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WO2003042187A1 - Inhibiteurs de serine protease - Google Patents

Inhibiteurs de serine protease Download PDF

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Publication number
WO2003042187A1
WO2003042187A1 PCT/EP2002/012697 EP0212697W WO03042187A1 WO 2003042187 A1 WO2003042187 A1 WO 2003042187A1 EP 0212697 W EP0212697 W EP 0212697W WO 03042187 A1 WO03042187 A1 WO 03042187A1
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WO
WIPO (PCT)
Prior art keywords
group
heterocycloalkyl
compounds
heteroaryl
heteroalkyl
Prior art date
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PCT/EP2002/012697
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German (de)
English (en)
Inventor
Katrin Illgen
Thilo Fuchs
Sven Nerdinger
Original Assignee
Morphochem Aktiengesellschaft für kombinatorische Chemie
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Filing date
Publication date
Application filed by Morphochem Aktiengesellschaft für kombinatorische Chemie filed Critical Morphochem Aktiengesellschaft für kombinatorische Chemie
Publication of WO2003042187A1 publication Critical patent/WO2003042187A1/fr

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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention describes new compounds, their pro-drugs, pharmacologically acceptable salts and drug compositions containing the same as an active ingredient.
  • These new compounds are serine protease inhibitors, in particular strong tryptase and uPA inhibitors, which they in the prevention and treatment of diseases in which tryptase is involved such.
  • B. asthma, rheumatoid arthritis, psoriasis or uPA is involved such as in the case of tumor diseases (both local tumors and in the advanced stage) and metastasis.
  • Tryptases are a family of homologous serine proteases that are particularly abundant in mast cells in a tetrameric complex with sulfated carbohydrates, e.g. B. heparin occur. When mast cells are activated, catalytically active tryptase is released from the mast cells into extracellular liquids.
  • a number of diseases and disease states are related to the proteolytic activity of tryptase, which is related to the activation of a number of other proteins such as cytokines and enzymes which are then involved in such diseases. Therefore, the new compounds of the present invention, which are tryptase inhibitors, are useful in the treatment and prevention of a number of other diseases by using either alone or in combination with other therapeutically useful agents become.
  • These diseases include or may include: inflammatory diseases of the lung system such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, emphysema, viral and bacterial lung infections and inflammatory reactions (Kyle C. Elrod, Robert P. Numerof, Emerging Therapeutic Targets, 1999, 203-212 ).
  • tryptase inhibitors can be of therapeutic use are rheumatoid arthritis, psoriasis, inflammatory bowel diseases, multiple sclerosis and cancer. Tryptase is often found in high concentrations in a number of biological fluids and has a relatively long half-life.
  • uPA urokinase plasminogen activator
  • Malignant tumor cells can detach from a primary tumor and migrate to neighboring tissues, blood vessels or lymph. They are then transported to more distant places, where they cause new tumors (secondary tumor, metastasis, daughter tumor). These secondary tumors ultimately lead to the death of the patient.
  • uPA is quickly activated by cathepsins B or L. The binding to the receptor focuses the proteolytic activity on the cell surface.
  • Plasminogen is activated by the uPA-uPAR complex to plasmin, which can break down important components of the extracellular matrix. Plasmin is also able to reactivate uPA thanks to a positive feedback mechanism. Furthermore, uPA also activates matrix metalloproteases, which ultimately contribute to the breakdown of basement membrane collagen. These proteolytic processes allow cancer cells to invade neighboring tissues and metastasize. It could also be shown that in a predominant number of tumor types the primary components of the uPA system, uPA, PAI-1 and uPAR are formed by different cell types.
  • uPA urokinase-type plasminogen activator
  • uPAR urokinase-type plasminogen activator
  • PAI-1 its receptor (uPAR) and its inhibitor (PAI-1)
  • Another aspect of the present invention is to provide a new process for the preparation of new piperazine derivatives which, if possible, takes place in the context of a multicomponent reaction and is widely applicable.
  • Multicomponent reactions are of great interest in the pharmaceutical industry, for example, for the production of substance libraries to find lead structures (A. Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300-3344).
  • the present invention describes compounds, their prodrugs, salts and formulations which are new and have high activity and selectivity.
  • the present invention comprises compounds of the general formula (I): wherein
  • R 1 is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl group, especially heteroalkylarylalkyl;
  • R 2 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl group;
  • R 3 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl group;
  • R 4 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or heteroaralkyl group;
