EP1086083A1 - Inhibiteurs de proteases - Google Patents

Inhibiteurs de proteases

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Publication number
EP1086083A1
EP1086083A1 EP99928614A EP99928614A EP1086083A1 EP 1086083 A1 EP1086083 A1 EP 1086083A1 EP 99928614 A EP99928614 A EP 99928614A EP 99928614 A EP99928614 A EP 99928614A EP 1086083 A1 EP1086083 A1 EP 1086083A1
Authority
EP
European Patent Office
Prior art keywords
leucyl
alkyl
pyrrolidin
group
quinolinecarbonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99928614A
Other languages
German (de)
English (en)
Other versions
EP1086083A4 (fr
Inventor
Ashley E. Fenwick
Andrew D. Gribble
Robert W. Marquis, Jr.
Jason Witherington
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Ltd
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Ltd, SmithKline Beecham Corp filed Critical SmithKline Beecham Ltd
Publication of EP1086083A1 publication Critical patent/EP1086083A1/fr
Publication of EP1086083A4 publication Critical patent/EP1086083A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D401/12—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 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to novel 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. Ill, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 211, 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. However, 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. See International Publication Number WO 94/04172, published on March 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 Al, and references cited therein. Two bacterial cysteine proteases from P.
  • 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.
  • the abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption.
  • selective inhibition of 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 synovium.
  • 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 most particularly inhibitors of cathepsin K, and these compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis and periodontal disease.
  • An object of the present invention is to provide protease inhibitors, such as inhibitors of cysteine and serine proteases.
  • the present invention relates to compounds which inhibit cysteine proteases, and particularly cysteine proteases of the papain superfamily.
  • this invention relates to 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.
  • this invention provides a compound according to formula (I).
  • this invention provides a pharmaceutical composition
  • 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.
  • this invention provides a method of producing the compounds having the formula (I) above.
  • the present invention provides alkoxypyrrolidinone compounds of formula (I):
  • X is selected from the group consisting of oxygen, sulfur, SO, and S0 2 ;
  • Y is selected from the group consisting of H 2 and oxygen; where if Y is H 2 , then the bond represents two single bonds and where if Y is O, then the bond represents a double bond;
  • R' is selected from the group consisting of hydrogen, Cj_g alkyl, C2-6 alkenyl, C2- 6 alkynyl, C 3 . 6 cycloalkyl-C 0 _6 alkyl, Ar-C 0 -6 alkyl, Het-C 0 -6 alkyl, (CH 2 ) 06 C0 2 R", and (CH 2 ) 0 ,Ar;
  • R 2 is selected from the group consisting of H, Ci .g alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.6 cycloalkyl-Co-6 alkyl, A ⁇ -CQ-O alkyl, and Het-Co-6 alkyl;
  • R 3 is selected from the group consisting of H, Cj.g alkyl, C2-6 alkenyl, C2-6 alkynyl, C .g cycloalkyl-C ⁇ -6 alkyl, Ar-C ⁇ -6 alkyl, and Het-C ⁇ -6 alkyl; or pharmaceutically acceptable salts, hydrates, and isomers thereof.
  • X is O.
  • Y is O.
  • R is selected from the group consisting of
  • R 2 is isobutyl or a substituted isobutyl.
  • R 3 is selected from the group consisting of
  • R" is selected from the group consisting of hydrogen, C1 _6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Q._._ cycloalkyl-Co-6 alkyl, Ar-Co-6 alkyl, and Het-Co-6 alkyl;
  • 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. If 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.
  • this invention provides novel intermediates useful in the preparation of formula (I) compounds represented by:
  • amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • t-Bu refers to the tertiary butyl radical
  • Boc or BOC refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz or CBZ or Z refers to the benzyloxycarbonyl radical.
  • DCC refers to dicyclohexylcarbodiimide
  • EDC or EDCI refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide
  • HOBT or HOBt refers to 1-hydroxybenzotriazole
  • DMF refers to dimethyl formamide
  • DIEA refers to di- isopropylethylamine
  • HoAt refers to l-hydroxy-7-aza-benzotriazote
  • Dess-Martin's reagent is l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one
  • TFA refers to trifluoroacetic acid
  • THF refers to tetrahydrofuran.
  • Ci-6 alkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • Any C ⁇ _6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R')2, C(0)N(R')2, carbamyl or C ⁇ _4alkyl, where R' is H or C ⁇ _6alkyl.
