EP1499591A1 - Amides d'acide carboxylique servant d'inhibiteurs du facteur de coagulation xa - Google Patents

Amides d'acide carboxylique servant d'inhibiteurs du facteur de coagulation xa

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Publication number
EP1499591A1
EP1499591A1 EP03747402A EP03747402A EP1499591A1 EP 1499591 A1 EP1499591 A1 EP 1499591A1 EP 03747402 A EP03747402 A EP 03747402A EP 03747402 A EP03747402 A EP 03747402A EP 1499591 A1 EP1499591 A1 EP 1499591A1
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EP
European Patent Office
Prior art keywords
phenyl
chlorophenyl
imino
acetamide
substituted
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Withdrawn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
EP03747402A
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German (de)
English (en)
Inventor
Dieter Dorsch
Werner Mederski
Johannes Gleitz
Bertram Cezanne
Christos Tsaklakidis
Christopher Barnes
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Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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Priority claimed from DE2002118974 external-priority patent/DE10218974A1/de
Priority claimed from DE10236868A external-priority patent/DE10236868A1/de
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1499591A1 publication Critical patent/EP1499591A1/fr
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • 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
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/46—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms attached to said nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems

Definitions

  • the invention relates to compounds of the formula
  • R 2 H A, - [C (R 3 ) 2 ] n -Ar, - [C (R 3 ) 2 ] n -Het, - [C (R 3 ) 2 ] n -cycloalkyl, - [C (R 3 ) 2 ] n -N (R 3 ) 2 or - [C (R 3 ) 2 ] n -OR 3 ,
  • R 2 ' H A, - [C (R 3 ) 2 ] n -Ar ⁇ - [C (R 3 ) 2 ] n -Hef, - [C (R 3 ) 2 ] n -cycloalkyl, - [C ( R 3 ) 2 ] n -N (R 3 ) 2 or - [C (R 3 ) 2 ] n -OR 3 ,
  • R 2 " H, A, - [C (R 3 ) 2 ] n -Ar 'or - [C (R 3 ) 2 ] n -cycloalkyl, - [C (R 3 ) 2 ] ⁇ -N (R 3 ) 2 or - [C (R 3 ) 2 ] n -OR 3 ,
  • 0 1, 2 or 3 mean, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions.
  • 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 diseases 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 VI la, factor IXa and thrombin in 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 in WO
  • the antithrombotic and anticoagulant effect of the compounds according to the invention is based on the inhibitory effect on the activated coagulation protease, known under the name of factor Xa, or attributed to the inhibition of other activated serine proteases such as factor VI la, 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.
  • thrombin Activation of thrombin can lead to the occurrence of thromboembolic disorders.
  • An inhibition of thrombin can, however, in the
  • Inhibit thrombus formation involved fibrin 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.
  • the inhibition of factor Xa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be carried out according to the usual in vitro or in vivo
  • a suitable method is e.g. by J. Hauptmann et al. in Thrombosis and Haemostes / s 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 VIIa thus prevents the development of factor Xa and thus a subsequent one
  • 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 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.
  • Tumor types KM Donnelly et al. in thromb. Haemost. 1998; 79: 1041-1047;
  • 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.
  • 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, furthermore for 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, also as anticoagulants in connection with artificial organs or in hemodialysis.
  • the compounds are also used in the cleaning of
  • Catheters and medical devices for patients in vivo, or as anticoagulants for the preservation of blood, plasma and other blood products in vitro 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 of 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.
  • t-PA tissue plasminogen activator
  • modified t-PA modified t-PA
  • streptokinase or urokinase
  • 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 (llb / llla) antagonists which inhibit platelet aggregation.
  • the invention relates to the compounds of formula I and their 5 salts and a process for the preparation of compounds of formula I according to claims 1-16 and their pharmaceutically usable derivatives, solvates and stereoisomers, characterized in that
  • the invention also relates to the optically active forms
  • 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 e.g. 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.
  • biodegradable polymer derivatives of the compounds according to the invention as described, for. B. in Int. J. Pharm. 115. 61-67 (1995).
  • the invention also relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example 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.
  • radicals that occur more than once such as A
  • the meanings are independent of one another.
  • radicals or parameters D, W, X, Y, T, R 1 have the meanings given in the formula I, unless expressly stated otherwise.
  • 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 preferably for example Trifluoromethyl.
  • 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.
  • Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert
  • Ar preferably means, for example, phenyl which is unsubstituted or mono-, di- or trisubstituted by shark, A, OR 2 , SO 2 A, COOR 2 or CN.
  • Ar particularly preferably means, for example, unsubstituted or mono- or disubstituted by shark, A, OA, S0 2 A, S0 2 NH 2 , COOR 2 or CN Phenyl, such as phenyl, 2-methylsulfonylphenyl, 2-aminosulfonylphenyl,
  • Ar very particularly preferably denotes unsubstituted phenyl, 4-
  • Chlorophenyl or 2-methylsulfonylphenyl are Chlorophenyl or 2-methylsulfonylphenyl.
  • Y is preferably het-diyl or ar-diyl, particularly preferably unsubstituted or 1, 4- or simply substituted by A, Cl or F
  • Phenylene also pyridine-diyl, preferably pyridine-2,5-diyl or piperidine-diyl.
  • Y in particular means 1, 3- or 1, 4-phenylene which is unsubstituted or simply substituted by methyl, ethyl, propyl, Cl or F.
  • 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- 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-yl, 1, 3,4 Thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-thiadiazol-4- or
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl,
  • T denotes 2-imino-piperidin-1-yl, 2-imino-pyrrolidin-1 -yl, 2-hydroxy-imino-piperidin-1-yl, 2-hydroxy-imino-pyrrolidin-1-yl, 2-methoxy-imino-piperidin-1 -yl, 2-methoxy-imino-pyrrolidin-1 -yl, 2-cyanimino-imidazolidin-1 -yl or 2-cyanimino-3-methylimidazolidin-1 -yl.
  • D especially means e.g. unsubstituted or mono- or disubstituted by shark, A, hydroxy, methoxy, ethoxy, hydroxycarbonyl,
  • D very particularly preferably denotes 4-chlorophenyl or 3-chloro-2-pyridyl.
  • R 1 is preferably, for example, H, unsubstituted or mono- or disubstituted by shark and / or A substituted phenyl or thienyl, or alkyl having 1-6 C atoms, which is substituted by thiophene, imidazole, indole
  • R also denotes Het ', where Het' is preferably a 5- or 6-membered heterocycle having one or two N, O or S atoms, for example 2-thienyl or 2-
  • R 1 is preferably H, phenyl, 2-fluorophenyl, 2-chlorophenyl, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, thienyl, methoxymethyl, (1-methyl-1 H-imidazolyl-4 -yl) -methyl or methylsulfonylethyl.
  • R 2 is preferably, for example, H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • n is preferably 0 or 1.
  • m is preferably 2.
  • Y preferably means e.g. unsubstituted or simply substituted by alkyl, 1,4-phenylene. W is preferably absent.
  • 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.
  • 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 partial formulas Ia to Iq, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which in la D is phenyl which is unsubstituted or mono- or disubstituted by shark, A, OR 2 or COOR 2 , or unsubstituted or monosubstituted by pyridyl or thienyl;
  • R 2 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms
  • Ic R 1 H phenyl or thienyl which is unsubstituted or mono- or disubstituted by shark and / or A, or alkyl having 1-6 C atoms, which is substituted by thiophene, imidazole, indole, S (0) m R 2 , OR 2 , cycloalkyl or phenyl, where the imidazole ring may have a substituent A;
  • Id X represents NH or O
  • Y means Ar-diyl or Het-diyl
  • Thiadiazolyl where the thiadiazole ring can additionally be substituted by A, CONH 2 or COOA, A 'is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, where 1-7 H atoms can be replaced by F. ;
  • R 2b is H, OH or OA ", A” is methyl, ethyl, propyl, isopropyl or butyl;
  • Ar is phenyl which is unsubstituted or mono- or disubstituted by shark, A, OA, S0 2 A, COOR 2 , S0 2 NH 2 or CN;
  • R 1 H phenyl or thienyl which is unsubstituted or mono- or disubstituted by shark and / or A, or alkyl having 1-6 C atoms, which is substituted by thiophene,
  • Imidazole, indole, S (0) m R 2 , OR 2 , cycloalkyl or phenyl may be substituted, where the imidazole ring may have a substituent A,
  • Phenyl or thienyl, R 1 H unsubstituted or simply substituted by shark
  • R 2b is H, OH or OA ", A” is methyl, ethyl, propyl, isopropyl or butyl;
  • R 1 H unsubstituted or simply substituted by shark
  • Phenyl alkyl with 1-6 C atoms or Het '
  • R 2b is H, OH or OA ", A" is methyl, ethyl, propyl, isopropyl or butyl,
  • COOA can be substituted, R 2b H, OH or OA
  • 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, III, IV and V are generally known. If they are new, they can be manufactured according to methods known per se.
  • the reaction is generally carried out in an inert solvent, in the presence of an acid-binding agent, preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium.
  • an acid-binding agent preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the phenol component of the formula II or the alkylation derivative of the formula III can also be favorable.
  • the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °.
  • 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
  • the reaction is usually carried out in an inert solvent and under conditions as stated above.
  • 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 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • an activated ester an imidazolide or alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • 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 or quinoline or an excess of the carboxy component of the formula V.
  • an acid-binding agent preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the carboxy component of the formula V.