  • alkyl refers to a saturated, straight-chain or branched hydrocarbon group which has 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly preferably 1 to 6 carbon atoms, for example the methyl, ethyl, propyl, isopropyl, isobutyl , tert-butyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.
  • alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups which have 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, particularly preferably 2 to 6 carbon atoms, e.g. B. the ethenyl, allyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group.
  • heteroalkyl refers to an alkyl, an alkenyl or an alkynyl group in which one or more (preferably 1, 2 or 3) carbon atoms or CH or CH 2 groups are replaced by an oxygen, nitrogen, Phosphorus or sulfur atoms are replaced (preferably oxygen or nitrogen), for example an alkyloxy group such as methoxy or ethoxy, or a methoxymethyl, nitrile, amino, methylcarboxyalkyl ester, carboxyalkyl ester or 2,3-dioxyethyl group ,
  • heteroalkyl also refers to a carboxylic acid or a group derived from a carboxylic acid, such as. B.
  • acyl, acyloxy, carboxyalkyl, carboxyalkyl esters for example methyl carboxyalkyl ester, carboxyalkylamide, alkoxycarbonyl or alkoxycarbonyloxy.
  • cycloalkyl or cyclo refers to a saturated or partially unsaturated cyclic group which has one or more rings which have 3 to 14 ring carbon atoms, preferably 3 to 10 ring carbon atoms, for example the cyclopropyl or cyclohexyl -, tetralin or cyclohex-2-enyl group.
  • heterocycloalkyl or heterocyclo refers to a cycloalkyl group as defined above, in which one or more (preferably 1, 2 or 3) ring carbon atoms or ring CH or CH 2 groups are replaced by an oxygen, nitrogen or , Phosphorus or sulfur atom are replaced, and can represent, for example, the piperidine, morpholine, N-methylpiperazine or N-phenylpiperazine group.
  • alkylcycloalkyl or heteroalkylcycloalkyl refer to groups which, in accordance with the above definitions, contain both cycloalkyl or heterocycloalkyl and also alkyl, alkenyl, alkynyl and / or heteroalkyl groups.
  • aryl or Ar refers to an aromatic group which has one or more rings which contain 5 or 6 to 14 ring carbon atoms, preferably 5 or 6 to 10 ring carbon atoms, for example a phenyl, naphthyl
  • heteroaryl refers to an aryl group in which one or more (preferably 1, 2 or 3) ring carbon atoms or ring CH or CH 2 groups are replaced by an oxygen, nitrogen, phosphorus or sulfur atom are, for example the 4-pyridyl, 2-imidazolyl, 3-pyrazolyl and isoquinolinyl group.
  • aralkyl or heteroaralkyl refer to groups which, according to the above definitions, contain both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups , Examples are arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heteroarylheteroalkyl, heteroarylheteroalkenyl, heteroarylheteroalkynyl, arylcycloalkyl, heteroaryocycloalkyl, heteroaryocycloalkyl, heteroaryoaryocycloalkyl, heteroaryoaryocycloalkyl, heteroaryoaryocycloalkylo - alkenyl, heteroarylcycloalkenyl, arylcycloal
  • Compounds of formula (I) may contain one or more centers of chirality due to their substitution.
  • the present invention therefore encompasses all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.
  • R 4 is particularly preferably a group of the formula -COOMe.
  • R 4 is more preferably a 4-pyridyl group.
  • n 0, 1 or 2 (preferably 0 or 1; particularly preferably 0).
  • Examples of pharmacologically acceptable salts of the compounds of the formula (I) are salts of physiologically acceptable mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid; or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid; or salts of alkali or alkaline earth metal salts such as e.g. B. sodium, potassium, lithium, calcium or magnesium salts, ammonium salts; or salts of organic bases such as e.g. B.
  • Compounds of formula (I) can be solvated, in particular hydrated. The hydration can occur during the manufacturing process or as a result of the hygroscopic nature of the initially anhydrous compounds of formula (I). If the compounds of the formula (I) contain asymmetric C atoms, they can be present either as achiral compounds, diastereomer mixtures, mixtures of enantiomers or as optically pure compounds.
  • a compound or a pharmacological composition of the present invention can be used to inhibit serine proteases (especially tryptase and uPA) and to treat and / or prevent diseases mediated by serine protease activity (especially tryptase and uPA activity).
  • serine proteases especially tryptase and uPA
  • diseases mediated by serine protease activity especially tryptase and uPA activity
  • INS special are the described compounds for the treatment of allergic or inflammatory diseases and especially for the treatment of asthma, allergic rhinitis, chronic obstructive pulmonary diseases, emphysema, viral and bacterial lung infections and inflammatory reactions, rheumatoid arthritis, multiple sclerosis, osteoarthritis, dermatological diseases, ulcerative colitis , Conjunctivitis, interstitial cystitis, mastocytosis, psoriasis, conjunctivitis, inflammatory bowel diseases, peptide ulcers, cardiovascular diseases and anaphylaxis of interest. Furthermore, the compounds described here can be used for tumor diseases (both local tumors and tumors in the advanced stage), metastasis formation and cancer.
  • compositions according to the present invention contain at least one compound of formula (I) or a pro-drug thereof as
