EP1303482A2 - Derives d'acide 1-amino-1,1-dialkylcarboxylique substitues en n - Google Patents

Derives d'acide 1-amino-1,1-dialkylcarboxylique substitues en n

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Publication number
EP1303482A2
EP1303482A2 EP01974078A EP01974078A EP1303482A2 EP 1303482 A2 EP1303482 A2 EP 1303482A2 EP 01974078 A EP01974078 A EP 01974078A EP 01974078 A EP01974078 A EP 01974078A EP 1303482 A2 EP1303482 A2 EP 1303482A2
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EP
European Patent Office
Prior art keywords
cooa
coo
cooh
alkyl
carbon atoms
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
EP01974078A
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German (de)
English (en)
Inventor
Horst Juraszyk
Dieter Dorsch
Werner Mederski
Christos Tsaklakidis
Christopher Barnes
Johannes Gleitz
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Merck Patent GmbH
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Merck Patent GmbH
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Publication of EP1303482A2 publication Critical patent/EP1303482A2/fr
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/46—Y being a hydrogen or a carbon atom
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C07D211/66—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having a hetero atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention relates to compounds of the formula
  • R 2 , R 2 ' , R 2 " each independently of one another H, A, CF 3 , Cl, F, COA, COOH, COOA, CONH 2 , CONHA, CONA2, CH2NH2, CH2NHCOA, CH 2 NHCOOA, OH, OA, OCF 3 , NO 2 , SO 2 A, SO2NH2, SO 2 NHA or SO 2 NA 2 ,
  • R 5 '" , R 5"" each independently of one another (CH 2 ) n -COOH, (CH 2 ) n -COOA, (CH 2 ) n-COO- (CH 2 ) m-Ar, (CH 2 ) n- COO- (CH 2 ) m-Het, Ar, Py or
  • R 7 each independently of one another H, shark, OH, OA, COOH,
  • COOA COO (CH 2 ) m Ar, CONH 2 , CONHA or CONA 2 , R 8 H, A, COA, COOA, (CH 2 ) n -COOH, (CH 2 ) m -COOA,
  • Y is missing, CH 2 , CO or SO 2 ,
  • Atoms in which one or two CH 2 groups can be replaced by O or S atoms, -CH CH or -C ⁇ C and / or 1-7 H atoms by F, Ar unsubstituted or single, double or triple by A, CF 3 ,
  • S (O) 2 A substituted phenyl or naphthyl, het mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1-4 N, O and / or S atoms, bonded via N or C, which is unsubstituted or mono-, di-, tri- or 'tetrasubstituted by A, CF3, Hal, OH, OA, OCF 3, SO 2 A, SO 2 -, Ar, SO 2 NH 2, SO2NHA, SO2NA2, NH 2 - (CH 2) m NHA, NA 2 , NHCHO, NHCOA, NHCOOA, NACOOA, NHSO 2 A, NHSO 2 Ar, COOH, COOA, COO- (CH 2 ) m -Ar ⁇ CONH 2 , CONHA, COA, COAr ', CH 2 NH 2 , CH 2 NHA, CH 2 NHCHO, CH 2 NHCOA, CH 2 NHCOOA,
  • CONH 2 CONHA, COOH, COOA, CH 2 NH 2 , CH 2 NHA, CH 2 NHCHO, CH 2 NHCOA, CH 2 NHCOOA, CH 2 OH, CH 2 OA, CH 2 OAr, CH 2 OCOA, NO 2 , NH 2 , NHA or NA 2 substituted 2-, 3- or 4-pyridyl, Hai F, Cl, Br or I, n 1 or 2, m is 0, 1 or 2, p is 2, 3, 4 or 5, and their pharmaceutically acceptable salts, solvates and stereoisomers.
  • the invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. Alcohololates, these compounds.
  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability.
  • they show factor Xa inhibitory properties and can therefore be used to combat and prevent thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
  • the compounds of the formula I according to the invention can furthermore be inhibitors of the coagulation factors factor VIIa, factor IXa and thrombin of the blood coagulation cascade.
  • Aromatic amidine derivatives with antithrombotic activity are known, for example, 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 described, for example, in WO 97/08165.
