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EP1149099A2 - Derives d'imidazo[4,5-c]pyridine-4-one - Google Patents

Derives d'imidazo[4,5-c]pyridine-4-one

Info

Publication number
EP1149099A2
EP1149099A2 EP99964639A EP99964639A EP1149099A2 EP 1149099 A2 EP1149099 A2 EP 1149099A2 EP 99964639 A EP99964639 A EP 99964639A EP 99964639 A EP99964639 A EP 99964639A EP 1149099 A2 EP1149099 A2 EP 1149099A2
Authority
EP
European Patent Office
Prior art keywords
acid
formula
compounds
group
acids
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Withdrawn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
EP99964639A
Other languages
German (de)
English (en)
Inventor
Werner Mederski
Horst Juraszyk
Hanns Wurziger
Christos Tsaklakidis
Dieter Dorsch
Sabine Bernotat-Danielowski
Guido Melzer
Soheila Anzali
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1149099A2 publication Critical patent/EP1149099A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to compounds of the formula I.
  • Ar, Ar ' are each independently of one another unsubstituted or mono-, di- or triple by R, OH, Hai, CN, N0 2 , CF 3 , NH 2 , NHR, NR 2 , pyrrolidin-1-yl, piperidin-1-yl , Benzyloxy, S0 2 NH 2 , S0 2 NHR, S0 2 NR 2 , -CONHR, -CONR 2 , - (CH 2 ) n -NH 2 ,
  • the invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. Alcohololates, these compounds.
  • the invention was based on the task of finding 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 claudication intermittently.
  • the compounds of the formula I according to the invention can furthermore be inhibitors of the coagulation factors factor VIIa, factor IXa and thrombin of the blood coagulation cascade.
  • Aromatic amidine derivatives with antithrombotic activity are e.g. known from EP 0 540 051 B1.
  • Cyclic guanidines for the treatment of thromboembolic disorders 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 - [(aminoimino-methyl) phenylalkyl] azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.
  • the antithrombotic and anticoagulant effect of the compounds according to the invention is 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 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 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
  • Activity can be determined using conventional in vitro or in vivo methods the.
  • 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 Biological Chemistry 1998, 273, 12089-12094.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for combating and preventing thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermediate.
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermediate.
  • 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
  • Protecting group sets free amino group, or
  • R represents alkyl, is unbranched (linear) or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • R 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.
  • R is also cycloalkyl and preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • A means alkyl with 1, 2, 3 or 4 carbon atoms and preferably means methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
  • Shark preferably means F, CI or Br, but also I.
  • Ar and Ar 'each independently of one another are preferably unsubstituted phenyl, naphthyl or biphenyl, further preferably, for example, by methyl, ethyl, propyl, isopropyl, butyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, Butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido Butylsulfonamido, dimethylsulfona
  • Ar and Ar ' are therefore, in each case independently of one another, very particularly preferably, for example, 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-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o- , m- or p- (N-methylamino) phenyl, o-, m- or p- (N-methylaminocarbonyl) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphen
  • R 3 preferably denotes, for example, H, shark, COOH, COOA or CONH 2 .
  • n is preferably 0 or 1.
  • 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 sub-formulas la to li, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • Biphenyl means; in Id Ar, Ar 'each independently independently independently independently
  • Hai F, CI, Br or l, m 1 or 2, n O or 1 means in Ih RH or unbranched or branched alkyl with 1-6 C-
  • Ar, Ar ' each independently of one another, simply substituted by S0 2 NH 2 or R 4, phenyl, naphthyl or biphenyl,

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne de nouveaux composés de la formule (I) dans laquelle R, R?1, R2, R3¿ et n ont la signification mentionnée dans la revendication 1. Ces nouveaux composés sont des inhibiteurs du facteur de coagulation Xa et s'utilisent pour assurer la prophylaxie et/ou le traitement d'affections thromboemboliques.
EP99964639A 1999-01-08 1999-12-21 Derives d'imidazo[4,5-c]pyridine-4-one Withdrawn EP1149099A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19900471A DE19900471A1 (de) 1999-01-08 1999-01-08 Imidazo[4,5c]-pyridin-4-on-derivate
DE19900471 1999-01-08
PCT/EP1999/010236 WO2000040583A2 (fr) 1999-01-08 1999-12-21 Derives d'imidazo[4,5-c]pyridine-4-one

Publications (1)

Publication Number Publication Date
EP1149099A2 true EP1149099A2 (fr) 2001-10-31

Family

ID=7893790

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99964639A Withdrawn EP1149099A2 (fr) 1999-01-08 1999-12-21 Derives d'imidazo[4,5-c]pyridine-4-one

