EP0923535A1 - Inhibiteurs de cysteine protease - Google Patents

Inhibiteurs de cysteine protease

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Publication number
EP0923535A1
EP0923535A1 EP97938632A EP97938632A EP0923535A1 EP 0923535 A1 EP0923535 A1 EP 0923535A1 EP 97938632 A EP97938632 A EP 97938632A EP 97938632 A EP97938632 A EP 97938632A EP 0923535 A1 EP0923535 A1 EP 0923535A1
Authority
EP
European Patent Office
Prior art keywords
6alkyl
het
alkyl
compound according
compound
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Withdrawn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
EP97938632A
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German (de)
English (en)
Other versions
EP0923535A4 (fr
Inventor
Dennis S. Yamashita
Renee L. Desjarlais
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 Corp
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SmithKline Beecham Corp
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Publication of EP0923535A1 publication Critical patent/EP0923535A1/fr
Publication of EP0923535A4 publication Critical patent/EP0923535A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • 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
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to novel protease inhibitors, particularly inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly 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) 7. Biol. Chem. 271, 1251 1 -12516; Bromme, D., et al., (1996) J. Biol. Chem. Ill, 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, thrombospondm, fibronectin, and bone sialoprotem 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 c , resorbing) surface
  • 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 pe ⁇ odontal disease
  • An object of the present invention is to provide protease inhibitors, particularly such inhibitors of cysteine and se ⁇ ne proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutical ly modified by alte ⁇ ng the activity of such proteases
  • this invention provides a compound according to formula (I)
  • this invention provide J 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 therapeutical ly modified by inhibiting proteases, particularly cysteine and se ⁇ ne proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K
  • the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gmgival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarth ⁇ tis and rheumatoid arthritis
  • the present invention provides compounds of formula (I)
  • R 2 is H, Ci.galkyl, C3_6cycloalkyl-C( )-6 alkyl, Ar-C 0 -6alkyl, Het-C 0 -6alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R'NC(0)-, R 5 R'NC(S)-, adamantyl-C(O)-, or
  • each R" independently is H, Cj.galkyl, Ar-C()-6alkyl, or Het-Co -O alkyl;
  • R'" is H, C ⁇ . 6 alkyl, C 3 _6cycloalkyl-C 0 . 6 alkyl, Ar-Crj- ⁇ alky I. or Het-C 0- 6alkyl;
  • R ⁇ and R 7 are connected to form a pyrrolidine, a piperidine, or a morpholine ring; each R' independently is H, C j.galkyl, Ar-C()-6alkyl, or Het-C ⁇ -rj alkyl; R* is H, C ⁇ _6alkyl, C3_ D cycloalkyl-C 0 -6alkyl, Ar-C 0 . 6 alkyl, or Het-C 0 -6alkyl;
  • Y is a single bond or O; each Z independently is CO or CH2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of formula (la):
  • X is CO, S0 2 , or CH 2 -CO; Y is a single bond or O; Z is CO or CH 2 ; each R independently is C ⁇ galkyl, C ⁇ galkenyl, or benzyl; R 4 is C;_ 6 alkyl, Ar-C 0 -6alkyl, R 5 CO-, R 5 S0 2 - R 5 OC(0)-, or R 5 NHCO; R' is H or C j _4alkyI; R 6 is H or C j .4alkyl; R 7 is C ⁇ _ 6 alkyl, Ar-C 0 -6alkyl, R 5 CO-, R 5 S0 2 - R 5 OC(0)-, or R 5 NHCO; each R ⁇ independently is Ar-C ⁇ _6alkyl or Het-C ⁇ -6alkyl; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
  • hydrates, solvates, complexes and prodrugs of the compounds of this invention are included in this invention.
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo.
  • this invention includes each unique nonracemic compound which may be synthesized and resolved by conventional techniques.
  • 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.
  • R 4 is R 5 OC(0)- and R 5 is preferably
  • R 2 is
  • R 7 is R 5 0C(0)- and R 5 is preferably
  • R' and R ⁇ are each H and each R ⁇ is i-butyl.
  • Specific representative compounds of this invention are: trans-N,N'-bis-(benzyloxycarbonyl-L-leucinyl)- 1 -3-diamino-cyclopentanone and trans-N,N'-bis-(benzyloxycarbonyl-L-leucinyl)-l-3-diamino-cyclohexanone; or a pharmaceutically acceptable salt thereof.
  • 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.
  • Cj-4alkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl groups.
  • Chalky] additionally includes substituted or unsubstituted pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • Any C ]-4alkyl or C]_6alkyl group may be optionally substituted by one to three groups selected from OR', N(R') 2 , SR', CF,, NO,. CN, C0 2 R', and CON(R'), unless otherwise indicated.
  • C()-4alkyl and Crj-6alkyl additionally indicates that no alkyl group need be present (e.g., that a covalent bond is present).
  • C3-6cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • C2-6alkenyl 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, l-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C2-6 a lkynyl 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.
  • Halogen or "halo" means F, Cl, Br, and I.
  • Ar or "aryl” means unsubstituted phenyl or naphthyl; or phenyl or naphthyl substituted by one or more of Ph-C()-6 a, kyl, Het-CQ-galkyl, C j.galkoxy, Ph-Co-6 a lkoxy, Het-C f j-6alkoxy, OH, (CH2)i-6 R'R', 0(CH2) I _6 R'R'; wherein each R ' independently is H, C j .galkyl, Ar-Co-6 a lkyl, or Het-C ⁇ _6alkyl; or phenyl or naphthyl substituted by one to three moieties selected from C1.4a.kyl, OR', N(R'),, SR', CF 3 , NO,, CN, CO 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 C]-4alkyl, OR', N(R')2, SR', CF 3 , 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, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyr
