EP1517685A1 - Derives de 2-(phenyl)-2h-pyrazol-3-acide carboxylique-n-4-(thioxo-heterocyclyl)-phenyl-amide, derives d imino-heterocyclyle c orrespondants et composes derives servant d inhibiteurs des facteurs de coagulation xa et/ou viia dans le traitement de thromboses - Google Patents

Derives de 2-(phenyl)-2h-pyrazol-3-acide carboxylique-n-4-(thioxo-heterocyclyl)-phenyl-amide, derives d imino-heterocyclyle c orrespondants et composes derives servant d inhibiteurs des facteurs de coagulation xa et/ou viia dans le traitement de thromboses

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Publication number
EP1517685A1
EP1517685A1 EP03732540A EP03732540A EP1517685A1 EP 1517685 A1 EP1517685 A1 EP 1517685A1 EP 03732540 A EP03732540 A EP 03732540A EP 03732540 A EP03732540 A EP 03732540A EP 1517685 A1 EP1517685 A1 EP 1517685A1
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EP
European Patent Office
Prior art keywords
imino
diyl
phenyl
formula
compounds
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
EP03732540A
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German (de)
English (en)
Inventor
Bertram Cezanne
Dieter Dorsch
Werner Mederski
Christos Tsaklakidis
Johannes Gleitz
Christopher Barnes
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Merck Patent GmbH
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Merck Patent GmbH
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Priority to EP06000157A priority Critical patent/EP1679073A1/fr
Publication of EP1517685A1 publication Critical patent/EP1517685A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non 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
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • 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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to compounds of the formula I.
  • D is absent or is a saturated, fully or partially unsaturated 3 to 4-membered alkylene chain in which 1 to 3 carbon atoms are represented by N and / or 1
  • 15 to 2 carbon atoms can be replaced by 1 to 2 O and / or 1 to 2 S atoms, but at most up to 3 C atoms are replaced and in addition one, two or three times substitution of the alkylene chain and / or one located therein
  • M is a phenyl ring or an aromatic heterocycle which can contain 1-2 N, O and / or S atoms,
  • W is a mono- or dinuclear saturated, unsaturated or aromatic carbocycle or heterocycle having 1 to 4 N, O and / or S atoms, which can be mono- or disubstituted by R 2 ,
  • N0 2 , CN, COOR 2 , CON (R 2 ) 2 , NR 2 COA, NR 2 CON (R 2 ) 2 , NR 2 S0 2 A, COR 2 , S0 2 NR 2 and / or S (0) m A can be substituted
  • Ar 1 unsubstituted or mono- or disubstituted by shark
  • 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 can be used.
  • Inhibitors of the coagulation factors factor VIIa, factor IXa and thrombin of the blood coagulation cascade are 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.
  • N - [(aminoiminomethyl) phenylalkylj-azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.
  • Pyrazole derivatives are known from WO 01/29006 or from WO 02/24690.
  • 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 VIIa, factor IXa or thrombin.
  • Factor Xa is one of the proteases involved in the complex process of
  • Factor Xa catalyzes the conversion of
  • thrombin in thrombin. Thrombin cleaves fibrinogen into fibrin monomers which, after cross-linking, make an elementary contribution to thrombus formation.
  • thromboembolic Activation of thrombin can lead to the occurrence of thromboembolic
  • Inhibit fibrin formation involved in thrombus formation The measurement of the inhibition of thrombin can e.g. using the method of G.F. 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.
  • 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 Vlla initiates the extrinsic part of the coagulation cascade after binding to the tissue factor and contributes to the activation of the
  • Factor X to factor Xa.
  • An inhibition of factor VIII prevents thus the emergence of factor Xa and thus a subsequent one
  • 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 carried out according to customary in vitro or in vivo
