WO2000009542A1 - INHIBITEURS DE SERINE PROTEASE CONTENANT DES α-CETO HETEROCYCLES - Google Patents

INHIBITEURS DE SERINE PROTEASE CONTENANT DES α-CETO HETEROCYCLES Download PDF

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WO2000009542A1
WO2000009542A1 PCT/US1998/017449 US9817449W WO0009542A1 WO 2000009542 A1 WO2000009542 A1 WO 2000009542A1 US 9817449 W US9817449 W US 9817449W WO 0009542 A1 WO0009542 A1 WO 0009542A1
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alkyl
optionally substituted
aryl
alkenyl
arg
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PCT/US1998/017449
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English (en)
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Albert C. Gyorkos
Lyle W. Spruce
Axel H. Leimer
John C. Cheronis
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Cortech, Inc.
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Priority to KR1020017002011A priority Critical patent/KR20010106444A/ko
Priority to PCT/US1998/017449 priority patent/WO2000009542A1/fr
Priority to JP2000564992A priority patent/JP2003505008A/ja
Priority to EP98942211A priority patent/EP1105412A1/fr
Priority to AU90315/98A priority patent/AU9031598A/en
Publication of WO2000009542A1 publication Critical patent/WO2000009542A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • serine proteases are a class of enzymes which includes elastase, proteinase 3, chymotrypsin, cathepsin G, trypsin, thrombin, prolyl oligopeptidase and others.
  • elastase proteinase 3
  • chymotrypsin cathepsin G
  • trypsin trypsin
  • thrombin prolyl oligopeptidase and others.
  • a breakdown in the balance of protease/antiprotease activity has been implicated in the pathogenesis of numerous disease states.
  • proteases For example, it is known that many human malignancies are associated with enhanced expression of proteases (Opdenakker et al., Cytokine, 4:251-258 (1992)). These proteases may be involved in growth, chemotaxis, endocytosis, exocytosis, blood coagulation, fibrinolysis and tissue invasion during metastasis of malignant cells (Eisenbrand, Synthesis, 1246-1252 (1996); Kazama, J.B.C. 270:66-72 (1995)). Specifically, plasmin, urokinase- plasminogen activator (uPA) and tissue plasminogen activator (tPA) and a tumor-associated trypsin show a substantial increase in activity in many malignancies.
  • uPA urokinase- plasminogen activator
  • tPA tissue plasminogen activator
  • Tumor-associated trypsin has been shown to participate in cancer cell-mediated degradation of extracellular matrix (Koivunen et al., Cancer Research, 51:2107-2112 (1991)) and has been implicated in tumor invasion.
  • Human urinary trypsin inhibitors have been shown to prevent both the intravasation and extravasation step of tumor metastasis (Int. J. Cancer, 63:455-462 (1995)).
  • Urokinase-plasminogen activator and tPA have also been shown to be important in tumor metastasis (Dowell, et al., Cancer Treatment Reviews, 19:283-296 (1993)).
  • a guanidinobenzoatase has been implicated in cancer metastasis, cell migration and tissue remodeling (Poustis-Delpont C. et al., J.B.C, 269:14666-71 (1994); Stevens et al., Br. J. Cancer, 46:934-939 (1982); Ohkoshi et al., J. Max. Fac. Surg., 12:148- 152 (1984); Poustis-Delpont et al., Cancer Research, 52:3622-3628 (1992); Stevens, Biol.
  • Increased plasmin activity has been directly correlated to increased plasminogen activator activity (Eisenbrand, Synthesis, 1246-1252 (1996)).
  • Compounds capable of inhibiting plasmin, tumor-associated rypsin, guanidinobenzoatase or plasminogen activator represent potential drug candidates for the treatment of the various human malignancies.
  • Hepsin a membrane associated serine protease
  • hum.an factor Nil has been shown to activate hum.an factor Nil and to initiate a pathway of blood coagulation on the cell surface leading to thrombin formation
  • neoplastic cells activate the blood coagulation system, causing hypercoagulability and intravascular thrombosis via this and other pathways and that hepsin plays a role in their cell growth, maintenance and morphology (Torres-Rosada et al., Proc. Natl. Acad. Sci. USA, 90:7181-7185 (1993)).
  • Hepsin is present at elevated levels in regions of active cell proliferation in animal models and anti-hepsin antibody has been shown to suppress the growth of human hepatoma cells in culture. Hepsin is also suspected to be a physiological inactivator of the tumor suppressor protein maspin.
  • Chymase is believed to be responsible for angiotensin I converting enzyme (ACE) independent activation of angiotensin II in the heart (Urata, et al., J.B. C, 265 :2963-2968
  • Pulmonary hypertension is commonly associated with congenital heart defects, pulmonary diseases associated with chronic hypoxia, hepatic disorders and connective tissue disease. Increased pulmonary artery elastolytic activity associated with the monocrotaline-induced pulmonary hypertension model has been shown to be moderated by treatment with an elastase inhibitor (Ye, et al., Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H1255-H1267 (1991); Cowan et al., J.