  • HetAr or “heteroaryl” means any heterocyclic moiety encompassed by the above definition of Het which is aromatic in character, e.g., pyridinyl, quinolinyl, isoquinolinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, furyl, thienyl, benzoxazolyl, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1 ,5-napthyridinyl, 1 ,6
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical.
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP is 2,6-dimethylaminopyridine
  • EDC refers to N-ethyl-N'(dimethylaminopropyl)- carbodiimide.
  • HOBt refers to 1 -hydroxybenzotriazole
  • DMF refers to dimethyl formamide
  • BOP refers to benzotriazol- l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
  • DMAP is dimethylaminopyridine
  • Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-l ,3- dithia-2,4-diphosphetane-2,4-disulfide
  • NMM is N-methylmorpholine
  • TFA refers to trifluoroacetic acid
  • TFAA refers to trifluoroacetic anhydride
  • THF refers to tetrahydrofuran.
  • the compounds of formula (I) are generally prepared using a process which comprises: reacting a compound of the formual (II):
  • R , R 2 , R", R'" and n are as defined in formula (I), with any reactive functional groups protected, with an oxidizing agent; and thereafter removing any protecting groups and optionally forming a pharmaceutically acceptable salt.
  • a LAH
  • b triphenylphosphine, DEAD, phthalimide
  • c NaBH
  • d NBS
  • e KOH
  • f NH3
  • g Cbz-Leu-OH, EDCI, HOBT
  • h Jones
  • trans- 1 ,3-diamino cyclopentanol which was acylated with Cbz-leucine/ HBTU and oxidized to provide the desired trans-N,N'-bis-(benzyloxycarbonyl-L-leucinyl)- 1-3- diamino-cyclopentanone.
  • Compounds of the formula I wherein n is 2 are prepared by methods analogous to those described in Scheme 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 PRACTICE OF PEPTIDE SYNTHESIS, Springer- Veriag, 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. 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.
  • compositions of 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 poly vinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternately, these compounds may be encapsulated, tableted or prepared in a 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 p.o. 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
  • This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration of a compound of formula (I) and other inhibitors of bone resorption, such as bisphosphonates (1 e , allendronate), hormone replacement
  • parenteral administration of a compound of formula (I) is preferred
  • 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 04 to about 400 g/kg/day
  • the precise level and method by which the compounds are administered is readily determined by one routinely skilled in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect
  • 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 other such 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
  • cathepsin K proteolytic catalytic activity All assays for cathepsin K were carried out with human recombmant enzyme de ⁇ ved from osteoclastoma cells Procedures for obtaining such enzyme, such as those disclosed by Inaoka, et al , Biochem Biophys Res Commun , 1995, 206, 89, Shi, et al , FEBS Lett., 1995, 357, 129; and Bromme, et ai, Biol. Chem. Hoppe-Seyler, 1995, 376, 379, are known in the art.
  • Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 M EDTA.
  • Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrate concentration in the assays. All assays contained 10% DMSO. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. All assays were conducted at ambient temperature.
  • Product fluorescence excitation at 360 nM; emission at 460 nM
  • Product progress curves were generated over 20 to 30 min following formation of AMC product.
  • v is the velocity of the reaction with maximal velocity V m
  • A is the concentration of substrate with Michaelis constant of K a
  • / is the concentration of inhibitor
  • [AMC] v ss t + (vo - vss) [1 - exp (-k 0 b s t)J / k Q b s (2)
  • 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 min 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 4 /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 uM in the EMEM medium).
  • a positive control (87MEM 1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL).
  • the tubes were incubate at 37°C for 30 min.
  • 0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-weIl plate and incubated at 37°C for 2 h.
  • Each treatment was screened in quadruplicate.
  • the slices were washed in six changes of warm PBS (10 L / well in a 6- well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h.
  • the slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C.
  • the slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min 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.
  • Cyclopent-2-ene-ol (1.05 g, 12.5 mmol) (as described in Brown, H. C; Hess, H.M. J. Org. Chem. 1969, 34, 2206) was dissolved in THF (20 ml). Then phthalimide (2.05 g, 14 mmol), triphenyl phosphine (3.675 g, 14 mmol), and diethyl azo dicarboxylate (2.43 g, 14 mmol) were added and the reaction was stirred at RT for lh.
  • N-Cbz-L-leucine (Bachem) (0.64 g, 2.4 mmol) in 10 mL of DMF was added (+-)-trans- 1 ,3-diamino cyclopentanol (0.14 g, 1.2 mmol), 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.46 g, 2.4 mmol) and 1- hydroxybenzotriazole (0.324 g, 2.4 mmol).
  • Trans-N,N'-bis-(benzyloxycarbonyl-L-leucinyl)- 1 -3-diamino-cyclopentanol (0.22 g, 0.35 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was added added and the reaction was stirred overnight. The excess Jones reagent was then quenched with isopropanol (1 ml) and the reaction was diluted with water (10 ml) and was extracted with EtOAc (2 x 20 ml).