  • the compounds according to the invention can furthermore be used for the treatment of tumors, tumor diseases and / or tumor metastases.
  • the compounds of formula I can be used as active pharmaceutical ingredients in the
  • 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 prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary bypass surgery.
  • PTCA percutaneous transluminal angioplasty
  • the compounds according to the invention are also used for the prevention of rethrombosis in microsurgery, furthermore as
  • Anticoagulants related to artificial organs or in hemodialysis are known.
  • the compounds are also used in the cleaning of catheters and medical devices 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 10 compounds according to the invention are also used in combination with other thrombolytically ineffective compounds, such as, for example, the “tissue plasminogen activator” t-PA, modified t-PA, streptokinase or urokinase.
  • t-PA tissue plasminogen activator
  • modified t-PA modified t-PA
  • streptokinase or urokinase.
  • the compounds of the invention are with the -. 5 given other substances 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
  • the invention relates to the compounds of formula I and their salts and a process for the preparation of compounds of formula I according to claims 1-20 and their pharmaceutically usable derivatives, solvates and stereoisomers, characterized in that
  • L means Cl, Br, I or a free or reactive functional OH group and R 1 , R 1 ' , D, M and W have the meanings given in Claim 1, with the proviso that if another OH and / or amino group is present, this is protected,
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean the addition of inert solvent molecules to the compounds, which are formed on account of their mutual attraction. Solvates are, for example, mono- or dihydrates or alcoholates.
  • compositions are e.g. the salts of the compounds according to the invention and also so-called prodrug compounds.
  • Prodrug derivatives are understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.
  • the invention also relates to mixtures of the compounds of the formula I according to the invention, e.g. Mixtures of two diastereomers e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.
  • Trt trityl (triphenylmethyl).
  • the ring M is preferably phenyl.
  • Single substitution with A or NH 2 is very particularly preferred.
  • D preferably denotes a saturated 3- to 4-membered alkylene chain in which 1 to 3 C atoms can be replaced by N and / or 1 to 2 C atoms by 1 to 2 O atoms, but at most up to 3 carbon atoms are replaced and a one or two substitution of the alkylene chain and / or of a nitrogen therein by NH 2 can additionally occur, or D is missing.
  • A means alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • A is preferably methyl, furthermore
  • Atoms preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or
  • Alkoxy preferably means e.g. Methoxy, ethoxy, propoxy, isopropoxy, butoxy, trifluoromethoxy or cyclopentoxy.
  • Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Alkylene preferably means methylene, ethylene, propylene, butylene, pentylene or hexylene, furthermore branched alkylene.
  • COR 2 means, for example, CHO or -COA.
  • -COA acyl
  • acyl preferably means acetyl, propionyl, but also butyryl
  • Pentanoyl hexanoyl or e.g. Benzoyl.
  • A is preferably alkyl having 1, 2, 3 or 4 carbon atoms.
  • R 1 is preferably H.
  • R 2 is preferably, for example, H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • R 2 is preferably, for example, H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • R 2 preferably means, for example, H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • W denotes a mononuclear or dinuclear saturated, unsaturated or aromatic carbo- or heterocycle having 1 to 4 N, O and / or S atoms, which can be mono- or disubstituted by R 2 .
  • W denotes a mononuclear, saturated, unsaturated or aromatic carbocycle or heterocycle having 1 to 2 N, O and / or S atoms, which can be mono- or disubstituted by R 2 .
  • W is, for example, unsubstituted or mono- or disubstituted by R 2 cyclohexane-diyl, cyclopentane-diyl, phenylene, biphenylene, furan-diyl,