  • ENE has been shown to be sensitive to leukocyte elastase (LE) inhibitors, it is believed that it is a novel enzyme distinct from LE.
  • Inhibitors of ENE may be useful in treating pulmonary vascular disease in infants, restenosis secondary to angioplasty, pulmonary hypertension myocarditis, bronchopulmonary dysplasia, myocardial necrosis after cardiac transplant, post-cardiac tr.ansplant coronary arteriopathy, atherosclerosis and reperfusion injury following myocardial infarct.
  • Prolyl oligopeptidase degrades oxytocin, neurotensin, substance P, thyrotropin releasing hormone, bradykinin, angiotensin II and vasopressin (U.S. patent 5,506,256; Tsutsumi, et al., J. Med. Chem., 37:3492-3502 (1994)). It is also believed to degrade amyloid precursor protein, and therefore is suspected to play a role in Alzheimer's disease.
  • aprotinin inhibits plasmin and several kallikreins. It is also used prophylactically to reduce perioperative blood loss and to reduce the need for blood transfusions, mainly in patients undergoing coronary artery bypass graft surgery.
  • aprotinin Although aprotinin is generally well tolerated, its main adverse side effects include increased incidence of postoperative renal dysfunction and allergic reactions, in some cases leading to anaphylaxis, which has in some cases been fatal. Patients who have had prior exposure to aprotinin are at higher risk for anaphylaxis. These two main adverse effects are both due to the properties of aprotinin as a protein, problems which may be overcome with a small, low molecular weight, synthetic drug with a similar inhibition profile as aprotinin. Additionally, new synthetic drugs would eliminate the need for extracting aprotinin from bovine lung or for its combinatorial expression.
  • the present invention provides methods of inhibiting the enzymatic activity of serine proteases comprising contacting such protease or proteases with an inhibitory amount of a compound of formula (I):
  • Rj is alkyl or alkenyl optionally substituted with 1-3 halo or hydroxy; alkylamino, dialkylamino, alkyldialkylamino; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, (C 5 - C 12 )aryl, (C 5 -C 12 )arylalkyl or (C 5 -C 12 )arylalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro, hydroxy, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C 5 -C 6 )aryl, -O-(C 5 -C 6 )aryl, arylcar
  • Ri is methyl, dimethylamino, phenyl or benzyl optionally substituted with methyl, halo, methylenedioxy, methoxy, dimethoxy, trimethoxy, trifluoromethyl and dimethylamino.
  • X is O and Y is N; X is N and Y is O; or both X and Y are N.
  • Z is of the formula (II):
  • AA,, AA 2 , AA 3 , AA 4 and AA 5 are independently an amino acid residue or amino acid residue mimetic; a direct bond or absent;
  • R 4 and R 4 ' are independently -C(O)R 5 , -C(O)NHR 5 , -S(O) 2 R 5 , -C(O)OR 5 , -C(O)-(C 5 - C 6 )aryl-C(O)-R 5 , -CR 5 or R 5 , where R 5 is H, alkyl, alkenyl or alkynyl optionally substituted with halo, cyano, nitro, hydroxy, alkoxy, haloalkyl, amino, aminoalkyl, dialkylamino, haloalkoxy, carboxyl, carboalkoxy or alkylcarboxamide; cycloalkyl, alkylcycloalkyl, (C 5 -C 12 ) aryl or (C 5 -C, 2 )arylalkyl optionally comprising 1-4 heteroatoms selected from N, O and S, and optionally substituted with halo, cyano, nitro,
  • R 4 and R 4 ' form a ring comprising 5-7 atoms selected from C, N, S and O.
  • Z comprises a pentapeptidyl, tetrapeptidyl, tripeptidyl or dipeptidyl binding moiety.
  • the amino acids are selected from arginine or an arginine mimetic; proline; aspartic and glutamic acid and the aryl and alkyl esters thereof; alanine and glycine optionally substituted at the ⁇ -carbon or ⁇ -nitrogen with alkyl, cycloalkyl or aryl; leucine, isoleucine; cysteine optionally substituted at the sulfur atom with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydro-phenylalanine, indoline-2- carboxylic acid; tetra
  • X' is CR 2 ' or N
  • R 2 , R 2 ' and R 2 " are independently H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxy, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or - RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C 5 -C 6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl- oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C 5 -C 12 ) aryl, (C 5 -
  • AA 2 may be described by the formula (Illb):
  • R 3 , R' 3 and R" 3 are independently H; alkyl or alkenyl optionally substituted with 1-3 halo, hydroxy, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl or amidylguanidine; -RCOR', -RCOOR', -RNR'R"R° or - RC(O)NR'R" where R is alkyl or alkenyl, and R', R" and R° are independently H, alkyl, alkenyl, cycloalkyl or (C 5 -C 6 )aryl; or cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl- oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C 5 -C I2 ) aryl, (C 5 -
  • Rg, R 7 , R' 6 , R' 7 are independently H, alkyl, alkenyl, halo, alkoxy, carboxyl, carboalkoxy, amino, aminoalkyl, dialkylamino; cycloalkyl, (C 5 -C 6 ) aryl or (C 5 -C 6 ) arylalkyl optionally comprising 1-3 heteroatoms selected from N, O and S, and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, haloalkyl, hydroxy, amino, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, guanidine, alkylguanidine, dialkylguanidine, amidine, alkylamidine or dialkylamidine; and
  • U, V, W and Y' are independently or together N, C, C(O), N(R ⁇ ) where Ro is H, alkyl, halo, alkoxy, carboalkoxy, cycloalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or aryl, fused aryl or cycloalkyl optionally comprising 1 or more heteroatoms selected from O, S and N, and optionally substituted with halo or alkyl; N(R, 0 ) where R l0 is
  • AA 3 , AA 4 and AA 5 may be either a direct bond or absent; or, where an amino acid, preferably selected from arginine or an arginine mimetic; proline; aspartic and glutamic acid and the aryl and alkyl esters thereof; alanine or glycine optionally substituted at the ⁇ -carbon or ⁇ -mtrogen with alkyl, cycloalkyl or aryl; leucine, isoleucine; cysteine optionally substituted at the sulfur atom with alkyl, alkenyl or phenyl optionally substituted with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine
  • X' is N.
