenyla
  • Ar particularly preferably means, for example, unsubstituted phenyl or simply substituted by SO2NH 2 , SO 2 CH 3 , fluorine or alkoxy, such as methoxy, phenyl.
  • Ar 'means - (CH 2 ) n -Ar preferably unsubstituted or mono-, di- or trisubstituted by fluorine and / or chlorine-substituted benzyl.
  • Y preferably means e.g. Methoxycarbonyl, ethoxycarbonyl or 1-methyl-tetrazol-5-yl.
  • n is preferably e.g. 1 or 2.
  • Het preferably means e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, -3- or 5 -yl, 1- or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or - 5-yi, 1, 3,4-thiadiazole- 2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrroiyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2 - or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,
  • Het particularly preferably means e.g. Furyl, thienyl, thiazolyl, imidazolyl, [2,1,3] benzothiadiazolyl, oxazolyl, pyridyl, indolyl, 1-methyl-piperidinyl, piperidinyl or pyrrolidinyl, pyridyl, 1-methyl-piperidin-4- is very particularly preferred yl or piperidin-4-yl.
  • R preferably means e.g. Amidino, N-methoxycarbonyl-amidino, N-
  • R is preferably in the meta position of the phenyl ring.
  • R 1 preferably denotes, for example, benzyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, pentyl, pent-3-yl, cyclohexylmethyl, 4-fluorobenzyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, (1-methyl - tetrazol-5-yl) ethyl, methoxyethyl, methoxymethyl or methoxybutyl.
  • R 2 preferably means, for example, simply substituted phenyl by SO 2 NH 2 or SO 2 Me.
  • the compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms.
  • Formula I encompasses all of these forms. Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • R 1 denotes unbranched, branched or cyclic alkyl with 1-8 C atoms, in which a CH 2 group can be replaced by O, denote Ar, Ar 'or X;
  • R 1 unbranched, branched or cyclic alkyl with 1-8
  • CH 2 is NHA, CN or OA substituted phenyl
  • R 1 unbranched, branched or cyclic alkyl with 1-8
  • R 1 unbranched, branched or cyclic alkyl with 1 -8
  • Ar is phenyl which is unsubstituted or simply substituted by A, OA, CF 3 , shark or SO 2 NH2;
  • R 1 unbranched, branched or cyclic alkyl with 1-8
  • Ar is phenyl which is unsubstituted or substituted simply by A, OA, CF 3 , shark or SO 2 NH 2 , Ar 'is benzyl which is unsubstituted or mono-, di- or trisubstituted by fluorine;
  • R 1 unbranched, branched or cyclic alkyl with 1-8
  • R 2 is simply phenyl substituted by SA, SOA, S0 2 A, S0 2 NHA, CF 3 , COOA, CH 2 NHA, CN or OA,
  • R 1 unbranched, branched or cyclic alkyl with 1-8
  • R 2 simply by SA, SOA, S0 2 A, S0 2 NHA, CF 3) COOA,
  • Fluorine-substituted benzyl Het is a mononuclear saturated or aromatic heterocycle having 1 to 2 N and / or O atoms,
  • COOA, COSA, COSAr, COOAr, COOAr ', COA, COAr, COAr 'or can be substituted by a conventional amino protecting group
  • R 1 unbranched, branched or cyclic alkyl with 1-8
  • R 2 simply by SA, SOA, S0 2 A, S0 2 NHA, CF 3 , COOA,
  • Fluorine-substituted benzyl Het is a mononuclear saturated or aromatic heterocycle having 1 to 2 N and / or O atoms,
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • Compounds of formula I can preferably be obtained by liberating compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H- Atoms which are connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R 'represents an amino protective group and / or those which replace the H- Atoms of a hydroxy group carry a hydroxy protecting group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" denotes a hydroxyl protective group.
  • Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
  • the release of the amidino group from its oxadiazole derivative can e.g. by treatment with hydrogen in the presence of a catalyst (e.g. water-moist Raney nickel).
  • a catalyst e.g. water-moist Raney nickel
  • Suitable solvents are those specified below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other locations in the molecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protecting groups according to the desired
  • acyi group is to be understood in the broadest sense in connection with the present method. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr.
  • Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
  • Amides such as DMF, halogenated hydrocarbons such as dichloromethane, ner also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
  • the groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15 -30 °.
  • Hydrogenolytically removable protective groups can, for. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal).
  • a catalyst z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal.
  • Suitable solvents are the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar.
  • Hydrogenolysis of the CBZ group succeeds e.g. B. well on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 2-dichloroethane, carbon tetrachloride, trifluoromethylbenzene, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide,
  • NMP dimethylformamide
  • DMF dimethylformamide
  • Nitriles such as acetonitrile
  • Sulfoxides such as Dimethyl sulfoxide (DMSO); Carbon disulphide
  • Carboxylic acids such as formic acid or acetic acid
  • Nitro compounds such as nitromethane or nitrobenzene
  • Esters such as ethyl acetate or mixtures of the solvents mentioned.
  • An S0 2 NH 2 group for example in R 2 , is preferably used in the form of its tert-butyl derivative.
  • the tert-butyl group is split off, for example, using TFA with or without the addition of an inert solvent, preferably with the addition of a small amount of anisole (1-10% by volume).
  • the addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H 2 S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH 3 I, which in turn contains NH 3 reacts to the amidine, b) the nitrile is converted into the corresponding imidoester with an alcohol, for example ethanol in the presence of HCl and treated with ammonia, or c) the nitrile is reacted with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.
