WO2000029408A1 - Inhibiteurs de morpholino-ethoxybenzofuran protease - Google Patents

Inhibiteurs de morpholino-ethoxybenzofuran protease Download PDF

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Publication number
WO2000029408A1
WO2000029408A1 PCT/GB1999/003777 GB9903777W WO0029408A1 WO 2000029408 A1 WO2000029408 A1 WO 2000029408A1 GB 9903777 W GB9903777 W GB 9903777W WO 0029408 A1 WO0029408 A1 WO 0029408A1
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compound according
compound
compounds
formula
amino
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PCT/GB1999/003777
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English (en)
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Andrew D. Gribble
Jason Witherington
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Smithkline Beecham P.L.C.
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Priority to AU13939/00A priority Critical patent/AU1393900A/en
Publication of WO2000029408A1 publication Critical patent/WO2000029408A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • This invention relates to novel morpholinoethoxybenzofuran containing cyclic alkoxyketone protease inhibitors, particularly inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases.
  • the compounds of this invention even more particularly relate to those compounds which inhibit cysteine proteases of the papain superfamily, and particularly cysteine proteases of the cathepsin family.
  • this invention relates to compounds which inhibit cathepsin K.
  • Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
  • Cathepsin K is a member of the family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.
  • Cathepsin K has been variously denoted as cathepsin O, cathepsin X or cathepsin 02 in the literature.
  • the designation cathepsin K is considered to be the more appropriate one (name assigned by Nomenclature Committee of the International Union of Biochemistry and Molecular Biology).
  • Cathepsins of the papain superfamily of cysteine proteases function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue.
  • elevated levels of these enzymes in the body can result in pathological conditions leading to disease.
  • cathepsins have been implicated in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like.
  • Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated.
  • Type I Collagen represents the major structural protein of bone comprising approximately 90% of the structural protein. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
  • Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
  • Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage.
  • the osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
  • the low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed.
  • osteoblasts lay down a new protein matrix that is subsequently mineralized.
  • disease states such as osteoporosis and Paget's disease
  • the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle.
  • this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
  • cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
  • Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synoviu .
  • selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis.
  • Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix.
  • selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.
  • protease inhibitors are protease inhibitors, most particularly inhibitors of cathepsin K, and that these compounds are useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
  • An object of the present invention is to provide morpholinoethoxybenzofuran containing cyclic alkoxyketone protease inhibitors, particularly inhibitors of cysteine and serine proteases.
  • the present invention relates to such compounds which inhibit cysteine proteases, and particularly cysteine proteases of the papain superfamily.
  • this invention relates to such compounds which inhibit cysteine proteases of the cathepsin family and particularly, compounds which inhibit cathepsin K.
  • the compounds of the present invention are useful for treating diseases, which may be therapeutically modified by altering the activity of such proteases. Accordingly, in the first aspect, this invention provides a compound according to formula (I):
  • this invention provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
  • this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, such as cysteine and serine proteases.
  • the method includes treating diseases by inhibiting cysteine proteases, and particularly cysteine proteases of the papain superfamily. More particularly, the inhibition of cysteine proteases of the cathepsin family, such as cathepsin K is described.
  • the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
  • the present invention provides compounds of formula (I):
  • n 1 or 2; or a pharmaceutically acceptable salt thereof.
  • the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
  • Prodrugs are any covalently bonded compounds which release the active parent drug according to formula (I) in vivo.
  • Prodrugs of compounds of the present invention may be a prodrug of the ketone functionality of formula (I) compounds, specifically ketals or hemiketals.
  • a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • the preferred compounds of this invention are: 4- R,S -Amino-N-[[5-(2-N-mo holinoethoxy)-benzo[b]furan-2-ylcarbonyl]-S-leucine]- tetrahydrofuran-3-one; and
  • TEMPO means 2,2,6,6-tetramethyl-l-piperidinyloxy, free radical.
  • 3,4-Epoxytetrahydrofuran or 3,4-epoxytetrahydropyran (1 -Scheme- 1) is added to a solution of sodium azide in aqueous methanol to provide the corresponding trar ⁇ -4-azido-3- hydroxytetrahydrofuran or tr ⁇ » -4-azido-3-hydroxytetrahydropyran 2-Scheme- 1 , which is reduced over palladium on charcoal to give trc7w.s-4-amino-3-hydroxytetrahydrofuran or tr ⁇ ».s-4-amino-3- hydroxytetrahydropyran respectively 3-Scheme- 1.
  • 3-Scheme-l is then reacted with trimethyl acetyl chloride and N-Cbz-L-leucine to provide the corresponding trans-4-(R,S)-amino-N- [(benzyloxycarbonyl)-S-leucine]-3-hydroxytetrahydrofuran or pyran (4-Scheme-l).
