WO1996005189A1 - Nouveaux inhibiteurs de type benzamidine - Google Patents

Nouveaux inhibiteurs de type benzamidine Download PDF

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Publication number
WO1996005189A1
WO1996005189A1 PCT/CH1995/000174 CH9500174W WO9605189A1 WO 1996005189 A1 WO1996005189 A1 WO 1996005189A1 CH 9500174 W CH9500174 W CH 9500174W WO 9605189 A1 WO9605189 A1 WO 9605189A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon atoms
radical
straight
thrombin
compounds
Prior art date
Application number
PCT/CH1995/000174
Other languages
German (de)
English (en)
Inventor
Jörg STÜRZEBECHER
Helmut Vieweg
Peter Wikstroem
Original Assignee
Pentapharm Ag
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 Pentapharm Ag filed Critical Pentapharm Ag
Priority to AU31077/95A priority Critical patent/AU3107795A/en
Publication of WO1996005189A1 publication Critical patent/WO1996005189A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/974—Thrombin

Definitions

  • the invention relates to new thrombin inhibitors of the amidinophenylalanine type, their preparation and their use for combating diseases. They are distinguished in particular by the fact that they carry a substituted piperazine residue in different positions of the molecule.
  • trypsin-like serine proteinases such enzymes are of particular physiological importance that trigger coagulation and fibrinolysis in the blood. Since the pathologically increased activity of the enzymes or the lack of natural inhibitors can lead to diseases, attempts are made to control these diseases by increasing the inhibitor potential. Accordingly, natural inhibitors - endogenous to the body such as antithrombin III or those from other natural sources such as hirudin - are used or prepared for the therapy.
  • inhibitors of the coagulation enzymes are being worked on particularly intensively. Extensive biochemical and (animal) experimental pharmacological studies have shown that inhibitors of throbine in particular are effective anticoagulants and antithrombotics.
  • the present invention relates to new thrombin inhibitors having a benzidine structure of the general formulas I and II
  • R 1 in the general formula I is a straight-chain alkylsulfonyl radical having 1 to 16 carbon atoms, preferably 6 to 10 carbon atoms
  • R * 2 is a straight-chain Alkylsulfonyl radical having 1 to 8 carbon atoms
  • R ⁇ in the general formula II is a straight-chain alkylsulfonyl radical having 1 to 4 carbon atoms, an alkanoyl radical having 1 to 4 carbon atoms and n is an integer of 1 or 2.
  • the inhibitor derivatives of the general formulas I and II according to the invention can be treated with a mineral acid, e.g. HC1, HBr, H2SO4 or H3PO4, or with an organic acid, e.g. Formic, acetic, oxalic or tartaric acid may be protonized.
  • a mineral acid e.g. HC1, HBr, H2SO4 or H3PO4
  • an organic acid e.g. Formic, acetic, oxalic or tartaric acid may be protonized.
  • the compounds of the general formula I are prepared by the known production process described below.
  • amidine derivatives of the formula I are prepared from these cyanphenylalanine derivatives obtained by known processes (via thioamide, thioimido ester or imido ester route).
  • the amidino derivatives of the general formula II are built up in stages in accordance with the production process known per se and described below.
  • (D) -4-cyanophenylalanine is first N-acylated with an acid-labile protective group and then the ⁇ (carboxyl group is converted to a piperidide. After the o-amino protective group has been cleaved off, the (D) - -4-cyanophenylalanine piperidide is also converted a No ⁇ - -2-naphthylsulfonyl derivative of the formula IV,
  • R ⁇ is an acid labile carboxyl protecting group, e.g. t-butyl, and n represents the number 1 or 2, implemented.
  • the compounds according to the invention can be used per se or - in combination with carriers and auxiliaries - as medicaments, and they can be administered subcutaneously, intravenously, but especially orally or rectally.
  • carriers and auxiliaries - as medicaments
  • they can be administered subcutaneously, intravenously, but especially orally or rectally.
  • the compounds according to the invention can be used in particular in test kits for determining thrombin.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Neurosurgery (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Molecular Biology (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux inhibiteurs de thrombine de type amidinophénylalanine. Les composés sont résorbables notamment par voie rectale et par voie orale.
PCT/CH1995/000174 1994-08-09 1995-08-09 Nouveaux inhibiteurs de type benzamidine WO1996005189A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31077/95A AU3107795A (en) 1994-08-09 1995-08-09 Inhibitors of the benzamidine type

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH2469/94-9 1994-08-09
CH246994 1994-08-09