  • an acid-binding agent preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the carboxy component of the formula V.
  • Alkali or alkaline earth metals preferably of potassium, sodium,
  • the reaction time is between a few minutes and 14 days, the reaction temperature between about
  • Compounds of formula I can also 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 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 1 denotes an amino protective group, and / or those which have one instead of the H atom Hydroxy group carry a hydroxy protective 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 hydroxy 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 an amino group from chemical Protect (block) settlements that are easily removable after the desired chemical reaction has been performed elsewhere 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
  • 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. Examples of such 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 against 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 acyl groups mentioned above, and also alkyl groups. The nature and size of the hydroxyl-protecting groups is not critical, since it depends on the desired chemical
  • hydroxyl protecting groups include benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p- Toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.
  • 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 e.g. CBZ, benzyl or the release of the amidino group from their oxadiazole derivative
  • a catalyst z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal.
  • Suitable solvents are specified above, in particular z. B. alcohols such as methanol or
  • 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 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
  • Esters can e.g. are saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • 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, e.g. Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • 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 hydroxysulfonic acid, ethane-sulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, , p-toluenesulfonic acid, naphthalene mono- and disul
  • compounds of the 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 for example sodium or potassium hydroxide or carbonate
  • Physiologically harmless organic bases such as ethanol amine, can also be used.
  • Compounds of the formula I according to the invention can be chiral due to their molecular structure and can accordingly occur in various enantiomeric forms. They can therefore be in racemic or optically active form.
  • 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.
  • Chromatographic separation of enantiomers with the aid of an optically active separating agent e.g.
  • 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 used 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 are brought into a suitable dosage form.
  • the invention further relates to medicaments 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 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 resulting lyophilisates e.g. for production of
  • Injectables are used.
  • 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 substances, coloring agents,
  • Contain flavor and / or several other active ingredients e.g. 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, migraines, tumors, tumor diseases and / or tumor metastases can be used.
  • thrombo-embolic diseases such as thrombosis, myocardial infarction, Arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, migraines, tumors, tumor diseases and / or tumor metastases can 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 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,
  • the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or their 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 boxes, individual bottles, bags or ampoules.
  • suitable containers such as boxes or boxes, individual bottles, bags or ampoules.
  • the set can contain, for example, separate ampoules, each containing an effective amount of one Compound of formula I and / or their pharmaceutically usable
  • 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 further relates to the use of compounds of the formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, migraines, tumors, tumor diseases and / or tumor metastases, in combination with at least one other active pharmaceutical ingredient.
  • 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 dried and dried organic phase over sodium sulfate, evaporated and purified by chromatography
  • Mass spectrometry (MS): El (electron impact ionization) M + FAB (Fast Atom Bombardment) (M + H) +
  • reaction mixture is added to saturated sodium bicarbonate solution and the precipitate formed is filtered off: (R) - 2- [3- (4-chlorophenyl) -ureido] - ⁇ - [3-methyl-4- (2-thioxo-pyrrolidin-1-yl ) - phenyl] -2-phenyl-acetamide as a colorless solid; ESI 493.
  • DAPECI Dimethylaminopropyl) ⁇ / -ethylcarbodiimide hydrochloride
  • HOBt hydroxybenzotriazole hydrate
  • Example 3 Analogously to Example 3, the following compounds are obtained by reacting the corresponding carboxylic acids with the amine described in Example 1 c)
  • 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
  • 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 under sterile conditions. Each ampoule contains 10 mg of active ingredient.