  • Aromatic heterocycles with factor Xa inhibitory activity are known, for example, from WO 96/10022.
  • N - [(aminoiminomethyl) phenylalkylj-azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.
  • the antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibitory effect against the activated coagulation protease, known under the name factor Xa, or to the inhibition of other activated serine proteases such as factor VIII, factor IXa or thrombin.
  • Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin cleaves fibrinogen into fibrin monomers which, after cross-linking, make an elementary contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders. However, inhibition of thrombin can inhibit fibrin formation involved in thrombus formation. The 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 determined by customary in vitro or in vivo methods.
  • a suitable method is e.g. by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.
  • the measurement of the inhibition of factor Xa can e.g. using the method of T. Hara et al. in thromb. Haemostas. 1994, 71, 314-319.
  • the coagulation factor VIa initiates the extrinsic part of the coagulation cascade after binding to the tissue factor and contributes to the activation of factor X to factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and thus the subsequent formation of thrombin.
  • the inhibition of the factor VIIa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A common method for measuring the inhibition of factor VIIa is described, for example, by HF Ronning et al. in Thrombosis Research 1996, 84, 73-81.
  • Coagulation factor IXa is generated in the intrinsic coagulation cascade and is also involved in the activation of factor X to factor Xa. Inhibition of factor IXa can therefore otherwise prevent factor Xa from being formed.
  • the inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods.
  • a suitable method is e.g. by J. Chang et al. in Journal of Biologicalat Chemistry ⁇ WZ, 273, 12089-12094.
  • the compounds according to the invention can furthermore be used for the treatment of tumors, tumor diseases and / or tumor metastases.
  • tissue factor TF / factor Vlla A connection between the tissue factor TF / factor Vlla and the development of various types of cancer was described by T.Taniguchi and N.R. Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis of Pancreatic Cancer), 57-59.
  • 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 of 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.
  • thrombolytics for myocardial infarction
  • prophylaxis for reocclusion after thrombolysis
  • percutaneous transluminal angioplasty PTCA
  • coronary bypass surgery percutaneous transluminal angioplasty
  • the compounds according to the invention are also used for the prevention of rethrombosis in microsurgery, also as anticoagulants in connection with artificial organs or in hemodialysis.
  • the compounds are also used in the 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 e.g. cancer including metastasis, inflammatory diseases including arthritis and diabetes.
  • the compounds according to the invention are also used in combination with other thrombolytically active compounds, such as e.g. with 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 according to the invention are administered with the other substances mentioned either simultaneously or before or after.
  • Simultaneous administration with aspirin is particularly preferred in order to prevent recurrence of thrombus formation.
  • the compounds according to the invention are also used in combination with platelet glycoprotein receptor (IIb / IIla) antagonists which inhibit platelet aggregation.
  • IIb / IIla platelet glycoprotein receptor
  • the invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that they are obtained from one of their functional derivatives by treatment with a solvolysing and / or Frees hydrogenation agents by i) releases an amidino group from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis,
  • A is also cycloalkyl and preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • A therefore also means, for example, CF 3 or C 2 F 5 .
  • Prodrug compounds are also those compounds of formula I in which R 8 ⁇ H.
  • R 3 preferably denotes A or CH 2 Ar, where A preferably denotes alkyl having 1, 2, 3 or 4 carbon atoms and Ar preferably phenyl.
  • R 3 particularly preferably denotes alkyl having 1, 2, 3 or 4 carbon atoms.
  • R 4 is preferably A or CH 2 Ar, where A is preferably alkyl with
  • Ar is preferably phenyl.
  • R 4 particularly preferably denotes alkyl having 1, 2, 3 or 4 carbon atoms.
  • R 3 , R 4 together preferably mean, for example, (CH 2 ) 4, (CH 2 ) s, (CH 2 ) 2 NHCH 2 , (CH 2 ) 2 NH (CH 2 ) 2, (CH 2 ) 2 O (CH 2 ) 2 , (CH 2 ) 2 -S (O) m - (CH 2 ) 2 ,
  • R 5 preferably means, for example, SO 2 NH 2 , S0 2 NHA, CH 2 COOH, phenyl substituted simply by SO 2 NHA, SO 2 NH 2 or SO 2 A, unsubstituted or simply substituted by CONH 2 4-pyridyl.