Publications (1)

Publication Number Publication Date
WO1996005189A1 true WO1996005189A1 (fr) 1996-02-22

Family

ID=4234519

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CH1995/000174 WO1996005189A1 (fr) 1994-08-09 1995-08-09 Nouveaux inhibiteurs de type benzamidine

Country Status (2)

Country Link
AU (1) AU3107795A (fr)
WO (1) WO1996005189A1 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997029104A1 (fr) * 1996-02-05 1997-08-14 Zeneca Limited Composes aminoheterocycliques produisant un effet antithrombotique et anticoagulant
WO1998054164A1 (fr) * 1997-05-30 1998-12-03 Takeda Chemical Industries, Ltd. Derives de la sulfonamide, leur production et leurs utilisations
WO1999064392A1 (fr) * 1998-06-08 1999-12-16 Ajinomoto Co., Inc. Derive de benzamidine
WO2000004954A2 (fr) * 1998-07-20 2000-02-03 Wilex Biotechnology Gmbh Nouveaux inhibiteurs d'urokinase
EP1016663A1 (fr) * 1999-01-02 2000-07-05 Aventis Pharma Deutschland GmbH Dérivés de l'acide malonique, procédé pour leur préparation, leur utilisation comme médicaments et compositions les contenant (inhibiteurs du facteur Xa )
WO2000040571A1 (fr) * 1999-01-02 2000-07-13 Aventis Pharma Deutschland Gmbh Nouveaux derives d'acide malonique, procedes de preparation de ces derives, leur utilisation et compositions pharmaceutiques les contenant (inhibition de l'activite du facteur xa)
US6093718A (en) * 1996-08-14 2000-07-25 Zeneca Limited Substituted pyrimidine derivatives and their pharmaceutical use
US6225309B1 (en) 1994-09-26 2001-05-01 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
EP1127884A1 (fr) * 2000-02-26 2001-08-29 Aventis Pharma Deutschland GmbH Dérivés de l'acide malonique, procédés pour leur préparation, leur utilisation comme inhibiteur du facteur XA et compositions les contenants
US6300330B1 (en) 1996-11-08 2001-10-09 Zeneca Limited Heterocycle derivatives which inhibit factor Xa
US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
US6391880B1 (en) 1997-02-13 2002-05-21 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
US6440972B1 (en) 1997-02-13 2002-08-27 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
WO2002074756A2 (fr) * 2001-03-21 2002-09-26 Pentapharm Ag Inhibiteurs d'urokinase
US6486154B1 (en) 1997-07-29 2002-11-26 Zeneca Limited (Hetero) aryl-sulfonamide derivatives, their preparation and their use as factor XA inhibitors
US6538017B2 (en) 2001-03-09 2003-03-25 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6680312B2 (en) 1998-02-05 2004-01-20 Takeda Chemical Industries, Ltd. Sulfonamide derivatives, their production and use
US6710061B2 (en) 2001-03-09 2004-03-23 Ortho-Mcneil Pharamceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6723723B1 (en) 1999-02-11 2004-04-20 Astrazeneca Heterocyclic derivatives as inhibitors of factor Xa
US7342018B2 (en) 1998-07-20 2008-03-11 Wilex Ag Urokinase inhibitors and uses thereof
WO2022175136A2 (fr) 2021-02-16 2022-08-25 Dsm Ip Assets B.V. Nouveaux inhibiteurs de lrat

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2007663A (en) * 1977-11-07 1979-05-23 Dresden Arzneimittel Sulphonylated omega - amidinophenyl- alpha -aminocarhoxylic acid amides
DD155954A1 (de) * 1981-02-03 1982-07-21 Wagner Guenter Verfahren zur herstellung von n tief alpha aryl-bzw.n tief alpha heteroarylsulfonylaminoacylierten amidinophenylalaninamiden
EP0097630A2 (fr) * 1982-06-23 1984-01-04 KabiVitrum AB Dérivés de N-alpha-arylsulfonyl-p-guanidino-phénylalanine utiles comme inhibiteur de la thrombine
DD235866A1 (de) * 1985-03-29 1986-05-21 Univ Leipzig Verfahren zur herstellung von n alpha -sulfonylaminoacylierten amidinophenylalaninamiden
DD242404A1 (de) * 1985-11-04 1987-01-28 Univ Leipzig Verfahren zur herstellung n alpha-sulfonylaminoacylierter 3-amidino-phenylalaninester
EP0236164A1 (fr) * 1986-01-24 1987-09-09 Sanofi Dérivés des N alpha-arylsulfonylaminoacyl p-amidino-phénylalaninamides, leur procédé de préparation, leur application comme médicaments et leurs intermédiaires de synthèse
EP0236163A1 (fr) * 1986-01-24 1987-09-09 Sanofi Dérivés N alpha-substitués des N alpha-arylsulfonylaminoacyl p-amidinophénylalaninamides, leur préparation, leur application comme médicaments et intermédiaires pour leur synthèse
WO1992008709A1 (fr) * 1990-11-15 1992-05-29 Pentapharm Ag Derives de la phenylalanine metasubstitues
EP0508220A1 (fr) * 1991-04-09 1992-10-14 BEHRINGWERKE Aktiengesellschaft Dérivées d'amidino-phenylalanine, procédé de leur préparation, leur utilisation et composition les contenants