  • W is, for example, unsubstituted or mono- or disubstituted by A or shark cyclohexane diyl, cyclopentane diyl, phenylene, biphenylene, furan diyl, thiophene diyl, pyrrole diyl, imidazole diyl, pyrazole diyl , Oxazole diyl, isoxazole diyl, thiazole diyl, isothiazole diyl, pyridine diyl, pyrimidine diyl, pyrrolidine diyl, piperidine diyl or piperazine diyl.
  • W particularly preferably denotes unsubstituted or simply substituted by A, CONH 2 or COOA or pyrazole-diyl or thiazole-diyl, where A in particular denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF 3 .
  • X preferably denotes CONH, CONHCH 2 , CH 2 NH or CH 2 NHCH 2 , very particularly preferably CONH.
  • Y is preferably alkylene or ar-diyl, particularly preferably methylene, ethylene, propylene or unsubstituted or simply substituted by A, Cl or F, 1,4-phenylene, furthermore also pyridine-diyl, preferably pyridine-2,5-diyl.
  • Y means in particular unsubstituted or simply substituted by methyl, ethyl, propyl, Br, Cl or F
  • 1,3- or 1,4-phenylene, 1,4-phenylene is very particularly preferred.
  • Ar is preferably unsubstituted or mono-, di- or triple by shark, A, OH, NH 2 , N0 2 , CN, COOH, CONH 2 , NHCOA, NHCONH 2 , NHS0 2 A, COH, S0 2 NH 2 , S ( 0) m A, - (CH 2 ) n -COOR 2 ' or -0- (CH 2 ) 0 -COOR 2' substituted phenyl, naphthyl or biphenyl.
  • Ar means e.g. unsubstituted phenyl, naphthyl or biphenyl, further preferably e.g. by A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, sulfonamido , Methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl mono-, di
  • Het 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- Pyrazoiyl, 2-, 4- or 5- Oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-
  • the heterocyclic radicals can also be partially or completely hydrogenated.
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl,
  • Het 1 has the preferred meanings like Het.
  • T furthermore particularly preferably denotes 2-imino-piperidin-1-yl, 2-imino-pyrrolidin-1-yl, 2-imino-1 H-pyridin-1-yl, 3-imino-morpholin-4-yl, 4 - Imino-1 H-pyridin-1-yl, 2,6-diimino-piperidin1-yl, 2-imino-piperazin-1-yl, 2,6-diimino-piperazin-1-yl, 2,5-diimino pyrrolidin-1-yl, 2-imino-1, 3-oxazolidin-3-yl, 3-imino-2H-pyridazin-2-yl, 2-imino-azepan-1-yl, 2-hydroxy-6-imino piperazin-1-yi, pyrazol-2-yl, 1, 2-dihydropyrazol-2-yi, 2-methoxy-6-imino-piperazin-1-yl, 2-imino- [
  • heterocyclic radicals can preferably further be substituted once or twice by A, CONH 2 or COOA.
  • T is, for example, 2-imino-pyrrolidin-1-yl, 2-imino-piperidin-1-yl, 2-thioxopyrrolidin-1-yl, 2-imino- [1, 3,4] thiadiazol-3-yl, 2-methoxyimino-pyrrolidin-1-yl, 2-hydroxyimino-pyrrolidin-1-yl, 2-imino-imidazolidin-1-yl or 3-imino-1, 2-dihydro- pyrazol-2-yl, where the heterocyclic radicals can preferably further be substituted once or twice by A, CONH 2 or COOA.
  • the compounds of formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms.
  • Formula I encompasses all of these forms.
  • 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.
  • Ib M represents a phenyl ring
  • Ic D is a saturated, fully or partially unsaturated 3 to 4-membered alkylene chain in which 1 to 3 carbon atoms are represented by N and / or 1 to 2 carbon atoms by 1 to 2 O and / or 1 to 2 S atoms can be replaced, but at most up to 3 C atoms are replaced and additionally one, two or three times
  • Id D denotes a saturated, fully or partially unsaturated 3 to 4-membered alkylene chain in which 1 to 3 carbon atoms are represented by N and / or 1 to 2 carbon atoms by 1 to 2 O and / or 1 to 2 S atoms can be replaced, but at most up to 3 C atoms are replaced and additionally one, two or three times
  • li W in li W is a mononuclear saturated, unsaturated or aromatic carbocycle or heterocycle having 1 to 2 N, O and / or S atoms, which can be mono- or disubstituted by R 2 ;
  • Isothiazole diyl pyridine diyl, pyrimidine diyl, pyrrolidine diyl, piperidine diyl or piperazine diyl;
  • II X is CONH, CONHCH 2 , CH 2 NH or CH 2 NHCH 2 ;
  • In Y is alkylene or ar-diyl
  • Y is phenylene which is unsubstituted or mono- or disubstituted by A, Br, Cl or F;