Country Status (16)

Country Link
EP (1) EP1149099A2 (fr)
JP (1) JP2002534429A (fr)
KR (1) KR20010086085A (fr)
CN (1) CN1333772A (fr)
AR (1) AR022220A1 (fr)
AU (1) AU3041700A (fr)
BR (1) BR9916774A (fr)
CA (1) CA2357771A1 (fr)
CZ (1) CZ20012407A3 (fr)
DE (1) DE19900471A1 (fr)
HU (1) HUP0105054A3 (fr)
NO (1) NO20013384L (fr)
PL (1) PL349341A1 (fr)
SK (1) SK9442001A3 (fr)
WO (1) WO2000040583A2 (fr)
ZA (1) ZA200106454B (fr)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI1140941T1 (en) 1998-12-23 2005-04-30 Bristol-Myers Squibb Pharma Company Nitrogen containing heterobicycles as factor xa inhibitors
CN1439008A (zh) * 2000-06-23 2003-08-27 布里斯托尔-迈尔斯斯奎布药品公司 作为因子xa抑制剂的1－(杂芳环基－苯基)－稠合吡唑衍生物
WO2002094197A2 (fr) 2001-05-22 2002-11-28 Bristol-Myers Squibb Company Inhibiteurs bicycliques du facteur xa
GB0215293D0 (en) 2002-07-03 2002-08-14 Rega Foundation Viral inhibitors
GB0225399D0 (en) * 2002-10-31 2002-12-11 Merck Sharp & Dohme Therapeutic agents
PT1569912E (pt) 2002-12-03 2015-09-15 Pharmacyclics Llc Derivados 2-(2-hidroxibifenil-3-il)-1h-benzoimidazole-5- carboxamidina como inibidores do fator viia
KR20050122220A (ko) 2003-03-25 2005-12-28 다케다 샌디에고, 인코포레이티드 디펩티딜 펩티다제 억제제
US7638638B2 (en) 2003-05-14 2009-12-29 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7790736B2 (en) 2003-08-13 2010-09-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
ATE544765T1 (de) 2003-12-22 2012-02-15 Leuven K U Res & Dev Imidazoä4,5-cüpyridinverbindungen und verfahren zur antiviralen behandlung
JP2008524335A (ja) 2004-12-21 2008-07-10 ギリアド サイエンシズ， インコーポレイテッド イミダゾ［４，５−ｃ］ピリジン化合物および抗ウイルス処置法
WO2007009883A1 (fr) 2005-07-15 2007-01-25 F. Hoffmann-La Roche Ag Nouvelles amines cycliques fusionnés avec hétéroaryle
EP1942898B2 (fr) 2005-09-14 2014-05-14 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyl peptidase permettant de traiter le diabete
CN102675221A (zh) 2005-09-16 2012-09-19 武田药品工业株式会社 用于制备嘧啶二酮衍生物的方法中的中间体
WO2007112347A1 (fr) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Inhibiteurs de la dipeptidyl peptidase
ES2339298T3 (es) 2006-07-07 2010-05-18 Gilead Sciences, Inc. Compuesto de piridazina novedoso y uso del mismo.
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
UA99466C2 (en) 2007-07-06 2012-08-27 Гилиад Сайенсиз, Инк. Crystalline pyridazine compound
CN107074846B (zh) * 2014-08-12 2020-05-19 先正达参股股份有限公司 具有含硫取代基的杀有害生物活性杂环衍生物

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* Cited by examiner, † Cited by third party
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TW219935B (fr) * 1991-12-25 1994-02-01 Mitsubishi Chemicals Co Ltd
EP1039907A4 (fr) * 1997-12-01 2001-09-19 Merck & Co Inc Inhibiteurs de thrombine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0040583A2 *

Also Published As

Publication number Publication date
AU3041700A (en) 2000-07-24
HUP0105054A2 (hu) 2002-05-29
CN1333772A (zh) 2002-01-30
WO2000040583A3 (fr) 2000-09-21
SK9442001A3 (en) 2002-05-09
CA2357771A1 (fr) 2000-07-13
AR022220A1 (es) 2002-09-04
WO2000040583A2 (fr) 2000-07-13
NO20013384D0 (no) 2001-07-06
JP2002534429A (ja) 2002-10-15
NO20013384L (no) 2001-07-06
CZ20012407A3 (cs) 2001-12-12
PL349341A1 (en) 2002-07-15
HUP0105054A3 (en) 2002-12-28
ZA200106454B (en) 2002-11-06
KR20010086085A (ko) 2001-09-07
DE19900471A1 (de) 2000-07-13
BR9916774A (pt) 2001-10-30

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