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2007663A (en) * 1977-11-07 1979-05-23 Dresden Arzneimittel Sulphonylated omega - amidinophenyl- alpha -aminocarhoxylic acid amides
DD155954A1 (de) * 1981-02-03 1982-07-21 Wagner Guenter Verfahren zur herstellung von n tief alpha aryl-bzw.n tief alpha heteroarylsulfonylaminoacylierten amidinophenylalaninamiden
EP0097630A2 (fr) * 1982-06-23 1984-01-04 KabiVitrum AB Dérivés de N-alpha-arylsulfonyl-p-guanidino-phénylalanine utiles comme inhibiteur de la thrombine
DD235866A1 (de) * 1985-03-29 1986-05-21 Univ Leipzig Verfahren zur herstellung von n alpha -sulfonylaminoacylierten amidinophenylalaninamiden
DD242404A1 (de) * 1985-11-04 1987-01-28 Univ Leipzig Verfahren zur herstellung n alpha-sulfonylaminoacylierter 3-amidino-phenylalaninester
EP0236164A1 (fr) * 1986-01-24 1987-09-09 Sanofi Dérivés des N alpha-arylsulfonylaminoacyl p-amidino-phénylalaninamides, leur procédé de préparation, leur application comme médicaments et leurs intermédiaires de synthèse
EP0236163A1 (fr) * 1986-01-24 1987-09-09 Sanofi Dérivés N alpha-substitués des N alpha-arylsulfonylaminoacyl p-amidinophénylalaninamides, leur préparation, leur application comme médicaments et intermédiaires pour leur synthèse
WO1992008709A1 (fr) * 1990-11-15 1992-05-29 Pentapharm Ag Derives de la phenylalanine metasubstitues
EP0508220A1 (fr) * 1991-04-09 1992-10-14 BEHRINGWERKE Aktiengesellschaft Dérivées d'amidino-phenylalanine, procédé de leur préparation, leur utilisation et composition les contenants
DE4111394A1 (de) * 1991-04-09 1992-10-15 Behringwerke Ag Amidinophenylalaninderivate, verfahren zu deren herstellung, deren verwendung und diese enthaltende mittel

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 107, no. 5, 3 August 1987, Columbus, Ohio, US; abstract no. 40333v, page 758; column L; *
CHEMICAL ABSTRACTS, vol. 108, no. 11, 14 March 1988, Columbus, Ohio, US; abstract no. 94939m, page 702; column L; *
CHEMICAL ABSTRACTS, vol. 98, no. 13, 28 March 1983, Columbus, Ohio, US; abstract no. 107770b, page 645; column L; *