  • Crjalkyl means that no alkyl group is present in the moiety.
  • Ar-C ⁇ alkyl is equivalent to Ar.
  • C3-6 cycloalkyl as applied herein is meant to include substituted [i.e., alkyl, OR, SR or halogen) and unsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • C2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons, wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C2-6alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C2-6 alkynyl means an alkyl group of 2 to 6 carbons, wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C2-6 alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne, and the simple isomers of pentyne and hexyne.
  • Ar or "aryl” means unsubstituted phenyl or naphthyl; or phenyl or naphthyl substituted by one or more of Ph-C ⁇ -6 alkyl, Het-Crj-6 alkyl, Cj.g alkoxy, Ph-Co-6 alkoxy, Het-Co-6 alkoxy, OH, R', 0(CH2)i_6NR R'; wherein each R' independently is H, Cj.g alkyl, Ar-Co-6 alkyl, or Het- CQ_6 alkyl; or phenyl or naphthyl substituted by one to three moieties selected from C ⁇ _4alkyl, OR', N(R') 2 , SR, CF 3 , N0 2 , CN, C0 2 R', CON(R'), F, Cl, Br and I, or substituted by a methylenedioxy group.
  • Het represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C1.4a.kyl, OR', N(R')2, SR', CF3, N0 2 , CN, C0 2 R', CON(R'), F, Cl, Br and I, where R is as defined hereinbefore.
  • heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, thienyl, pyrrolyl, 4- piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, isothiazolyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzopyranyl, benzoxazolyl, benzofurany
  • the epoxide l-scheme-2 is treated with the in situ generated sodium salt of the alcohol or thiol, R'XH, in excess of the alcohol as solvent, or in an appropriate solvent such as methanol, for the thiol reagent, to afford 2-Scheme-2.
  • This compound is deprotected using trifluoroacetic acid in dichloromethane to give 3 ⁇
  • 6-Scheme-2 is then treated with a carboxylic acid having the formula R 3 COOH, N-methylmorpholine, N-ethyl- N'(dimethylaminopropyl)-carbodiimide, and HOAt in dichloromethane to give 6-Scheme-2.
  • 6-Scheme-2 can be produced directly from 2-Scheme-2. where R 3 is Z, by treating 2-Scheme-2 with Z-leuOH, N-ethyl-N'(dimethylaminopropyl)-carbodiimide, and HOAt in dichloromethane.
  • Compound 6 is then treated with Dess-Martin reagent in dichloromethane to give the final product 7-Scheme-2.
  • R 3 Z: Z-leuOH, N-methylmo holine, EDC, HOBt, CH 2 C1 2 ; b) MCPBA, CH 2 C1 2 ; c) R'OH, KO'Bu, THF; d) Dess-Martin reagent, CH 2 C1 2 .
  • Coupling methods to form amide bonds herein are generally well-known to the art.
  • the methods of peptide synthesis generally set forth by Bodansky et al., THE PRAC ⁇ CE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTiDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984, are generally illustrative of the technique and are incorporated herein by reference. Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions.
  • 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. Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate, or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
  • Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH4 + are specific examples of cations present in pharmaceutically acceptable salts.
  • Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
  • This invention also provides a pharmaceutical composition which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of formula (I) may be used in the manufacture of a medicament.
  • 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.
  • 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.
  • 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.
  • 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 resorption, 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 resorption, 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 morphogenic protein, iproflavone may be used to prevent bone loss or to increase bone mass.
  • an effective amount of the compounds of formula (I) is administered to inhibit the protease implicated with 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 resorption 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 (-k oos t)] / k 0 bs (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 K j value of less than 200 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 1.7g/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 ILM21W confocal microscope.
  • a sodium methoxide solution (50 mg sodium in 5 ml methanol) was added to a solution of benzyl mercaptan (0.68 g) and l-tert-butoxycarbonyl-3,4-epoxypyrrolidine (l.Og) in dry methanol (5 ml) and the solution stirred at 50° for 24 hours.
  • the solution was evaporated down under reduced pressure and water (20 ml) added.
  • the mixture was extracted with di- chloromethane (3 x 20ml) and the combined extracts washed with water and brine, dried (magnesium sulphate) and evaporated down under reduced pressure to give the title compound (1.54g) as a white solid, m.p. 97-8°.