  • an alkylating agent for example CH 3 I
  • R 1 has the meaning given in claim 1 with compounds of the formula III
  • L is Cl, Br, I or a free or reactive, functionally modified OH group
  • R 2 is, for example, Br. 0
  • L is preferably Cl, Br, I or a free or reactive modified OH group such as e.g. an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • a free or reactive modified OH group such as e.g. an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • reaction of the carboxylic acid derivatives of the formula III with the Aminkom- components of the formula II is carried out in a known manner, preferably in a protic or aprotic polar or apolar inert organic solvent Q see.
  • Suitable bases are preferably e.g. Alkali metal or alkaline earth metal hydroxides, carbonates, alcoholates or organic bases such as triethylamine or pyridine, which are also used in excess and can then simultaneously serve as solvents.
  • Alcohols such as methanol, ethanol, isopropanol, n-butanol or tert-butanol are particularly suitable as inert solvents; Ethers such as diethyl ether, diisopropyl ether, THF or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Nitriles such as acetonitrile; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate; Amides such as phosphoric acid hexamethyl triamide; Sulfoxides such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons such as dichloromethane, chloroform, trichlorethylene, 1, 2-dichloroethane or carbon tetrachloride; Hydrocarbon
  • Particularly suitable solvents are methanol, THF, dimethoxyethane, dioxane, water or mixtures which can be prepared therefrom.
  • temperatures between 20 ° and the boiling point of the solvent are suitable as the reaction temperature.
  • the reaction times are between 5 minutes and 30 hours.
  • an acid scavenger in the reaction.
  • Any type of base that does not interfere with the reaction itself is suitable for this.
  • the use of inorganic bases such as potassium carbonate or of organic bases such as triethylamine or pyridine is particularly suitable.
  • Esters can be saponified, for example, with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • the products obtained in the reaction of the compounds of the formula II with the compounds of the formula III are then reacted further, for example by reaction in a Suzuki reaction with the corresponding boronic acid derivatives to give the biphenyl precursors.
  • the Suzuki reaction is expediently carried out in a palladium mixture, preferably by adding Pd (PPh 3 ) 4 or PD (II) CI 2 dppf, in the presence of a base such as potassium carbonate in an inert solvent or solvent mixture, for example DMF, at temperatures between 0 ° and 150 °, preferably between 60 ° and 120 °.
  • a base such as potassium carbonate
  • the reaction time is between a few minutes and several days depending on the conditions used.
  • the boronic acid derivatives can be prepared by conventional methods or are commercially available.
  • the reactions can be carried out analogously to those described in Suzuki et al., J. Am. Chem. Soc. 1989, 111, 314ff. and in Suzuki et al. Chem. Rev. 1995, 95, 2457ff. specified methods are carried out.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • So inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polycarbonate, sulfonic or Sulfuric acids, e.g.
  • compounds of formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
  • bases e.g. sodium or potassium hydroxide or carbonate
  • organic bases e.g. Ethanolamine can be used.
  • the pharmaceutical activity of the racemates or the stereoisomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers.
  • the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or can already be used as such in the synthesis.
  • diastereomers are formed from the mixture by reaction with an optically active release agent.
  • Suitable release agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • Chromatographic separation of enantiomers with the aid of an optically active separating agent is also advantageous.
  • Suitable solvents are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example in a ratio of 82: 15: 3.
  • the invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route.
  • the invention thus also relates to pharmaceutical preparations containing at least one medicament according to one of claims 5 to 6 and, if appropriate, carriers and / or auxiliaries and, if appropriate, other active compounds. i These preparations can be used as medicinal products in human or veterinary medicine.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol acetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder.
  • the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, eg one or more vitamins.
  • the invention also relates to the use of compounds according to claims 1 and 2 and / or their physiologically acceptable salts for the production of a medicament for combating thromboembolic disorders such as thrombosis, myocardial infarction, arte- riosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication
  • thromboembolic disorders such as thrombosis, myocardial infarction, arte- riosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication
  • the substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and on the combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • Nitrophenyl carbonate compounds are derivatized, which are then further reacted with the amidino compounds.
  • V- (3-A / - ( ⁇ /, ⁇ / -diethylaminoethoxycarbonyl) -aminobenzyl) - / V-ethyl-2- (2'-sulfamoyl-biphenyI-4-yl) -acetamide, ⁇ / - ( 3- ⁇ / - ( ⁇ /, -diethylaminoethoxycarbonyl) -amido-benzyl) - / V-isopropyl-2-
  • the conversion of the cyano group into the 1 H-tetrazol-5-yl group is carried out by customary methods by reaction with sodium azide or trimethylsilyl azide. This gives ⁇ / - (3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl) -2- (2'-sulfamoyl-biphenyl-4-yl) - ⁇ / - (2 - (1 H-tetrazol-5-yl) ethyl) acetamide.
  • Example A Injection glasses
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