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6225309B1 (en) 1994-09-26 2001-05-01 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
US6730672B2 (en) 1994-09-26 2004-05-04 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
US6022869A (en) * 1996-02-05 2000-02-08 Zeneca Limited Aminoheterocyclic compounds with antithrombotic/anticoagulant effect
WO1997029104A1 (fr) * 1996-02-05 1997-08-14 Zeneca Limited Composes aminoheterocycliques produisant un effet antithrombotique et anticoagulant
US6093718A (en) * 1996-08-14 2000-07-25 Zeneca Limited Substituted pyrimidine derivatives and their pharmaceutical use
US6936610B2 (en) 1996-11-08 2005-08-30 Astrazeneca Uk Limited Heterocyclic derivatives
US6300330B1 (en) 1996-11-08 2001-10-09 Zeneca Limited Heterocycle derivatives which inhibit factor Xa
US6440972B1 (en) 1997-02-13 2002-08-27 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
US6391880B1 (en) 1997-02-13 2002-05-21 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
WO1998054164A1 (fr) * 1997-05-30 1998-12-03 Takeda Chemical Industries, Ltd. Derives de la sulfonamide, leur production et leurs utilisations
US6359134B1 (en) 1997-05-30 2002-03-19 Takeda Chemical Industries, Ltd. Sulfonamide derivatives, their production and use
US6486154B1 (en) 1997-07-29 2002-11-26 Zeneca Limited (Hetero) aryl-sulfonamide derivatives, their preparation and their use as factor XA inhibitors
US6680312B2 (en) 1998-02-05 2004-01-20 Takeda Chemical Industries, Ltd. Sulfonamide derivatives, their production and use
US6410538B2 (en) 1998-06-08 2002-06-25 Ajinomoto Co., Inc. Benzamidine derivatives
WO1999064392A1 (fr) * 1998-06-08 1999-12-16 Ajinomoto Co., Inc. Derive de benzamidine
EP1264828A1 (fr) * 1998-07-20 2002-12-11 Wilex AG Nouveau inhibiteur d'urokinase
WO2000004954A3 (fr) * 1998-07-20 2000-06-22 Wilex Biotechnology Gmbh Nouveaux inhibiteurs d'urokinase
JP2002521348A (ja) * 1998-07-20 2002-07-16 ヴィレックス アクチェンゲゼルシャフト 新規ウロキナーゼインヒビター
US7342018B2 (en) 1998-07-20 2008-03-11 Wilex Ag Urokinase inhibitors and uses thereof
WO2000004954A2 (fr) * 1998-07-20 2000-02-03 Wilex Biotechnology Gmbh Nouveaux inhibiteurs d'urokinase
US6624169B1 (en) 1998-07-20 2003-09-23 Wilex Biotechnology Gmbh Urokinase inhibitors
US6680320B2 (en) 1998-07-20 2004-01-20 Wilex Ag Urokinase inhibitors
WO2000040571A1 (fr) * 1999-01-02 2000-07-13 Aventis Pharma Deutschland Gmbh Nouveaux derives d'acide malonique, procedes de preparation de ces derives, leur utilisation et compositions pharmaceutiques les contenant (inhibition de l'activite du facteur xa)
EP1016663A1 (fr) * 1999-01-02 2000-07-05 Aventis Pharma Deutschland GmbH Dérivés de l'acide malonique, procédé pour leur préparation, leur utilisation comme médicaments et compositions les contenant (inhibiteurs du facteur Xa )
US6395737B1 (en) 1999-01-02 2002-05-28 Aventis Pharma Deutschland Gmbh Malonic acid derivatives, processes for their preparation, for their use and pharmaceutical compositions containing them
US6723723B1 (en) 1999-02-11 2004-04-20 Astrazeneca Heterocyclic derivatives as inhibitors of factor Xa
EP1127884A1 (fr) * 2000-02-26 2001-08-29 Aventis Pharma Deutschland GmbH Dérivés de l'acide malonique, procédés pour leur préparation, leur utilisation comme inhibiteur du facteur XA et compositions les contenants
WO2001062735A1 (fr) * 2000-02-26 2001-08-30 Aventis Pharma Deutschland Gmbh Nouveaux derives d'acide malonique, procedes de preparation de ceux-ci, leur utilisation comme inhibiteur de l'activite du facteur xa et compositions pharmaceutiques les contenant
US6794365B2 (en) 2000-02-26 2004-09-21 Aventis Pharma Deutschland Gmbh Malonic acid derivatives, processes for their preparation their use and pharmaceutical compositions containing them
US6630505B2 (en) 2001-03-09 2003-10-07 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6710061B2 (en) 2001-03-09 2004-03-23 Ortho-Mcneil Pharamceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6538017B2 (en) 2001-03-09 2003-03-25 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6890939B2 (en) 2001-03-09 2005-05-10 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6861435B2 (en) 2001-03-21 2005-03-01 Pentapharm Ag Urokinase inhibitors
WO2002074756A3 (fr) * 2001-03-21 2002-12-12 Pentapharm Ag Inhibiteurs d'urokinase
WO2002074756A2 (fr) * 2001-03-21 2002-09-26 Pentapharm Ag Inhibiteurs d'urokinase
WO2022175136A2 (fr) 2021-02-16 2022-08-25 Dsm Ip Assets B.V. Nouveaux inhibiteurs de lrat
WO2022175136A3 (fr) * 2021-02-16 2022-09-29 Dsm Ip Assets B.V. Nouveaux inhibiteurs de lrat

Also Published As

Publication number Publication date
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