  • Treatment of Scheme- 1 with bleach and TEMPO provides the corresponding 4-(R,S)-amino-N- [(benzyloxycarbonyl)-S-leucine]tetrahydrofuran-3-one or pyran-3-one (5-Scheme-l).
  • R and S diastereomers of the inventive compounds may be prepared as described above, from the individual diastereomers of intermediate 7-scheme-l, which are separated by chromatography or other well-known techniques.
  • amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
  • Acid addition salts of the compounds of formula (I) are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic acid.
  • an acid such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic acid.
  • compositions which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier, excipient or diluent.
  • the compounds of formula (I) may be used in the manufacture of a medicament.
  • Pharmaceutical compositions of the compounds of formula (I) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water, or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride, or sodium citrate.
  • excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride, or sodium citrate.
  • these compounds may be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
  • the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly or filled into a soft gelatin capsule.
  • the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
  • the compounds of formula (I) are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K.
  • the present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.
  • the present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia of malignancy, and metabolic bone disease.
  • Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
  • the present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of the present invention.
  • the present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof, an inhibitor of cathepsin K, including a compound of the present invention.
  • the present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
  • diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata;
  • This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of formula (I), alone or in combination with other inhibitors of bone reso ⁇ tion, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • a compound of formula (I) alone or in combination with other inhibitors of bone reso ⁇ tion, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • treatment with a compound of this invention and an anabolic agent, such as bone mo ⁇ hogenic protein, iproflavone may be used to prevent bone loss or to increase bone mass.
  • an effective amount of one or more compounds of formula (I) is administered to inhibit the protease implicated in a particular condition or disease.
  • this dosage amount will further be modified according to the type of administration of the compound.
  • " effective amount" for acute therapy parenteral administration of a compound of formula (I) is preferred.
  • An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful.
  • the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K.
  • the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
  • the precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
  • Prodrugs of compounds of the present invention may be prepared by any suitable method.
  • the conversion may be effected in accordance with conventional methods.
  • the compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone reso ⁇ tion or to achieve any other therapeutic indication as disclosed herein.
  • a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
  • the oral dose would be about 0.5 to about 20 mg/kg. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
  • the compounds of this invention may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect.
  • [AMC] v ss t + (vo - v ss ) [1 - exp (-kobs J / kobs (2)
  • the compounds used in the method of the present invention have a Kj value of less than 1 micromolar. Most preferably, said compounds have a Kj value of less than 100 nanomolar.
  • the cells were washed x2 with cold RPMI-1640 by centrifugation (1000 ⁇ m, 5 min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber.
  • Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium. The beads were mixed with the cells and the suspension was incubated for 30 minutes on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded.
  • the osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample.
  • the cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xl0 ⁇ /mL in EMEM medium, supplemented with 10% fetal calf serum and l Jg/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 ⁇ M in the EMEM medium).
  • a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL).
  • the tubes were incubated at 37°C for 30 minutes.
  • 0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37°C for 2 hours. Each treatment was screened in quadruplicate.
  • the slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 hours.
  • the slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 minutes, following which they were washed in water and incubated in buffer for 5 minutes at 37°C.
  • the slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 minutes at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
  • the TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21 W confocal microscope.
  • Trimethylorthoformate ( 4.2ml) was added slowly to a solution of 4-(R,S)-amino-N- [(benzyloxycarbonyl)-S-leucine]tetrahydropyran-3-one (4.4g, 12.6mmol) and /j-toluenesulphonic acid (119mg) in methanol (20ml) at reflux for 45min. After removing the solvent under reduced pressure, the resulting oil was chromatographed on silica gel (ethyl acetate / hexane gradient ) to give the title compound (4g, 80%)
  • Trifluoroacetic acid (1.5ml) was added to a stirred solution of 4-amino-N-[(5-(2-N- mo ⁇ holinoethoxy)benzo[b]furan-2-ylcarbonyl)-S-leucine]-3,3-dimethoxytetrahydrofuran
  • Trifluoroacetic acid (1ml) was added to a stirred solution of 4-amino-N-[(5-(2-N- mo ⁇ holino-ethoxy)-benzo[b]furan-2-ylcarbonyl)-S-leucine]-3,3- dimethoxytetrahydropyran, diastereomer 1 (0.065g, 2mmol) in dichloromethane (1ml).