  • X" is N.
  • X' is CR' 2 and X" is CR' 3 , where R' 2 and R' 3 are H.
  • X' is CR' 2 and R 2 is alkyl or alkenyl substituted with guanidinyl, amino or amidylguanidine; benzyl optionally substituted with amidine; alkylpyridine, alkylamino pyridine; alkylimidazole or alkylaminoimidazole substituted with amino; or alkylcyclohexane, said hexane ring optionally comprising 1 or more nitrogen atoms and optionally substituted with 1 or more keto and/or amidine groups.
  • AA 2 is Gly.
  • target serine protease is plasmin, preferably AA, is Arg or Arg mimetic; Lys or Orn; and more preferably Lys.
  • Z is R 4 -Pro-Phe- AA,-.
  • serine protease is trypsin, preferably AA, is Arg or Lys.
  • the serine protease is plasma kallikrein, where preferably Z is R 4 - AA 3 -AA 2 -AA,.-; where AA ! is Arg, Arg mimetic or Lys; AA 2 is Phe, Met or Leu; and AA 3 is Pro.
  • the serine protease is tissue kallikrein, and preferably Z is R 4 - AA 4 -AA 3 -AA 2 -AA,-; where AA, is Arg or Arg mimetic; AA 2 is Leu or Phe; AA 3 is Arg, Arg mimetic or Pro; and AA 4 is Thr.
  • the methods of the present invention may also be used to inhibit the protease guanidinobenzoatase, where preferably AA, is Arg or Arg mimetic; or a guanidinobenzoyl containing moiety.
  • the methods may be used to inhibit chymase, where preferably Z is R 4 - where AA, is Tyr, Phe, Trp or Leu.
  • AA 2 is Pro
  • AA 3 is His
  • AA 4 is He
  • AA 5 is Tyr.
  • AA 2 is a mimetic of formulas IN to XXIN.
  • serine protease is mast cell tryptase, preferably Z is R 4 -AA 3 -AA 2 -AAi-; where AA, is Arg or Arg mimetic; AA 2 is Gly, Nal, Arg, Arg mimetic, Leu or Phe; and AA 3 is Leu, Arg, Arg mimetic, Lys, Ser or Phe.
  • the serine protease is prolyl oligopeptidase, preferably AA, is Pro.
  • the methods may be used to inhibit viral serine proteases such as hepatitis C virus ⁇ S3 polyprotein endopeptidase, where Z is preferably R 4 -AA 4 -AA 3 -AA 2 -AA,-; where AA, is Cys; AA 2 is Cys or Ala; AA 3 is Nal; and AA 4 is Nal.
  • viral serine proteases such as hepatitis C virus ⁇ S3 polyprotein endopeptidase, where Z is preferably R 4 -AA 4 -AA 3 -AA 2 -AA,-; where AA, is Cys; AA 2 is Cys or Ala; AA 3 is Nal; and AA 4 is Nal.
  • serine protease is human cytomegalovirus protease
  • Z is R 4 - AA 4 -AA 3 -AA 2 -AA,-; where AA, is Ala; AA 2 is Asn, Asp, Gin, Glu or Lys, or selected from their derivatives or esters; AA 3 is Val, He or Leu; and AA 4 is Nal.
  • the methods may also be used to inhibit assemblins, where preferably Z is R 4 -AA 4 - AA 3 -AA 2 -AA,-; where AA, is Ala; AA 3 is Leu, Nal or lie; and AA 4 is Tyr; and preferably AA 2 is Gin or Lys, or their derivatives.
  • AA is R 4 -AA 4 -AA 3 -
  • AA,- where AA, is Arg, Arg mimetic or Lys; AA 2 is Arg or Arg mimetic, Lys or a derivative thereof, or Gly; and AA 3 is Ser; and preferably AA 4 is Gly.