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  • Life Sciences & Earth Sciences (AREA)
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  • Diabetes (AREA)
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  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP01960449A 2000-07-29 2001-07-03 Acetamidderivate und ihre verwendung als inhibitoren des koagulationsfaktors xa und viia Withdrawn EP1309549A1 (de)

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DE10037146A DE10037146A1 (de) 2000-07-29 2000-07-29 Acetamidderivate
DE10037146 2000-07-29
PCT/EP2001/007594 WO2002010127A1 (de) 2000-07-29 2001-07-03 Acetamidderivate und ihre verwendung als inhibitoren des koagulationsfaktors xa und viia

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DE19819548A1 (de) * 1998-04-30 1999-11-04 Merck Patent Gmbh Biphenylderivate
WO2000071508A2 (en) * 1999-05-24 2000-11-30 Cor Therapeutics, Inc. INHIBITORS OF FACTOR Xa
CA2382751A1 (en) * 1999-05-24 2000-11-30 Cor Therapeutics, Inc. Inhibitors of factor xa
AU2001243598A1 (en) * 2000-03-13 2001-09-24 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade

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US20030187037A1 (en) 2003-10-02
CZ2003465A3 (cs) 2003-05-14
HUP0301502A2 (hu) 2003-08-28
NO20030431L (no) 2003-01-28
DE10037146A1 (de) 2002-02-07
SK1972003A3 (en) 2003-06-03
PL358756A1 (en) 2004-08-23
WO2002010127A1 (de) 2002-02-07
AU2001281941A1 (en) 2002-02-13
ZA200301633B (en) 2004-06-22
BR0112813A (pt) 2003-07-01
KR20030029531A (ko) 2003-04-14
MXPA03000780A (es) 2003-06-04

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