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Abstract

Cette invention se rapporte à des composés représentés par la formule (I) dans laquelle R1 est représenté par l'une des formules (i), (ii), (iii), ou (iv); R2 est H, alkyle C¿1-6?, cycloalkyl C3-6-alkyle C0-6, Ar-alkyle C0-6, Het-alkyle C0-6, R?5¿C(O)-, R5C(S)-, R5SO2-, R5OC(O)-, R5R'NC(O)-, R5R'NC(S)-, adamantyl-C(O)- ou est représenté par la formule (v); chaque R'' est indépendamment H, alkyle C¿1-6?, Ar-alkyle C0-6 ou Het- alkyle C0-6; R''' est H, alkyle C1-6, cycloalkyl C3-6-al kyle C0-6, Ar-alkyle C0-6 ou Het-alkyle C0-6; chaque R?3¿ est indépendamment H, alkényle C¿2-6?, alkynyle C2-6, Het, Ar ou alkyle C1-6 éventuellement substitué par OR', SR', NR'2, R'NC(O)OR?5, CO¿2NR'2, N(C=NH)NH2, Het ou Ar; R4 est H, alkyle C¿1-6?, cycloalkyl C3-6-alkyle C0-6, Ar-alkyleC0-6, Het-alkyle C0-6, R?5¿C(O)-, R5C(S)-, R5SO2-, R5OC(O)-, R5R'NC(O)-, R5R'NC(S)-, R'HNCH(R')C(O)- ou R5OC(O)NR'CH(R')C(O)-; chaque R5 est indépendamment cycloalkyl C¿3-6?-alkyle C0-6, Ar-alkyle C0-6, Het-alkyle C0-6, Ar-alcoxyC0-6, Het-alcoxy C0-6, ou alkyle C1-6 éventuellement substitué par OR', SR', NR'2, R'NC(O)OR?5, CO¿2R', CO2NR'2, N(C=NH)NH2, Het ou Ar; R6 est H, alkyle C¿1-6?, Ar-alkyle C0-6 ou Het-alkyle C0-6 et R?7¿ est H, alkyle C¿1-6?, cycloalkyl C3-6-alkyle C0-6, Ar-alkyle C0-6, Het-alkyle C0-6, R?5¿C(O)-, R5C(S)-, R5SO2-, R5OC(O)-, R5R'NC(O)-, R5R'NC(S)-, R'HNCH(R')C(O)- ou R5OC(O)NR'CH(R')C(O)-; ou R6 et R7 sont liés pour former un noyau pyrrolidine, pipéridine ou morpholine; chaque R' étant indépendamment H, alkyle C¿1-6?, Ar-alkyle C0-6 ou Het-alkyle C0-6; R* étant H, alkyle C1-6, cycloalkyl C3-6-alkyle C0-6, Ar-alkyle C0-6 ou Het-alkyle C0-6; Y étant une liaison simple ou O; chaque Z étant indépendamment CO ou CH2 et n est égal à 1, 2 ou 3. L'invention se rapporte également à un sel pharmaceutiquement acceptable de ces composés qui sont des inhibiteurs de cystéine protéases, notamment de la cathepsine K, et qui s'avèrent utiles pour traiter des maladies nécessitant une inhibition de la déperdition osseuse.
EP97938632A 1996-08-28 1997-08-26 Inhibiteurs de cysteine protease Withdrawn EP0923535A4 (fr)

