EP1309573A1 - Derives d'urethane - Google Patents

Derives d'urethane

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Publication number
EP1309573A1
EP1309573A1 EP01951676A EP01951676A EP1309573A1 EP 1309573 A1 EP1309573 A1 EP 1309573A1 EP 01951676 A EP01951676 A EP 01951676A EP 01951676 A EP01951676 A EP 01951676A EP 1309573 A1 EP1309573 A1 EP 1309573A1
Authority
EP
European Patent Office
Prior art keywords
benzyl
amidino
biphenyl
sulfamoyl
coar
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Withdrawn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
EP01951676A
Other languages
German (de)
English (en)
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
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Publication of EP1309573A1 publication Critical patent/EP1309573A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • A61K31/4245—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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—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
    • 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
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/42—Y being a hetero atom
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to compounds of the formula
  • R ⁇ simply phenyl substituted by SA, SOA, SO 2 A, SONHA, SO 2 NHA, CF 3 , COOA, CH 2 NHA, CN or OA,
  • 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.
  • Zen. 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 claudication intermittently.
  • 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 human and veterinary medicine, in particular for the treatment and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, venous Thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia, unstable angina and thrombosis-based stroke.
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, venous Thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia, 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 disease.
  • the compounds are also used in combination with other thrombolytics for myocardial infarction, as well as 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 of the invention are also used in combination with platelet glycoprotein receptor (IIb / IHa) antagonists which inhibit platelet aggregation.
  • IIb / IHa platelet glycoprotein receptor
  • the invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that
  • Trt trityl (triphenylmethyl).
  • prodrug compounds are so-called prodrug compounds.
  • the unprotected compounds are easily released from these in the organism by hydrolysis.
  • R is particularly preferred in the meta position of the penyl 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, phenyl which is simply substituted by S0 2 NH 2 or S0 2 Me.
  • 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-M ethyl butyl, 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 ' preferably denotes 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. Cyclopentyl or cyclohexyl.
  • Ar means unsubstituted or single, double or triple by A ', OH, OA', NH 2 , NHA ', NA' 2 , N0 2 , CF 3) CN, shark, NHCOA, COOA, CONH 2 ,
  • substituents for phenyl or naphthyl are, for example, methyl, ethyl, propyl, butyl, OH, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, ethylamino, diethylamine, nitro, trifluoromethyl, fluorine, chlorine, acetamido, Methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, tert.-butylsulfonamido, ter
  • Ar 'means (CH 2 ) n -Ar, where n is preferably 1 or 2 and Ar has the preferred meanings indicated. Unsubstituted or mono-, di- or trisubstituted by fluorine and / or chlorine is very particularly preferred.
  • Y preferably means e.g. Methoxycarbonyl, ethoxycarbonyl or 1-methyl-tetrazol-5-yl.
  • n is preferably e.g. 1 or 2.
  • Het preferably means, for example, 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-l-, -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-yl, 1, 3, 4-thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-
  • 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-pyrrolyl, 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, 4
  • Het is unsubstituted or one, two or three times e.g. substituted by methyl, methoxy, amino, methylamino, dimethylamino, nitro, cyan, fluorine, chlorine, acetamido, methylsulfonylamino, methoxycarbonyl, aminocarbonyl, acetyl, aminosulfonyl, methylsulfonyl and / or carbonyl oxygen.
  • Het particularly preferably means, for example, furyl, thienyl, thiazolyl, imidazolyl, [2,1,3] benzothiadiazolyl, oxazolyl, pyridyl, indolyl, 1-methylpiperidinyl, piperidinyl or pyrrolidinyl, pyridyl, 1-methyl being very particularly preferred -piperidin-4-yl or piperidin-4-yl.
  • 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.
  • Some preferred groups of compounds can be expressed by the following sub-formulas la to li, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • 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 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 NH 2 ;
  • 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,
  • 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 mft 1-8
  • R 2 phenyl substituted simply 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
  • Het is a mononuclear saturated or aromatic heterocycle with 1 to 2 N and / or O atoms
  • COAr 'or can be substituted by a conventional amino protecting group, R 1 unbranched, branched or cyclic alkyl with 1-8
  • 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 making compounds of formula I from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the 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 atom, which is 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 have one instead of the H atom Hydroxy group carry a hydroxy protecting group, e.g. 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 be eliminated, for example, by treatment with hydrogen in the presence of a catalyst (for example * . ⁇ Water-moist Raney nickel).
  • a catalyst for example * . ⁇ 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.
  • the introduction of the oxadiazole group succeeds e.g. by reaction of the cyan compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformate, N.N'-carbonyldiimidazole or acetic anhydride.
  • 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 at other locations on the
  • acyl group is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, 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.
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and 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. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in metha ⁇ ol / 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, 1, 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 ether like
  • Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene
  • chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, triflu
  • 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, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); 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 nitro benzene; 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).
  • ammonia can also be added to a nitrile.
  • 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 and R 2 means Br or I,
  • the Suzuki reaction takes place, for example, by reaction in a Suzuki reaction with the corresponding boronic acid derivatives.
  • the Suzuki reaction is advantageously carried out in a palladium-mediated manner, preferably by adding Pd (PPh 3 ) 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 °.
  • 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.
  • 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, for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluen
  • 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.
  • physiologically harmless 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 for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of Carbohydrates or chiral derivatized methacrylate polymers fixed on silica gel.
  • an optically active separating agent for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of Carbohydrates or chiral derivatized methacrylate polymers fixed on silica gel.
  • Aqueous or alcoholic solvents are suitable as solvents
  • Solvent mixtures such as Hexane / isopropanol / acetonitrile e.g. in the
  • 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.
  • they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredients.
  • 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.
  • 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 triacetate, 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 auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer Contain substances, coloring, flavoring and / or several other active substances, for example one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer Contain substances, coloring, flavoring and / or several other active substances, for example 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 manufacture of a medicament for combating thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and Claudicatio intermittens
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and Claudicatio intermittens
  • 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 variety of factors, for example on the activity of the particular compound used, age, body weight, general health, sex, on the diet, on the administration time and route, and on the excretion rate, pharmaceutical ' combination and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • customary work-up means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Eluent: ethyl acetate / methanol 9: 1.
  • Oxycarbonyl) -amido- • benzyl) -3- (2'- sulfamoyl • biphenyl-4-yl) -1-butyl-urea 1- (3- / V - (/ V methyl-piperidine - 4-yloxycarbonyl) amidino-benzyl) -3- (2'- sulfamoyl biphenyl-4-yl) -1- isobutylurea, 1- (3- / V - (/ V- • methylpiperidine -4-yloxycarbonyl ) -aminino-benzyl) -3- (2'- sulfamoyl • biphenyl-4-yl) -1 pentylurea, 1- (3- / V - (/ V- methyl-piperidin--4-yloxycarbonyl) -amido-benzyl) -3- (2'-sulfamoyl-biphenyl-4-yl
  • the compound 1- (3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl) -3- (2'-sulfamoyl) is obtained by using 3-bromo-propionitrile biphenyl-4-yl) -1- (2-cyanoethyl) -hamstoff.
  • 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.
  • 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 is prepared from 1 g of an active ingredient of the formula I, 9.38 g - NaH 2 PO 4 • 2 H 2 0, 28.48 g Na 2 HPO 4 • 12 H 2 0 and 0.1 g 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne de nouveaux composés de formule (I), dans laquelle R, R1 et R2 ont la signification indiquée dans la revendication 1. Les composés selon l'invention sont des inhibiteurs du facteur de coagulation Xa et VIIa et peuvent être utilisés pour le traitement de thromboses, d'infarctus du myocarde, de l'artériosclérose, d'inflammations, de l'apoplexie, de l'angine de poitrine, de la resténose postangioplastie, de la claudication intermittente, de tumeurs, d'affections tumorales ou de métastases tumorales.
EP01951676A 2000-07-28 2001-07-13 Derives d'urethane Withdrawn EP1309573A1 (fr)