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Abstract

L'invention concerne de nouveaux composés de la formule (I) dans laquelle D, W, X, Y, T et R1 ont la signification donnée dans la première revendication. Lesdits composés servent d'inhibiteurs du facteur de coagulation Xa et peuvent être employés pour la prophylaxie et/ou la thérapie de maladies thromboemboliques et pour le traitement de tumeurs.
EP03747402A 2002-04-27 2003-03-31 Amides d'acide carboxylique servant d'inhibiteurs du facteur de coagulation xa Withdrawn EP1499591A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10218974 2002-04-27
DE2002118974 DE10218974A1 (de) 2002-04-27 2002-04-27 Carnonsäureamide
DE10236868A DE10236868A1 (de) 2002-08-12 2002-08-12 Carbonsäureamide
DE10236868 2002-08-12
PCT/EP2003/003331 WO2003093235A1 (fr) 2002-04-27 2003-03-31 Amides d'acide carboxylique servant d'inhibiteurs du facteur de coagulation xa

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US20040152741A1 (en) * 2002-09-09 2004-08-05 Nps Allelix Corporation Arylglycine derivatives and their use as glycine transport inhibitors
DE10247226A1 (de) * 2002-10-10 2004-04-22 Merck Patent Gmbh Heterocyclische Amide
DE10302500A1 (de) * 2003-01-23 2004-07-29 Merck Patent Gmbh Carbonsäureamidderivate
DE10358539A1 (de) * 2003-12-15 2005-07-07 Merck Patent Gmbh Carbonsäureamidderivate
FR2866886B1 (fr) * 2004-02-26 2007-08-31 Sanofi Synthelabo Derives d'aryl-et d'heteroaryl-akylcarbamates, leur preparation et leur application en therapeutique
WO2006089952A1 (fr) * 2005-02-24 2006-08-31 Novo Nordisk Health Care Ag Composes amidino servant a stabiliser des formulations de polypeptides du facteur vii

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FR2624698A1 (fr) * 1987-12-18 1989-06-23 Bernard Lyon I Universite Clau Derives heterocycliques de n-carbamoyl-, n-thiocarbamoyl- ou n-amidino-aminomalonyl ou aminosuccinyl amides utiles comme agents edulcorants
EP1162194A1 (fr) * 2000-06-06 2001-12-12 Aventis Pharma Deutschland GmbH Dérivés de (thio)-urée inhibiteurs du facteur VIIa, procédé de leur préparation et leur utilisation
DE10063008A1 (de) * 2000-12-16 2002-06-20 Merck Patent Gmbh Carbonsäureamidderivate
DE10102322A1 (de) 2001-01-19 2002-07-25 Merck Patent Gmbh Phenylderivate

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AR039450A1 (es) 2005-02-16
CA2483228C (fr) 2011-07-05
AU2003226755A1 (en) 2003-11-17
WO2003093235A1 (fr) 2003-11-13
JP2005531547A (ja) 2005-10-20
US20050171154A1 (en) 2005-08-04

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