  • heterocyclic radicals can furthermore be mono- or disubstituted by A, CONH 2 or COOA;
  • -NH-N CH-
  • -CH N-NH-
  • R 1 H, CH 2 NH 2 , CONH 2 , C ( S) NH 2 or NH 2 ,
  • W is a mononuclear saturated, unsaturated or aromatic carbocycle or heterocycle with 1 to 2 N-, 0-? and / or S atoms, which can be mono- or disubstituted by R, R 2 H or alkyl having 1, 2, 3, 4, 5 or 6 C atoms, R 2 'H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, X CONH, CONHCH 2 , CH 2 NH or CH 2 NHCH 2 ,
  • -NH-N CH-
  • -CH N-NH-
  • R 1 H, CH 2 NH 2 , CONH 2 , C ( S) NH 2 or NH 2 , R 1 'H, W unsubstituted or mono- or disubstituted by R 2 cyclohexane diyl, cyclopentane diyl, phenylene, biphenylene, furan diyl, thiophene diyl, pyrrole diyl, imidazole diyl, pyrazole diyl, oxazole diyl, isoxazole diyl , Thiazole diyl,
  • Piperidine diyl or piperazine diyl R 2 H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, R 2 ' H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms , X CONH, CONHCH 2 , CH 2 NH or CH 2 NHCH 2 ,
  • -NH-N CH-
  • -CH N-NH-
  • heterocyclic radicals can furthermore be mono- or disubstituted by A, CONH 2 or COOA,
  • A can be unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms and / or 1-7 H atoms can be replaced by F;
  • the invention furthermore relates in particular to those
  • Radicals has one of the preferred meanings given above.
  • W is a mononuclear saturated, unsaturated or aromatic carbocycle or heterocycle having 1 to 2 N, O and / or S atoms, which can be mono- or disubstituted by R 2 ,
  • R 2 is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms
  • R 1 is unsubstituted or simply substituted by OH
  • R 2 unsubstituted or mono- or disubstituted by R 2 cyclohexane diyl, cyclopentane diyl, phenylene, biphenylene, furan diyl, thiophene diyl, pyrrole diyl, imidazole diyl, pyrazole diyl, oxazole diyl, isoxazole diyl , Thiazole diyl, isothiazole diyl, pyridine diyl, pyrimidine diyl, pyrrolidine diyl, piperidine diyl or piperazine diyl,
  • R 2 is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms
  • a unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms and / or 1-7 H atoms can be replaced by F,
  • R 1 CN, NH 2 , CH 2 NH 2 , CH 2 CH 2 NH 2 , unsubstituted or monosubstituted by OH
  • A can mean unbranched or branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms and / or 1-7 H atoms can be replaced by F;
  • the compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail. If desired, 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.
  • the starting compounds of the formulas II and III are generally known. If they are new, they can be manufactured according to methods known per se.
  • the reaction is usually carried out in an inert solvent.
  • Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, 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 or dimethylformamide (DMF); Ni
  • L is preferably Cl, Br, I or a free or a reactively modified OH group such as e.g. an activated ester, an imidazolide or alkylsulfonyloxy with 1 -6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • an activated ester an imidazolide or alkylsulfonyloxy with 1 -6 carbon atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • Activated esters are conveniently formed in situ, e.g. B. by adding HOBt or N-hydroxysuccinimide.
  • the reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine, N-methylmorpholine, or quinoline or an excess of the carboxy component of the formula II.
  • an acid-binding agent preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine, N-methylmorpholine, or quinoline or an excess of the carboxy component of the formula II.
  • alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metal or alkaline earth metal preferably potassium, sodium, calcium or cesium
  • a weak acid of the alkali metal or alkaline earth metal preferably potassium, sodium, calcium or cesium
  • reaction time is between a few minutes and 14 days, the reaction temperature between about
  • 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.
  • 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 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.
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or