Applications Claiming Priority (3)

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DE10036852 2000-07-28
DE10036852A DE10036852A1 (de) 2000-07-28 2000-07-28 Urethanderivate
PCT/EP2001/008130 WO2002010145A1 (fr) 2000-07-28 2001-07-13 Derives d'urethane

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US (1) US20030171579A1 (fr)
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JP (1) JP2004505069A (fr)
KR (1) KR20030024716A (fr)
CN (1) CN1444571A (fr)
AU (1) AU2001272539A1 (fr)
BR (1) BR0112777A (fr)
CA (1) CA2417268A1 (fr)
CZ (1) CZ2003466A3 (fr)
DE (1) DE10036852A1 (fr)
HU (1) HUP0303691A2 (fr)
MX (1) MXPA03000781A (fr)
NO (1) NO20030408D0 (fr)
PL (1) PL358752A1 (fr)
SK (1) SK1992003A3 (fr)
WO (1) WO2002010145A1 (fr)
ZA (1) ZA200301638B (fr)

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CA2293824A1 (fr) * 1997-06-19 1998-12-23 Mimi Lifen Quan Agents aromatiques a six membres amidino utiles en tant qu'inhibiteurs du facteur xa
WO2000071508A2 (fr) * 1999-05-24 2000-11-30 Cor Therapeutics, Inc. Inhibiteurs du facteur xa
DE10040783A1 (de) * 2000-08-21 2002-03-07 Merck Patent Gmbh AZA-Aminosäurederivate (Faktor X¶a¶-Inhibitoren 15)

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MXPA03000781A (es) 2003-06-04
US20030171579A1 (en) 2003-09-11
CN1444571A (zh) 2003-09-24
DE10036852A1 (de) 2002-02-07
HUP0303691A2 (hu) 2004-03-01
KR20030024716A (ko) 2003-03-26
WO2002010145A1 (fr) 2002-02-07
AU2001272539A1 (en) 2002-02-13
JP2004505069A (ja) 2004-02-19
PL358752A1 (en) 2004-08-23
NO20030408L (no) 2003-01-27
SK1992003A3 (en) 2003-06-03
NO20030408D0 (no) 2003-01-27
ZA200301638B (en) 2004-06-22
CA2417268A1 (fr) 2003-01-24
CZ2003466A3 (cs) 2003-05-14
BR0112777A (pt) 2003-07-08

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