  • Z is preferably R 4 -AA 3 -AA 2 - AA,- where AA, Arg, Arg mimetic or Lys; AA 2 is Arg or Arg mimetic, Lys or a derivative thereof, Gly or Ala; and AA 3 is Arg or Arg mimetic.
  • the methods may also be used to inhibit Schistosoma serine proteases.
  • the present invention further provides the following novel inhibitors: ⁇ -[ ⁇ -(4-phenyl-l-ketobutane)-(L)-prolyl]-2-(S)-[(3-(3-phenylpropane)-l,2,4- oxadiazolyl)-ketomethane]-pyrrolidine (CQ-0006);
  • the compounds described herein may also be used as research and diagnostic tools, as coatings adsorbed or covalently attached to the surfaces of medical equipment and instruments such as bypass pumps, catheters and tubing, and as preservatives of transplantation tissues and organs.
  • the term "serine protease binding moiety” means a chemical group capable of binding to the substrate binding site of a serine protease, typically defined in the literature as the S,-S n site. The term includes both peptides and peptide mimetics.
  • the binding moiety is selected such that when linked to the keto-heterocycle, the moiety provides the resulting compound with inhibitory activity against the target serine protease of less than 100 ⁇ M (I , value); and more preferably of less than 10 ⁇ M.
  • the term “optionally substituted” means, when substituted, mono to fully substituted.
  • alkyl means C,-C 15 , however, preferably C,-C 7 .
  • alkenyl means C,-C, 5 , however, preferably C,-C 7 .
  • alkynyl means C,-C, 5 , however, preferably C,-C 7 . It will be understood that alkyl, alkenyl and alkynyl groups, whether substituted or unsubstituted, may be linear or branched.
  • aryl means aryl groups preferably comprising 5 to 12 carbons, and more preferably 5 to 6 carbons. Unless otherwise indicated, the term aryl includes mono-and bi-cyclic, as well as fused ring systems, including aryl- cylcoalkyl ring systems. As used herein, the term “arylalkyl” includes mono-substituted alkyl groups (e.g., benzyl), as well as di-substituted alkyl groups such as -alkyl(phenyl) 2 (e.g., -CH(phenyl) 2 ).
  • arylalkyl or “arylalkenyl” is defined by the general formula (C x -C y )arylalkyl or (C x -C y )arylalkenyl
  • x and y refer to the number of carbons making up the aryl group.
  • the alkyl group is as defined above.
  • Peptidyl inhibitors of elastase comprising elastase binding moieties and certain keto- heterocycles have been previously described in the parent and grandparent applications of the present application (see also, WO 96/16080, incorporated herein). It has been surprisingly found that compounds comprising these keto-heterocycles are highly potent and specific inhibitors of a wide variety of other serine proteases as well.
  • the inhibiting activity can be directed against any serine protease by identifying the binding moiety specific for that protease.
  • the characteristics for the P, . . . P n residues using substrate nomenclature by
  • inhibitors may be designed based on the aprotinin binding profile, where the binding moieties may comprise Pro-Phe in the P3-P2 positions, and Arg or an Arg mimetic, Lys or Orn in the PI position.
  • Lys is preferred over Arg or its mimetic in the PI position.
  • Such inhibitors may be used to treat coagulation disorders.
  • Arg or an Arg mimetic is again preferred over Lys in the PI position.
  • Such inhibitors may be effective in treating, for example, pancreatitis.
  • Substrates of plasma kallikrein which acts on kininogen to release kallidin and activates Factor XII, typically have Arg or Lys in the PI position, although Arg is again preferred; bulky residues are preferred for P2, such as Phe, Met or Leu; and Pro is tolerated in P3 (Hibino et al., J Invest. Dermatol. 90:505-510 (1988); Page et al., J.B.C 266:8142-8148 (1991)).
  • Tissue kallikrein prefers Arg in PI; whereas bulky or negative residues are preferred in P2, such as Leu and Phe; Arg or Pro (with Arg preferred) in P3; and Thr in P4 (Hibino et al, J Invest. Dermatol. 90:505-510 (1988); Page et al, J.B.C 266:8142-8148 (1991)).
  • Guanidinobenzoatases prefer Arg, Arg mimetics or guanidinobenzoyl containing moieties in the PI. Such inhibitors may be used, for example, to inhibit cancer cell growth.
  • Thrombin which hydrolyzes fibrinogen to form fibrin and release fibrinopeptides, prefers Arg in PI and Gly in P2.
  • Inhibitors may be used, for example, to treat coagulopathies.
  • Inhibitors of chymase may be used, for example, to treat hypertension as well as progressing myocardial deterioration.
  • Mast cell tryptase which acts on vasoactive octaicosapeptide, fibrinogen and fibronectin and other substrates, prefers Arg in PI; Gly in P2, although Nal, Arg, Leu and Phe are also accepted; and Leu or Arg in P3, while Lys, Ser and Phe are also acceptable.
  • Inhibitors may be used to treat asthma, allergies, arthritis, cutaneous mastocytosis and psoriasis (Tanaka et al., J.B.C, 258:13552-13557 (1983); Caughey, Am. J. Respir. Crit. Care Med. 150:S138-S142 (1994)).