  • hydroxyl protective groups are not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred.
  • hydroxy protecting groups include Benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
  • Sulfonic acids such as benzene or p-toluenesulfonic acid.
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as
  • Tetrahydrofuran or dioxane Tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol,
  • 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, in particular 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 at 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DM F at 20-30 °.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, 5
  • Glycols such as ethylene glycol monomethyl or monoethyl ether
  • Ketones such as acetone or butanone; Amides such as acetamide, -. j- dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide
  • DMF dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • 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. 0
  • 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 c .
  • a base of the formula I can be converted into the associated acid with an acid
  • 35 addition salt are converted, 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
  • Toluenesulfonic acid naphthalene mono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used to isolate and / or purify the compounds of the
  • 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 e.g. optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • Aqueous or alcoholic solvent mixtures such as e.g. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.
  • the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of a medicament (pharmaceutical preparation), in particular in a non-chemical way. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention further relates to pharmaceutical compositions containing at least one compound of the formula I and / or their pharmaceutically usable
  • 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 in particular 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 or as a nasal spray.
  • the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations.
  • the specified preparations can be sterilized and / or contain auxiliary substances 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, for example one or more vitamins.
  • auxiliary substances 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, for example one or more vitamins.
  • the compounds of the formula I and their physiologically acceptable salts can be used to combat and prevent thrombo-embolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, tumors, tumor diseases and / or tumor metastases be used.
  • thrombo-embolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, tumors, tumor diseases and / or tumor metastases be used.
  • 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 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, combination of drugs and The severity of the disease to which the therapy applies. Oral application is preferred.
  • the invention further relates to medicaments containing at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
  • the invention also relates to a set (kit) consisting of separate packs of
  • the set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules.
  • suitable containers such as boxes or cartons, individual bottles, bags or ampoules.
  • the set can e.g. separate
  • Derivatives, solvates and stereoisomers, including their mixtures in all proportions, and an effective amount of another active pharmaceutical ingredient are dissolved or in lyophilized form.
  • the invention furthermore relates to the use of compounds of the formula I and / or their pharmaceutically usable derivatives,
  • Tumors, tumor diseases and / or tumor metastases in combination with at least one other active pharmaceutical ingredient.
  • DCM is provided with conc. Sodium hydroxide solution to a pH of 12.
  • 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 l and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • Example E tablets
  • a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
  • 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 sterile. Each ampoule contains 10 mg of active ingredient.