  • Active ingredient and optional carriers and / or adjuvants are optional carriers and / or adjuvants.
  • the pro-drugs which are also the subject of the present invention, consist of a compound of the formula (I) and at least one pharmacologically acceptable protective group which is eliminated under physiological conditions, for example an alkoxy, aralkyloxy, acyl or acyloxy group such as an ethoxy, benzyloxy, acetyl or acetyloxy group.
  • A is preferred Hydrogen atom of the amidine replaced by a hydroxy group or alkoxy group.
  • the present invention also relates to the use of these active ingredients for the production of medicaments for the prevention and / or treatment of thromboembolytic diseases.
  • compounds of formula (I) are administered using the known and acceptable modes, either individually or in combination with any other therapeutic agent.
  • Such therapeutically useful agents can be administered in one of the following ways: orally, for example as dragées, coated tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenterally, for example as an injectable solution; rectally as suppositories; by inhalation, for example as a powder formulation or spray, transdermally or intranasally.
  • the therapeutically usable product can be mixed with pharmacologically inert, inorganic or organic drug carrier substances, for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or Derivatives thereof, talc, stearic acid or its salts, dry skimmed milk and the like.
  • pharmacologically inert, inorganic or organic drug carrier substances for example with lactose, sucrose, glucose, gelatin, malt, silica gel, starch or Derivatives thereof, talc, stearic acid or its salts, dry skimmed milk and the like.
  • pharmaceutical carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat, polyols can be used.
  • drug carriers such as water, alcohols, aqueous salt solution, aqueous dextrose, polyols, glycerin, vegetable oils, petroleum, animal or synthetic oils
  • pharmaceutical carriers such as vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols
  • Compressed gases suitable for this purpose such as oxygen, nitrogen and carbon dioxide, can be used for aerosol formulations.
  • the pharmaceutically usable agents can also contain additives for preservation, stabilization, emulsifiers, sweeteners, flavorings, salts for changing the osmotic pressure, buffers, coating additives and antioxidants.
  • the dose of the biologically active compound according to the invention can vary within wide limits and can be adjusted to individual needs. In general, a dose of 0.1 ⁇ g to 10 mg / kg body weight per day is suitable, with a preferred dose being 0.5 to 4 mg / kg per day. In suitable cases, the dose can also be below or above the values given above.
  • (I) can e.g. B. by implementing compounds of Formulas (II) (U. Schöllkopf et al. Liebigs Ann. Chem. 1979, 1444-1446), (III) and (IV) can be produced.
  • the reaction is preferably carried out in an alcohol such as. B. ethanol, methanol, isopropanol, butanol or benzyl alcohol (preferably methanol) as a solvent.
  • an alcohol such as. B. ethanol, methanol, isopropanol, butanol or benzyl alcohol (preferably methanol) as a solvent.
  • reaction in the presence of a Lewis acid such as. B. boron trifluoride etherate, p-toluenesulfonic acid, ytterbium triflate or indium trichloride.
  • a Lewis acid such as. B. boron trifluoride etherate, p-toluenesulfonic acid, ytterbium triflate or indium trichloride.
  • reaction is preferably carried out at a temperature of -80 ° C to 100 ° C (again preferably a temperature of -10 ° C to 50 ° C; particularly preferably at room temperature).
  • Assay to determine inhibition of uPA uPA (high molecular weight, Calbiochem. No. 672081) was carried out for 10 min in a buffer (0.1 M Hepes, 0.14 M NaCl, 0.1% PEG 6000, 0.05% Tween 80, pH 7.8) with various Concentrations of the inhibitor (0.001-1000 ⁇ M) incubated. Subsequently, substrate (Bachern 1-1140) was added. The final concentration of enzyme was 3 nM, the final concentration of substrate 150 ⁇ M. The fluorescence was monitored continuously for 20 min using a Tecan SpectraFluorPlus microtiter plate reader (Tecan, Crailsheim) (ex: 360nm / era: 465nm).
  • the enzyme assays were carried out at room temperature in 96 or 384-well microtiter plates.
  • the IC 50 values were calculated using the "GraFit 4" program from Erithacus Software Ltd. (Staines, Middlesex, UK).
  • Catalyst are dissolved in 3 ml of methanol and
  • the following compounds were prepared according to the general synthetic procedure.
  • the products were characterized by mass spectroscopy.
  • the tested compounds showed IC 50 values between 0.1 and 10 ⁇ M in the tryptase assay described above and between 1 and 50 ⁇ M in the uPA assay IC 50 values.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne les composés de formule (I) ou un sel, un solvate, un hydrate ou une formulation pharmaceutiquement acceptable de ces composés. Les composés selon l'invention peuvent servir à l'inhibition de sérine protéases, notamment de tryptases et uPA, et à la prévention et/ou au traitement de maladies associées à l'activité de tryptases ou uPA.
PCT/EP2002/012697 2001-11-13 2002-11-13 Inhibiteurs de serine protease WO2003042187A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10155727A DE10155727A1 (de) 2001-11-13 2001-11-13 Serin Protease Inhibitoren
DE10155727.2 2001-11-13