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US2484896P 1996-08-28 1996-08-28
US24848P 1996-08-28
PCT/US1997/015029 WO1998008802A1 (fr) 1996-08-28 1997-08-26 Inhibiteurs de cysteine protease

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EP0923535A1 true EP0923535A1 (fr) 1999-06-23
EP0923535A4 EP0923535A4 (fr) 2001-01-10

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US6586466B2 (en) 1995-10-30 2003-07-01 Smithkline Beecham Corporation Carbohydrazide-protease inhibitors
TR199800767T2 (xx) * 1995-10-30 1998-07-21 Smithkline Beecham Corporation Proteaz engelleyicileri.
DE19817461A1 (de) 1998-04-20 1999-10-21 Basf Ag Neue substituierte Benzamide, deren Herstellung und Anwendung
US20030144175A1 (en) 1998-12-23 2003-07-31 Smithkline Beecham Corporation Protease inhibitors
TW200404789A (en) 1999-03-15 2004-04-01 Axys Pharm Inc Novel compounds and compositions as 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
US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
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
HUP0300068A2 (en) 2000-03-21 2003-05-28 Smithkline Beecham Corp Protease inhibitors, their preparation, their use and pharmaceutical compositions containing them
WO2002051983A2 (fr) 2000-12-22 2002-07-04 Axys Pharmaceuticals, Inc. Composes et compositions en tant qu'inhibiteurs de cathepsine
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
DK1362052T3 (da) 2001-01-17 2007-07-09 Amura Therapeutics Ltd Inhibitorer af cruzipain og andre cysteinproteaser
US7132449B2 (en) 2001-01-17 2006-11-07 Amura Therapeutics Limited Inhibitors of cruzipain and other cysteine proteases
EP1362042A1 (fr) * 2001-01-17 2003-11-19 Amura Therapeutics Limited 2-carbonylaminocetones cycliques, 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
WO2003024924A1 (fr) 2001-09-14 2003-03-27 Aventis Pharmaceuticals Inc. Nouveaux composes et nouvelles compositions utiles comme inhibiteurs de la cathepsine
MXPA04004450A (es) 2001-11-14 2004-08-11 Aventis Pharma Inc Nuevos compuestos y composiciones como inhibidores de catepsina s.
EP1465862A1 (fr) 2002-01-17 2004-10-13 SmithKline Beecham Corporation Derives de cetoamides a substitution cycloalkyle, utiles comme inhibiteurs de cathepsine k
WO2003075853A2 (fr) 2002-03-08 2003-09-18 Bristol-Myers Squibb Company Derives cycliques servant de modulateurs de l'activite du recepteur de la chimiokine
KR100962972B1 (ko) 2002-07-26 2010-06-09 주식회사유한양행 1-페닐피페리딘-3-온 유도체 및 그의 제조방법
DE202014101592U1 (de) 2014-04-04 2014-06-30 Wilkhahn Wilkening + Hahne Gmbh + Co. Stuhl
CN114981251B (zh) * 2020-01-21 2023-11-21 深圳信立泰药业股份有限公司 一种二苯并呋喃类衍生物组织蛋白酶k抑制剂及其制备方法和医药用途

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EP0603873A1 (fr) * 1992-12-25 1994-06-29 Mitsubishi Chemical Corporation Dérivés d'aminocétone
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