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Abstract

La présente invention concerne de nouveaux composés de formule (I), dans laquelle D, M, W, X, Y, T, R<1> et R<1'> ont les significations énoncées dans la revendication 1, qui sont des inhibiteurs du facteur de coagulation Xa et qui peuvent être utilisés pour prévenir et/ou traiter des maladies thromboemboliques et pour traiter des tumeurs.
EP03732540A 2002-06-28 2003-06-05 Derives de 2-(phenyl)-2h-pyrazol-3-acide carboxylique-n-4-(thioxo-heterocyclyl)-phenyl-amide, derives d imino-heterocyclyle c orrespondants et composes derives servant d inhibiteurs des facteurs de coagulation xa et/ou viia dans le traitement de thromboses Withdrawn EP1517685A1 (fr)

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EP06000157A EP1679073A1 (fr) 2002-06-28 2003-06-05 Derivés de 2-(phenyl)-2h-pyrazol-3-acide carboxylique-n-4-(imino-heterocyclyl)-phenyl-amide et composes derivés servant d'inhibiteurs des facteurs de coagulation xa et/ou viia dans le traitement de thromboses

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DE10229070A DE10229070A1 (de) 2002-06-28 2002-06-28 Phenylderivate 5
DE10229070 2002-06-28
PCT/EP2003/005898 WO2004002477A1 (fr) 2002-06-28 2003-06-05 Derives de 2-(phenyl)-2h-pyrazol-3-acide carboxylique-n-4-(thioxo-heterocyclyl)-phenyl-amide, derives d'imino-heterocyclyle correspondants et composes derives servant d'inhibiteurs des facteurs de coagulation xa et/ou viia dans le traitement de thromboses

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EP03732540A Withdrawn EP1517685A1 (fr) 2002-06-28 2003-06-05 Derives de 2-(phenyl)-2h-pyrazol-3-acide carboxylique-n-4-(thioxo-heterocyclyl)-phenyl-amide, derives d imino-heterocyclyle c orrespondants et composes derives servant d inhibiteurs des facteurs de coagulation xa et/ou viia dans le traitement de thromboses

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AU2001269531A1 (en) * 2000-07-17 2002-01-30 Takeda Chemical Industries Ltd. Sulfone derivatives, process for their production and use thereof
EP1564213A4 (fr) * 2002-11-22 2009-05-27 Takeda Pharmaceutical Derives d'imidazole, leur procede de production et d'utilisation
TWI396686B (zh) * 2004-05-21 2013-05-21 Takeda Pharmaceutical 環狀醯胺衍生物、以及其製品和用法
DE102004051277A1 (de) * 2004-10-21 2006-04-27 Merck Patent Gmbh Heterocyclische Carbonylverbindungen
US7446210B2 (en) 2004-10-26 2008-11-04 Janssen Pharmaceutica N.V. Factor Xa compounds
DE102005038947A1 (de) 2005-05-18 2006-11-30 Grünenthal GmbH Substituierte Benzo[d]isoxazol-3-yl-amin-Verbindungen und deren Verwendung in Arzneimitteln
DE102005045115A1 (de) * 2005-09-21 2007-04-05 Siemens Ag Verfahren und Vorrichtung zum Betrieb eines Kommunikationsendgeräts
US8338367B2 (en) 2008-10-15 2012-12-25 Boehringer Ingelheim International Gmbh Fused heteroaryl diamide compounds useful as MMP-13 inhibitors
CA2738929A1 (fr) 2008-10-17 2010-04-22 Boehringer Ingelheim International Gmbh Composes indole a substitution heteroaryle utilises comme inhibiteurs de mmp-13
CN110269856A (zh) 2010-03-30 2019-09-24 维颂公司 多取代芳族化合物作为凝血酶的抑制剂
CA3051327A1 (fr) 2013-03-15 2014-09-18 Verseon Corporation Composes aromatiques multisubstitues en tant qu'inhibiteurs de serine protease
US9951025B2 (en) 2013-03-15 2018-04-24 Verseon Corporation Halogenopyrazoles as inhibitors of thrombin
CN107935988A (zh) 2013-10-14 2018-04-20 卫材R&D管理有限公司 选择性取代的喹啉化合物
PT3057964T (pt) 2013-10-14 2020-02-25 Eisai R&D Man Co Ltd Compostos de quinolina seletivamente substituídos
KR102510427B1 (ko) 2014-03-07 2023-03-14 바이오크리스트파마슈티컬즈,인코포레이티드 인간 혈장 칼리크레인 저해제
KR20170048410A (ko) 2014-09-17 2017-05-08 베르선 코포레이션 세린 프로테아제 저해제로서의 피라졸릴-치환된 피리돈 화합물
JP2018506563A (ja) * 2015-02-27 2018-03-08 ヴァーセオン コーポレイション セリンプロテアーゼ阻害剤としての置換ピラゾール化合物

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ZA985247B (en) * 1997-06-19 1999-12-17 Du Pont Merck Pharma Guanidine mimics as factor Xa inhibitors.
WO1998057937A2 (fr) * 1997-06-19 1998-12-23 The Du Pont Merck Pharmaceutical Company INHIBITEURS DU FACTEUR Xa COMPRENANT UN GROUPE A SPECIFICITE P1 NEUTRE

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JP2005535630A (ja) 2005-11-24
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AR040472A1 (es) 2005-04-06

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