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  • Orthopedic Medicine & Surgery (AREA)
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Abstract

L'invention concerne des composés selon la formule (I) dans laquelle n représente 1 ou 2, ou un sel pharmaceutiquement acceptable de ces derniers. Ces composés sont des inhibiteurs des cystéines protéases, en particulier, de la cathepsine K et permettent de traiter avec efficacité les maladies dans lesquelles l'inhibition de la perte osseuse ou de dégradation de cartilage est un facteur.
PCT/GB1999/003777 1998-11-13 1999-11-12 Inhibiteurs de morpholino-ethoxybenzofuran protease WO2000029408A1 (fr)

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AU13939/00A AU1393900A (en) 1998-11-13 1999-11-12 Morpholino-ethoxybenzofuran protease inhibitors

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US10841098P 1998-11-13 1998-11-13
US60/108,410 1998-11-13

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AU (1) AU1393900A (fr)
CO (1) CO5150165A1 (fr)
PE (1) PE20001237A1 (fr)
WO (1) WO2000029408A1 (fr)

Cited By (12)

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WO2002057249A1 (fr) * 2001-01-17 2002-07-25 Amura Therapeutics Limited 2-carbonylaminocetones cycliques, inhibiteurs de la cruzipain et autres cysteine proteases
WO2002057248A2 (fr) * 2001-01-17 2002-07-25 Amura Therapeutics Limited Inhibiteurs de la cruzipain et autres cysteine proteases
WO2002057246A2 (fr) * 2001-01-17 2002-07-25 Amura Therapeutics Limited Inhibiteurs de la cruzipaine et d'autres cysteines proteases
WO2002088106A2 (fr) * 2000-11-17 2002-11-07 Medivir Ab Inhibiteurs de la cysteine protease
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
US6583137B1 (en) 1999-11-10 2003-06-24 Smithkline Beecham Corporation Protease inhibitors
US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
US7425562B2 (en) 2001-01-17 2008-09-16 Amura Therapeutics Ltd. Inhibitors of cruzipain and other cysteine proteases
EP2719700A1 (fr) 2008-01-09 2014-04-16 Amura Therapeutics Limited Derives de tetrhydrofur(3,2-b)pyrrol-3-one comme inhibiteurs des proteases de cysteine

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WO1998050534A1 (fr) * 1997-05-08 1998-11-12 Smithkline Beecham Corporation Inhibiteurs de proteases
WO1999053039A1 (fr) * 1998-04-09 1999-10-21 Smithkline Beecham Corporation Traitement de maladies parasitaires par l'inhibition des cysteine-proteases de la superfamille de la papaine
WO1999059526A2 (fr) * 1998-05-21 1999-11-25 Smithkline Beecham Corporation Inhibiteurs de protease

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994004172A1 (fr) * 1992-08-20 1994-03-03 Prototek, Inc. Inhibiteurs cetoniques actives par peptidyle et contenant des sequences peptidiques naturelles et non naturelles
EP0603873A1 (fr) * 1992-12-25 1994-06-29 Mitsubishi Chemical Corporation Dérivés d'aminocétone
WO1998048799A1 (fr) * 1997-04-29 1998-11-05 Smithkline Beecham Corporation Inhibiteurs de proteases
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WO1998050534A1 (fr) * 1997-05-08 1998-11-12 Smithkline Beecham Corporation Inhibiteurs de proteases
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
US6583137B1 (en) 1999-11-10 2003-06-24 Smithkline Beecham Corporation Protease inhibitors
US7563784B2 (en) 2000-03-21 2009-07-21 Smithkline Beecham Corporation Protease inhibitors
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
WO2002088106A2 (fr) * 2000-11-17 2002-11-07 Medivir Ab Inhibiteurs de la cysteine protease
WO2002088106A3 (fr) * 2000-11-17 2003-09-04 Medivir Ab Inhibiteurs de la cysteine protease
WO2002057246A3 (fr) * 2001-01-17 2002-11-21 Incenta Ltd Inhibiteurs de la cruzipaine et d'autres cysteines proteases
WO2002057249A1 (fr) * 2001-01-17 2002-07-25 Amura Therapeutics Limited 2-carbonylaminocetones cycliques, inhibiteurs de la cruzipain et autres cysteine proteases
US6958358B2 (en) 2001-01-17 2005-10-25 Amura Therapeutics Limited Inhibitors of cruzipain and other cysteine proteases
WO2002057248A3 (fr) * 2001-01-17 2002-10-03 Incenta Ltd Inhibiteurs de la cruzipain et autres cysteine proteases
US7132449B2 (en) 2001-01-17 2006-11-07 Amura Therapeutics Limited Inhibitors of cruzipain and other cysteine proteases
WO2002057246A2 (fr) * 2001-01-17 2002-07-25 Amura Therapeutics Limited Inhibiteurs de la cruzipaine et d'autres cysteines proteases
US7425562B2 (en) 2001-01-17 2008-09-16 Amura Therapeutics Ltd. Inhibitors of cruzipain and other cysteine proteases
WO2002057248A2 (fr) * 2001-01-17 2002-07-25 Amura Therapeutics Limited Inhibiteurs de la cruzipain et autres cysteine proteases
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
EP2719700A1 (fr) 2008-01-09 2014-04-16 Amura Therapeutics Limited Derives de tetrhydrofur(3,2-b)pyrrol-3-one comme inhibiteurs des proteases de cysteine

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PE20001237A1 (es) 2000-12-23
AU1393900A (en) 2000-06-05
AR021241A1 (es) 2002-07-03

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