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Abstract

Cette invention concerne des composés de formule (I) ou un sel pharmaceutiquement acceptable de ces derniers qui sont des inhibiteurs de cystéine protéases, particulièrement de la cathepsine K, et qui sont utilisés dans le traitement des maladies dans lesquelles la déperdition osseuse est un facteur.
EP99928614A 1998-06-12 1999-06-11 Inhibiteurs de proteases Withdrawn EP1086083A4 (fr)

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US8905698P 1998-06-12 1998-06-12
US89056P 1998-06-12
PCT/US1999/013334 WO1999064399A1 (fr) 1998-06-12 1999-06-11 Inhibiteurs de proteases

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EP1086083A1 true EP1086083A1 (fr) 2001-03-28
EP1086083A4 EP1086083A4 (fr) 2001-09-26

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AU (1) AU4564499A (fr)
CA (1) CA2334652A1 (fr)
CO (1) CO5040090A1 (fr)
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MA (1) MA24877A1 (fr)
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US20030144175A1 (en) 1998-12-23 2003-07-31 Smithkline Beecham Corporation Protease inhibitors
AU1588901A (en) 1999-11-10 2001-06-06 Smithkline Beecham Corporation Protease inhibitors
JP2003513972A (ja) 1999-11-10 2003-04-15 スミスクライン・ビーチャム・コーポレイション プロテアーゼ阻害剤
JP2003513924A (ja) 1999-11-10 2003-04-15 スミスクライン・ビーチャム・コーポレイション プロテア−ゼ阻害剤
SK13632002A3 (sk) 2000-03-21 2003-02-04 Smithkline Beecham Corporation C1-6-alkyl-4-amino-azepán-3-ónové zlúčeniny, spôsob ich prípravy, farmaceutický prostriedok s ich obsahom, ich použitie a medziprodukty
WO2002080920A1 (fr) * 2001-04-06 2002-10-17 Axys Pharmaceuticals, Inc. Arylacetamido-cetobenzoxazole comme inhibiteurs de la cysteine protease
WO2003062192A1 (fr) 2002-01-17 2003-07-31 Smithkline Beecham Corporation Derives de cetoamides a substitution cycloalkyle, utiles comme inhibiteurs de cathepsine k
JP5587790B2 (ja) 2008-01-09 2014-09-10 アミュラ セラピューティクス リミティド 化合物
AR127031A1 (es) 2021-09-14 2023-12-13 Boehringer Ingelheim Int Derivados de 3-fenoxiazetidin-1-il-heteroaril pirrolidina y el uso de estos como medicamento

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995013069A1 (fr) * 1993-11-09 1995-05-18 Merck & Co., Inc. Piperidines, pyrrolidines et hexahydro-1h-azepines favorisant la liberation de l'hormone de croissance
WO1996016080A1 (fr) * 1994-11-21 1996-05-30 Cortech, Inc. Inhibiteurs d'elastase neutrophile humaine

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US5770573A (en) * 1993-12-06 1998-06-23 Cytel Corporation CS-1 peptidomimetics, compositions and methods of using the same

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995013069A1 (fr) * 1993-11-09 1995-05-18 Merck & Co., Inc. Piperidines, pyrrolidines et hexahydro-1h-azepines favorisant la liberation de l'hormone de croissance
WO1996016080A1 (fr) * 1994-11-21 1996-05-30 Cortech, Inc. Inhibiteurs d'elastase neutrophile humaine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
See also references of WO9964399A1 *
T.HOEG-JENSEN ET AL.: "Peptide Thioacylation with High Stereochemical Preservation" SYNTHESIS, vol. 3, 1996, pages 383-387, XP002173434 *
THOMPSON S K ET AL: "DESIGN OF POTENT AND SELECTIVE HUMAN CATHEPSIN K INHIBITORS THAT SPAN THE ACTIVE SITE" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA,US,NATIONAL ACADEMY OF SCIENCE. WASHINGTON, vol. 94, no. 26, 23 December 1997 (1997-12-23), pages 14249-14254, XP002913847 ISSN: 0027-8424 *

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JP2002517485A (ja) 2002-06-18
DZ2815A1 (fr) 2003-12-01
CA2334652A1 (fr) 1999-12-16
CO5040090A1 (es) 2001-05-29
AR018652A1 (es) 2001-11-28
WO1999064399A1 (fr) 1999-12-16
AU4564499A (en) 1999-12-30
PE20000725A1 (es) 2000-09-28
MA24877A1 (fr) 1999-12-31
EP1086083A4 (fr) 2001-09-26

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