  • Prolyl oligopeptidase prefers Pro in PI (Yoshimoto et al., J.B.C, 255:4786-4792 (1980); Tsutsumi et. al, J. Med. Chem., 37:3492-3502 (1994); U.S. patent 5,506,256).
  • Inhibitors may be used, for example, to treat Alzheimer's disease.
  • Hepatitis C virus ⁇ S3 polyprotein endopeptidase is specific for Cys in PI; prefers Cys over Ala in P2; and Nal in P3 and P4 (Steinkuehler et al., J. Virology, 70:6694-6700 (1996)). Inhibitors may be used to treat hepatitis C infections.
  • Human cytomegalovirus protease which is responsible for production of mature virions and processing of viral assembly protein precursors, prefers small residues in PI, such as Ala; Asn, Asp, Gin, Glu or Lys in P2; Nal, He or Leu in P3; and Val in P4 (Chen et al., Cell, 86:835-843 (1996); Tong, et al., Nature, 383:272-275 (1996)).
  • Assemblins (HSNI protease and HSNII protease) or Herpesvirus assemblin prefer Ala in PI ; are flexible with respect to P2, although Gin or Lys are preferred; Leu is preferred over Nal and He in P3; and Tyr in P4.
  • Inhibitors may be used to treat Herpes virus infections. In the case of u-plasminogen activator, which hydrolyzes plasminogen to form plasmin primarily in migrating cells, Arg is preferred over Lys in PI; Gly in P2; Ser in P3; and Gly may be preferred in P4. Inhibitors may be used to inhibit cancer invasion and metastasis, and to treat stroke (Lindgren, Stroke, 27:1066-1071 (1996); Opdenakker et al., Cytokine, 4:251-258 (1992)).
  • Arg is preferred in PI, although Lys may be tolerated; Gly is preferred over Ala in P2; while Arg is required in P3 for uPA vs. tPA specificity.
  • Indications include angiogenesis and neovascularization in cancer, and stroke (Lindgren, Stroke, 27:1066-1071 (1996); Opdenakker, et al., Cytokine, 4:251-258 (1992); Coombs, J.B.C,
  • the substituent on the heterocycle can be varied to further increase the specificity of these compounds toward the desired serine protease.
  • substituents include methyl, dimethylamino; phenyl or benzyl optionally substituted with methyl, halo, methylenedioxy, methoxy, dimethoxy, trimethoxy, trifiuoromethyl and dimethylamino.
  • the heterocycle's heteroatoms can be varied to enhance the activity of the compound.
  • the heterocycle is a 1,2,4-oxadiazole, 1,3,4-oxadiazole or a 1,2,4-triazole.
  • an alternative method may be used where suitably protected peptides are converted by the action of an activating coupling reagent such as BOP-C1 or HBTU to a Weinreb amide.
  • an activating coupling reagent such as BOP-C1 or HBTU
  • the Weinreb amide is then reacted with a 5-substituted 2-lithio- 1,3,4-oxadiazole at appropriate temperatures ranging from -78 °C to -25 °C in a suitable solvent such as THF or ether to provide the desired keto-oxadiazoles in a single step.
  • a suitable solvent such as THF or ether
  • AA combi means AA 2 . . . AA 5 .
  • the compounds described herein are useful in inhibiting the activity of serine proteases, by contacting the compound with the targeted protease, either in an in vivo or an in vitro environment.
  • the term "contacting” means directly or indirectly causing the inhibitor and the protease to come into physical association with each other. Contacting thus includes physical acts such as placing the inhibitor and protease together in a container, or administering the inhibitors to a patient.
  • administering a compound of the invention to a human patient evidencing a disease or disorder associated with abnormal and/or aberrant activity of such proteases in a method for inhibiting the enzymatic activity of such proteases which are associated with disease or disorder falls within the scope of the definition of the term "contacting.”
  • Pharmaceutically acceptable salts of serine protease inhibitors described herein may also be used in practicing the methods of the present invention.
  • pharmaceutically acceptable salts as used herein includes organic and inorganic acid addition salts such as chloride, acetate, maleate, fumarate, tartrate and citrate.
  • Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt or potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt and zinc salt.
  • Examples of pharmaceutically acceptable ammonium salts are ammonium salt, trishydroxymethylaminomethane and tetramethylammonium salt.
  • Examples of pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine and phenylalanine.
  • the compounds described herein and/or their salts may be administered as the pure chemicals, it is preferable to present the active ingredient as a pharmaceutical composition.
  • the invention thus further provides the use of a pharmaceutical composition comprising one or more compounds and/or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and or prophylactic ingredients.
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, topical or parenteral (including intramuscular, subcutaneous and intravenous) administration.
  • the compositions may, where appropriate, be conveniently presented in discrete unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with liquid carriers, solid matrices, semi-solid carriers, finely divided solid carriers or combination thereof, and then, if necessary, shaping the product into the desired delivery system.