  • R 5 very particularly preferably means, for example, simply substituted by SO 2 NHA, S0 2 NH 2 or SO 2 A phenyl or 4-pyridyl.
  • R 6 preferably means, for example, methyl.
  • R 7 preferably denotes, for example, H, methyl, ethyl, propyl, butyl or phenyl, but very particularly preferably H.
  • R 7 , R 7 , R 7 " preferably denote H.
  • R 8 preferably denotes, for example, H, CH 2 COOH, CH 2 CH 2 COOH, COOA, CH 2 COOA, CH 2 CH 2 COOA, COOPhenyl, CH 2 COOPhenyl, COOCH 2 phenyl, CH 2 COOCH 2 phenyl or CH 2 CONH 2 , where A is preferably alkyl having 1, 2, 3 or 4 carbon atoms.
  • R 8 very particularly preferably denotes CH 2 COOH, COOA or CH 2 COOA, where A preferably denotes alkyl having 1, 2, 3 or 4 carbon atoms.
  • R 8 also means, for example, S0 2 CH 3 .
  • R 9 preferably denotes, for example, H, methyl, ethyl or benzyl.
  • U preferably means, for example, CO.
  • V preferably means, for example, NH.
  • W is preferably absent.
  • Y is preferably absent, it also means, for example, S0 2 or CO.
  • Ar means unsubstituted or mono-, di- or trisubstituted phenyl or naphthyl.
  • Preferred substituents for phenyl or naphthyl are e.g. Methyl, ethyl, propyl, butyl, trifluoromethyl, F, Cl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethoxy, methylsulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, Formanido, acetamido, methoxycarbonylamino, ethoxycarbonylamino, methoxycarbonyl-N-methylamino, methylsulfonylamino, phenylsulfonylamino, carboxy, methoxycarbon
  • Ar ' preferably means e.g. unsubstituted or mono-, di- or trisubstituted phenyl.
  • Preferred substituents are e.g. Methyl, methoxy, trifluoromethoxy, F, Cl, cyan acetamido, methoxycarbonyl, carboxy or methylsulfonyl.
  • Het preferably means, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5 -Pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4 -Pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2, 3-triazol-1-, -4- or -5-yl, 1, 2,4-triazoM-, -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-thiadia
  • 6- or 7-benzisothiazolyl 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1, 4] oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.
  • heterocyclic radicals can also be partially or completely hydrogenated.
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2 - or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-
  • Het particularly preferably means, for example, furyl, thienyl, thiazolyl, imidazolyl, [2,1,3] benzothiadiazolyl, oxazolyl, pyridyl, indolyl, 1-methylpiperidinyl, piperidinyl or pyrrolidinyl, pyridyl, 1-methyl being very particularly preferred -piperidin-4-yl or piperidin-4-yl.
  • Py preferably means 2-, 3- or 4-pyridyl, for example unsubstituted or simply substituted by aminocarbonyl.
  • the compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric 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 sub-formulas Ia to Ij, which correspond to formula I and
  • Ar is phenyl
  • R 2 , R 2 ' , R 2 each independently of one another H or F,
  • Ar is phenyl
  • R 2 , R 2 ' , R 2 each independently of one another H or F,
  • R 3 alkyl with 1, 2, 3 or 4 carbon atoms
  • R 3 , R 4 together also (CH 2 ) 4 , (CH 2 ) 5 , (CH 2 ) 2 NHCH 2 ,
  • R 1 F NH 2 , NHCOA, NHCOOA, NH- (CH 2 ) n -Ar, CN, CONH 2 ,
  • R 2 , R 2 ' , R 2' are each independently of one another H or F, Ar phenyl, R 3 alkyl having 1, 2, 3 or 4 carbon atoms,
  • R 5 '" , R 5'" mean H
  • V NH, W missing, X CH or N V NH, W missing, X CH or N
  • R 2 , R 2 ' R 2 each independently of one another H or F,
  • R 3 alkyl with 1, 2, 3 or 4 carbon atoms
  • R 3 , R 4 together also (CH 2 ) 4 , (CH 2 ) 5 , (CH 2 ) 2NHCH 2 ,
  • (CH 2 ) 2 S (0) m - (CH2) 2 or (CH 2 ) 2-0- (CH 2 ) 2, where A is alkyl with 1, 2, 3 or 4 carbon atoms, R 5 S0 2 NH 2 , SO 2 NHA, CH2COOH, simply substituted by S0 2 NHA, S0 2 NH 2 or S0 2 A
  • R 8 (CH 2 ) n -COOH, (CH 2 ) m -COOA, (CH 2 ) m-COO- (CH 2 ) n-Ar, (CH 2 ) m -COO- (CH2) n-Het, ( CH 2 ) m-CONH2, (CH 2 ) m -CONHA or (CH 2 ) m-CONA 2 ,
  • Ar is phenyl, n is 1 or 2, m is 0, 1 or 2, P 4 or 5; R 1 H,
  • R 2 ' , R 2' each independently of one another H, i
  • R 3 , R 4 together also (CH 2 ), (CH 2 ) 5 , (CH 2 ) 2 NHCH2,
  • R 5 S0 2 NH 2 , SO2NHA, CH2COOH, simply substituted by S0 2 NHA, S0 2 NH 2 or S0 2 A.