Publications (1)

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WO2003042187A1 true WO2003042187A1 (fr) 2003-05-22

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999037304A1 (fr) * 1998-01-27 1999-07-29 Aventis Pharmaceuticals Products Inc. COMPOSES OXOAZAHETEROCYCLYLE SUBSTITUES INHIBITEURS DU FACTEUR Xa
WO1999051605A1 (fr) * 1998-03-31 1999-10-14 Shionogi & Co., Ltd. DERIVE DE PYRROLO[1,2-a]PYRAZINE INHIBANT sPLA¿2?
WO2001007419A1 (fr) * 1999-07-26 2001-02-01 Santen Pharmaceutical Co., Ltd. Nouveaux dérivés de la thiazine ou de la pyrazine
WO2001014320A1 (fr) * 1999-08-23 2001-03-01 Morphochem Ag Composes inhibiteurs de l'action de la tryptase
WO2001066541A1 (fr) * 2000-03-08 2001-09-13 Takeda Chemical Industries, Ltd. Procede de preparation de derives d'hydrazine
EP1217000A1 (fr) * 2000-12-23 2002-06-26 Aventis Pharma Deutschland GmbH Inhibiteurs du factor Xa et factor VIIa

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999037304A1 (fr) * 1998-01-27 1999-07-29 Aventis Pharmaceuticals Products Inc. COMPOSES OXOAZAHETEROCYCLYLE SUBSTITUES INHIBITEURS DU FACTEUR Xa
WO1999051605A1 (fr) * 1998-03-31 1999-10-14 Shionogi & Co., Ltd. DERIVE DE PYRROLO[1,2-a]PYRAZINE INHIBANT sPLA¿2?
WO2001007419A1 (fr) * 1999-07-26 2001-02-01 Santen Pharmaceutical Co., Ltd. Nouveaux dérivés de la thiazine ou de la pyrazine
EP1211249A1 (fr) * 1999-07-26 2002-06-05 Santen Pharmaceutical Co., Ltd. Nouveaux derives de la thiazine ou de la pyrazine
WO2001014320A1 (fr) * 1999-08-23 2001-03-01 Morphochem Ag Composes inhibiteurs de l'action de la tryptase
WO2001066541A1 (fr) * 2000-03-08 2001-09-13 Takeda Chemical Industries, Ltd. Procede de preparation de derives d'hydrazine
EP1217000A1 (fr) * 2000-12-23 2002-06-26 Aventis Pharma Deutschland GmbH Inhibiteurs du factor Xa et factor VIIa

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CROSSFIRE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002232081, Database accession no. 8319621 (BRN) *
DIMAIO J, BELLEAU B: "Synthesis of Chiral Piperazin-2-ones as Model Peptidomimetics", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY. LETCHWORTH, GB, no. 9, 1989, pages 1687 - 1689, XP009005768, ISSN: 0300-922X *
MILLER J F ET AL: "Formation and Isolation of Simple, Stable, Acyclic Di- and Tripeptide Hemiacetals", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 37, no. 15, 8 April 1996 (1996-04-08), pages 2521 - 2524, XP004029726, ISSN: 0040-4039 *

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