  • compositions suitable for oral administration may be presented as discrete unit dosage forms such as hard or soft gelatin capsules, capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or as granules; as a solution, a suspension or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art., e.g., with enteric coatings.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservative.
  • the compounds may also be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and may be presented in unit dose form in ampules, pre-filled syringes, small bolus infusion containers or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • the compounds may be formulated as ointments, creams or lotions, or as the active ingredient of a transdermal patch.
  • Suitable transdermal delivery systems are disclosed, for example, in Fisher et al. (U.S. Patent No. 4,788,603) or Bawas et al. (U.S. Patent No. 4,931,279, 4668,504 and 4,713,224).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • the active ingredient can also be delivered via iontophoresis, e.g., as disclosed in U.S. Patent Nos. 4,140,122, 4,383,529, or 4,051,842.
  • compositions suitable for topical administration in the mouth include unit dosage forms such as lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • unit dosage forms such as lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; mucoadherent gels, and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the above-described compositions can be adapted to provide sustained release of the active ingredient employed, e.g., by combination thereof with certain hydrophilic polymer matrices, e.g., comprising natural gels, synthetic
  • compositions may also be administered via inhalation, using a suitable delivery vehicle.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg/day, e.g., from about 1 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently administered in unit dosage form; for example, containing 0.5 to 1000 mg, conveniently 5 to 750 mg, most conveniently, 10 to 500 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 ⁇ M, more preferably, about 1 to 50 ⁇ M, most preferably, about 2 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 0.5-500 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/Tir or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the inhibitors described herein may be also used for the detection and quantification of the activity of a serine protease in a pure sample, mixture or biological fluid or tissue.
  • the activity can be measured with a protease substrate in the absence and presence of a known concentration of the inhibitor.
  • Specific inhibitors can also be used to confirm that the observed activity is due to a particular protease.
  • the inhibitors described herein may also be used to identify and purify serine proteases.
  • the inhibitors can be covalently linked to a solid support, such as an affinity column or beads used in batch methods, and used to purify a protease or enrich a mixture containing the protease.
  • the inhibitor may be linked to the solid support or bead either directly, via a linker of variable length such that linkage does not interfere with the binding properties (see, e.g., Thornberry, N., Methods in Enz., 244:615-31 (1994)).
  • the inhibitor may be covalently linked to biotin and arrayed on a solid support via avidin/biotin interaction.
  • the present invention further provides a method of reducing perioperative blood loss by introducing an inhibitor into a patient directly, or by pretreating, coating or priming medical equipment and devices such as bypass pumps, tubes and catheters, with a suitable liquid composition, or whole blood, comprising one or more inhibitors described herein.
  • a suitable liquid composition or whole blood, comprising one or more inhibitors described herein.
  • Such compositions may also be used to preserve tissues and organs used in transplantation.
  • N-benzyloxycarbonyl-2-(S)-(2-acetoxyethanamide oxime)-pyrrolidine hydrochloride (12.0 g, 0.032 mol) was dissolved in a mixture of toluene (60 ml) and chloroform (35 ml). This mixture was then cooled to 0°C and triethylamine (6.8 ml, 0.049 mol) was added. After
  • N-Benzyloxycarbonyl-2-(S)-[acetoxy-(3-(3-phenylpropane)-l, 2, 4-oxadiazolyl)- methanej-pyrrolidine In toluene ( 100 ml) was placed N-Benzyloxycarbonyl-2-(S)-[N-(4-phenyl- 1 -keto- butane)-2-acetoxyethanamide oxime]-pyrrolidine (3.91 g). This mixture was then refluxed for 90 hrs.
  • N-Benzyloxycarbonyl-2-(S)-[hydroxy-(3-(3-phenylpropane)-l,2,4-oxadiazolyl)- methanef-pyrrolidine In methanol (100 ml) was placed N-Benzyloxycarbonyl-2-(S)-[acetoxy-(3-(3- phenylpropane)-l,2,4-oxadiazolyl)-methane]-pyrrolidine (2.86 g, 6.0 mmol). To this was added potassium carbonate (2.0 g, 14.5 mmol) in water (20 ml). This was then stirred at room temperature for 1 hr.
  • reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (2 x 100 ml).
  • the organic layer was dried (anhydrous magnesium sulfate) and the solvent evaporated to yield the product (2.36 g, 94.0%) as a pale yellow oil. This was then used without further purification.
  • the ether was extracted with 2N hydrochloric acid and the aqueous layer was washed with ether. The aqueous layer was then neutralized with sodium bicarbonate and then extracted with ether. The organic layer was then dried (anhydrous magnesium sulfate) and evaporated to yield the product (0.46 g, 29.3%) as a yellow oil. This was then used without further purification.
  • N-chlorosuccinimide (0.25 g, 1.89 mmol) was placed in dry toluene (10 ml) and this was cooled to 0°C. Then dimethylsulfide (0.20 ml, 2.69 mmol) was added and allowed to stir for 30 min. at 0°C.