  • R 9 is H, A or benzyl
  • Ar phenyl, n 1 or 2, m represents 0, 1 or 2, p 4 or 5;
  • R 3 alkyl with 1, 2, 3 or 4 carbon atoms
  • P 4 or 5
  • R 3 alkyl with 1, 2, 3 or 4 carbon atoms
  • R 3 , R 4 together also (CH 2 ), (CH 2 ) 5 , (CH 2 ) 2 NHCH 2 , (CH 2 ) 2NH (CH 2 ) 2, (CH 2 ) -N (COOA) -CH 2 , (CH 2 ) -N (CH 2 COOA) -CH 2 , (CH 2 ) -N (CH 2 COOH) -CH 2 , (CH2) -N (CH 2 COOA) - (CH 2 ) 2, (CH 2 ) -N (CH 2 COOH) - (CH 2 ) 2 , (CH 2 ) 2 -S (0) m - (CH 2 ) 2 or (CH 2 ) 2 -0- (CH 2 ) 2 , where A is alkyl with 1, 2, 3 or 4 carbon atoms means
  • Y is missing, S0 2 or CO
  • P represents 4 or 5; as well as their pharmaceutically acceptable salts, solvates and stereoisomes.
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • Compounds of formula I can preferably be obtained by liberating compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H- Atoms which are connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R 'represents an amino protective group, and / or those which replace the H atoms of a hydroxyl group carry a hydroxyl 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 hydroxyl protective group.
  • Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
  • the release of the amidino group from its oxadiazole derivative can e.g. by treatment with hydrogen in the presence of a catalyst (e.g. Raney nickel).
  • a catalyst e.g. Raney nickel
  • Suitable solvents are those specified below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar.
  • the oxadiazole group can be introduced, for example, by reacting the ( - ) cyano compounds with hydroxylamine and reacting with phosgene, dialkyl carbonate, chloroformate, N, N'-carbonyldiimidazole or acetic anhydride.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other locations in the molecule. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms.
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • 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, BOG (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr.
  • Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
  • Amides such as DMF, halogenated hydrocarbons such as dichloromethane, ner also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
  • the groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15 -30 °.
  • Hydrogenolytically removable protective groups can, for. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal).
  • a catalyst z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal.
  • Suitable solvents are the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar.
  • Hydrogenolysis of the CBZ group succeeds e.g. B. well on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 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
  • NMP dimethylformamide
  • DMF dimethylformamide
  • Nitriles such as acetonitrile
  • Sulfoxides such as Dimethyl sulfoxide (DMSO); Carbon disulphide
  • Carboxylic acids such as formic acid or acetic acid
  • Nitro compounds such as nitromethane or nitrobenzene
  • Esters such as ethyl acetate or mixtures of the solvents mentioned.
  • the biphenyl-SO 2 NH 2 group is preferably used in the form of its tert-butyl derivative.
  • the tert-butyl group is split off, for example, using TFA with or without the addition of an inert solvent, preferably with the addition of a small amount of anisole (1% by volume).
  • ammonia can also be added to a nitrile.