  • Example II Synthesis of Acetyl-L-leucyl-N-[l-[2-[(5-phenyl)-l,3,4-oxadiazolyl]carbonyl]- 4-(guanidino)-butyl]-L-leucyl]amide) (CQ-0002).
  • 2-Phenyl-1, 3, 4-oxadiazole intermediate Benzoyl hydrazide (200 mg) freshly crystallized from chloroform was suspended in 5 mL of triethyl orthoformate and heated at reflux under nitrogen in a 160 °C oil bath for 3 hours. The mixture was cooled to room temperature, chilled in ice, and treated with 50 mL water and 10 mL 10% KHSO 4 solution.
  • Acetyl-L-leucyl-L-leucyl-arginine(Mtr) (N-methyl)-(N-Methoxy) -amide Acetyl- Leu-Leu-OH (133 mg) and arginine (Mtr) -N-methyl-N-methoxy amide (200 mg) were dissolved in 10 mL of DMF and were treated with 243 uL of DIEA nd 212 mg of HBTU. The reaction stirred at room temperature for 15 hours and was worked up according to method A. Drying over Na ⁇ O ⁇ rotary evaporation of the solvent and flash chromatography on silica gel (50% acetone in hexane) provided 270 mg of the title compound as a foam.
  • bovine pancreatic trypsin (Sigma) was prepared at a concentration of 0.2 mg/mL in 0.05 M acetate buffer (pH5.1) containing 0.1M NaCl, 10 mM CaCl 2 , 0.005% Triton X-100 (v/v).
  • the working stock of CQ-0002 was prepared in 0.1M HEPES buffer at pH 7.5, containing 0.1M NaCl, lOmM CaCl 2 , 0.005% Triton X-100 (v/v), 10% DMSO (v/v).
  • Proteinase 3 was stable due to the presence of Triton X- 100 during 4-6 hours on ice without any loss of activity.
  • 50 mM Boc-Ala-OPh ⁇ O 2 in DMSO was used as a substrate, final concentration was 0.625 mM.
  • Residual activity of the enzyme was determined after preincubation of the enzyme (6 ⁇ i) with different concentrations of inhibitors at 25 °C in 0.1 M HEPES buffer, containing 0.1 M NaCl, 10 mM CaCl 2 , 0.0005% Triton X-100 and 5% DMSO, pH 7.5. The release of nitrophenol was monitored at 410 nm. Results are presented in Table 1.
  • Each compound was diluted in 0.12M NaCl and added to lmL of 0.2mM tosyl-Gly- Pro-Lys-p-nitroanilide in 40mM HEPES, pH 7.4, at room temperature. Enzymatic reactions were initiated by addition of 30ng of purified human lung-derived tryptase that had been stabilized with 150ng of Dextran sulfate. Initial velocities were monitored spectrophotometrically at 410nm over a 1.5 min time sp.an. Percent inhibition was calculated as: [(vo - Vi) / v 0 ] x lOO.
  • Example VI Measurement of Inhibitory Activity against Prolyl Oligopeptidase
  • prolyl oligopeptidase flavobacterium
  • NHMec 9-NHMec 7-(4-methylcoumarylamide) were obtained from Sigma (St. Louis, MO).
  • the enzyme assay was performed as described elsewhere (Tadashi Yoshimoto et al., J. Biol. Chem., 255, 4786-4792, 1980), except that a Quanta Master QM1 (Photon Technologies International, South Brunswick, NJ) was used and S «K m .
  • the inhibitor was preincubated for 20 min at room temperature with the enzyme before starting the reaction by adding substrate. Four inhibitor concentrations were used to estimate the IC 50 value which approximates the Kj constant directly (Cheng, et al., Biochemical Pharmacology, 22:3099- 3108).
  • Buffers were prepared as follows: 0.1 M HEPES, 0.1M ⁇ aCl, lOnM CaCl 2 , 0.005%
  • Triton X-100 pH7.5 (assay buffer); 0.05M ⁇ aCH 3 CO 2 , 0.1M NaCl, lOmM CaCl 2 , pH 5.1
  • N-succinyl-Ala-Ala-Pro-Leu-pNA ( ⁇ -chym, PPE) was prepared as a 200mM stock in DMSO.
  • N-succinyl-Ala-Ala-Pro-Phe-pNA (Cat-G) was prepared as a 100 mM stock in DMSO.
  • the final substrate concentrations for the assays were 0.5mM, LOmM and 2.0mM for ⁇ -chym, Cat-G and PPE, respectively.
  • the enzyme ⁇ -chym was in a 2.0 mg/ml stock solution. An aliquot was diluted to
  • PPE 0.025 mg/ml in the enzyme dilution buffer.
  • PPE was a 2.0 mg/ml solution.
  • the material was diluted to 0.05 mg/ml in dilution buffer.
  • Cat-G (lmg) was prepared at a concentration of 2 mg/ml in dilution buffer as a stock. Aliquots of this were further diluted to 0.2 mg/ml.
  • the following reagents were applied to 1-ml cuvettes (Dynalab): 0.945 ml assay buffer; (40-x) ⁇ l DMSO (final concentration of DMSO was 5%); x ⁇ l diluted inhibitor (from lOmM stocks); and 10 ⁇ l substrate. The reaction was commenced with the addition of enzyme (5 ⁇ l).

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Abstract

La présente invention concerne un procédé d'inhibition de l'activité enzymatique d'une sérine protéase qui consiste à contacter une telle protéase avec une quantité inhibitrice d'un composé de formule (I), dans laquelle Z est un site de fixation d'une sérine protéase, et R1 est un groupe alkyle, alcényle, cycloalkyle ou aryle éventuellement substitué.
PCT/US1998/017449 1998-08-17 1998-08-17 INHIBITEURS DE SERINE PROTEASE CONTENANT DES α-CETO HETEROCYCLES WO2000009542A1 (fr)

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KR1020017002011A KR20010106444A (ko) 1998-08-17 1998-08-17 알파-케토 헤테로사이클을 포함하는 세린 프로테아제 억제제
PCT/US1998/017449 WO2000009542A1 (fr) 1998-08-17 1998-08-17 INHIBITEURS DE SERINE PROTEASE CONTENANT DES α-CETO HETEROCYCLES
JP2000564992A JP2003505008A (ja) 1998-08-17 1998-08-17 α−ケトヘテロ環類を含有するセリンプロテアーゼ阻害剤
EP98942211A EP1105412A1 (fr) 1998-08-17 1998-08-17 Inhibiteurs de serine protease contenant des alpha-ceto heterocycles
AU90315/98A AU9031598A (en) 1998-08-17 1998-08-17 Serine protease inhibitors comprising alpha-keto heterocycles

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004515464A (ja) * 2000-07-21 2004-05-27 シェリング・コーポレーション Ｃ型肝炎ウイルスのｎｓ３−セリンプロテアーゼ阻害剤としての新規イミダゾリジノン
WO2006044133A1 (fr) * 2004-09-24 2006-04-27 Axys Pharmaceuticals, Inc. Inhibiteurs de la tryptase, contenant de la cetone active
WO2006058720A2 (fr) 2003-11-03 2006-06-08 Probiodrug Ag Nouveaux composes pour le traitement de troubles neurologiques
WO2009007415A2 (fr) * 2007-07-10 2009-01-15 Probiodrug Ag Nouveaux composés
US9409895B2 (en) 2012-12-19 2016-08-09 Novartis Ag Autotaxin inhibitors
US9630945B2 (en) 2012-12-19 2017-04-25 Novartis Ag Autotaxin inhibitors
WO2020060964A1 (fr) * 2018-09-18 2020-03-26 Alxerion Biotech Corp. Dérivés de 1, 2, 4-oxadiazole et leurs utilisations
US11014935B2 (en) 2012-08-23 2021-05-25 Janssen Biopharma, Inc. Compounds for the treatment of paramyxovirus viral infections

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996016080A1 (fr) * 1994-11-21 1996-05-30 Cortech, Inc. Inhibiteurs d'elastase neutrophile humaine
WO1997031937A1 (fr) * 1996-03-01 1997-09-04 Akzo Nobel N.V. Inhibiteur de la serine-protease
WO1998024806A2 (fr) * 1996-12-06 1998-06-11 Cortech, Inc. Inhibiteurs de la serine protease

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996016080A1 (fr) * 1994-11-21 1996-05-30 Cortech, Inc. Inhibiteurs d'elastase neutrophile humaine
WO1997031937A1 (fr) * 1996-03-01 1997-09-04 Akzo Nobel N.V. Inhibiteur de la serine-protease
WO1998024806A2 (fr) * 1996-12-06 1998-06-11 Cortech, Inc. Inhibiteurs de la serine protease

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004515464A (ja) * 2000-07-21 2004-05-27 シェリング・コーポレーション Ｃ型肝炎ウイルスのｎｓ３−セリンプロテアーゼ阻害剤としての新規イミダゾリジノン
WO2006058720A2 (fr) 2003-11-03 2006-06-08 Probiodrug Ag Nouveaux composes pour le traitement de troubles neurologiques
WO2006044133A1 (fr) * 2004-09-24 2006-04-27 Axys Pharmaceuticals, Inc. Inhibiteurs de la tryptase, contenant de la cetone active
WO2009007415A2 (fr) * 2007-07-10 2009-01-15 Probiodrug Ag Nouveaux composés
WO2009007415A3 (fr) * 2007-07-10 2009-03-12 Probiodrug Ag Nouveaux composés
US11014935B2 (en) 2012-08-23 2021-05-25 Janssen Biopharma, Inc. Compounds for the treatment of paramyxovirus viral infections
US9409895B2 (en) 2012-12-19 2016-08-09 Novartis Ag Autotaxin inhibitors
US9630945B2 (en) 2012-12-19 2017-04-25 Novartis Ag Autotaxin inhibitors
WO2020060964A1 (fr) * 2018-09-18 2020-03-26 Alxerion Biotech Corp. Dérivés de 1, 2, 4-oxadiazole et leurs utilisations

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