  • the addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H 2 S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH 3 I, which in turn contains NH 3 reacts to the amidine, b) the nitrile is converted into the corresponding imidoester with an alcohol, for example ethanol in the presence of HCl, and treated with ammonia, or c) the nitrile is reacted with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.
  • an alkylating agent for example CH 3 I
  • NH 3 alkylating agent
  • Esters can e.g. with acetic acid or with NaOH or KOH in water,
  • Water THF or water dioxane can be saponified at temperatures between 0 and 100 °.
  • free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between - 60 and + 30 °.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • So inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon, sulfonic or Sulfuric acids, e.g.
  • compounds of formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
  • physiologically harmless organic bases e.g. Ethanolamine can be used.
  • the pharmaceutical activity of the racemates or the stereo isomers 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,
  • N-protected amino acids e.g. N-benzoylproline or N-benzenesulfonylproline
  • suitable optically active separating agent e.g. dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of
  • Aqueous or alcoholic solvent mixtures such as e.g. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.
  • the invention further relates to the use of the compounds
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and with the new compounds
  • 35 do not react, 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, coated tablets, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions for parenteral use, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for which topical application ointments, creams or powder.
  • the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or contain 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, eg one or more vitamins.
  • the compounds of formula I and their physiologically acceptable salts can be used in the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
  • the substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • N-arylations of - disubstituted amino acids described in Examples 1 and 2 are carried out analogously to processes known from the literature (Tetrahedron: Asymmetry, Vol. 7, No. 11, page 3075, 1996).
  • compound 2 is obtained from 3- (3-iodophenyl) -5-methyl- [1, 2,4] oxadiazole (obtainable by heating 3-iodobenzonitrile and hydroxylamine, hydrochloride in pyridine) and 2-methylalanine - [3- (5-Methyl- [1,2,4] oxadiazol-3-yl) phenylamino] -2-methylpropionic acid ("AB”), FAB 262.
  • AB 2-methylalanine - [3- (5-Methyl- [1,2,4] oxadiazol-3-yl) phenylamino] -2-methylpropionic acid
  • Example 3 Analogously to Example 3, the following products are obtained by reacting 4'-aminobiphenyl-2-sulfonamide with the compounds obtained in Example 2
  • 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 soy lecithin and 1400 g cocoa butter, pour into molds and let cool. Each suppository contains 20 mg of active ingredient.
  • a solution of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • 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

De nouveaux composés de la formule (I) où R?1, R2, R2', R2', R3, R4, R5, R5', R5', R5''', R''''¿, X, Y, U, V et W ont la signification donnée dans la revendication 1. Ces composés sont des inhibiteurs du facteur de coagulation Xa et VIIa et peuvent être utilisés pour traiter la thrombose, l'infarctus du myocarde, l'artériosclérose, les inflammations, l'apoplexie, l'angine de poitrine,la resténose après angioplastie, la claudication intermittente, les tumeurs, les maladies tumorales et/ou les métastases tumorales.
EP01974078A 2000-07-25 2001-07-03 Derives d'acide 1-amino-1,1-dialkylcarboxylique substitues en n Withdrawn EP1303482A2 (fr)

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PCT/EP2001/007596 WO2002008177A2 (fr) 2000-07-25 2001-07-03 Derives d'acide 1-amino-1,1-dialkylcarboxylique substitues en n

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US7030141B2 (en) 2001-11-29 2006-04-18 Christopher Franklin Bigge Inhibitors of factor Xa and other serine proteases involved in the coagulation cascade
EP1476419B1 (fr) * 2002-02-08 2006-02-01 Merck & Co., Inc. Derives de n-biphenylmethyl aminocycloalcanecarboxamide
US6919343B2 (en) 2002-02-08 2005-07-19 Merck & Co., Inc. N-biphenyl(substituted methyl) aminocycloalkane-carboxamide derivatives
CA2497003A1 (fr) * 2002-09-11 2004-03-25 Warner-Lambert Company Llc Inhibiteurs de facteur xa et autres serine proteases intervenant dans la cascade de coagulation
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US4310429A (en) * 1978-06-19 1982-01-12 The B. F. Goodrich Company Stabilized polymers, novel stabilizers, and synthesis thereof
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