WO2008051763A1 - Inhibiteurs de protéases de type cathepsines - Google Patents

Inhibiteurs de protéases de type cathepsines Download PDF

Info

Publication number
WO2008051763A1
WO2008051763A1 PCT/US2007/081635 US2007081635W WO2008051763A1 WO 2008051763 A1 WO2008051763 A1 WO 2008051763A1 US 2007081635 W US2007081635 W US 2007081635W WO 2008051763 A1 WO2008051763 A1 WO 2008051763A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
cathepsin
optionally substituted
compounds
pharmaceutically acceptable
Prior art date
Application number
PCT/US2007/081635
Other languages
English (en)
Inventor
Robert Epple
Ross Russo
Original Assignee
Irm Llc
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 Irm Llc filed Critical Irm Llc
Priority to BRPI0717348-2A2A priority Critical patent/BRPI0717348A2/pt
Priority to CA002667816A priority patent/CA2667816A1/fr
Priority to MX2009004290A priority patent/MX2009004290A/es
Priority to JP2009534774A priority patent/JP2010507681A/ja
Priority to AU2007309195A priority patent/AU2007309195A1/en
Priority to EP07844341A priority patent/EP2078027A1/fr
Publication of WO2008051763A1 publication Critical patent/WO2008051763A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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

Definitions

  • cathepsins are endopeptidases belonging to the family of papain-like cysteine proteases. Cathepsins are generally highly concentrated in lysosomal and endosomal compartments and play a role in a broad array of physiological processes. Among them are nonspecific functions such as degradation of both internalized and cellular proteins, as well as more specialized functions in the processing of enzymes and hormones. Various diseases are linked to the overexpression of certain proteases. For example, inhibition of specific cathepsin proteases is believed to have therapeutic implications on pathological conditions associated with cellular homeostasis, apoptosis, tumor invasion and metastasis, bone resorption and antigen presentation.
  • Most small molecule inhibitors of proteases consist of a peptidomimetic that recognizes specific pockets in the enzyme and defines substrate selectivity, and an electrophilic "warhead" that makes important contacts to the catalytic domain.
  • the nature of the electrophilic group determines the classification of these small molecules into reversible and irreversible inhibitors.
  • electrophilic groups have been routinely employed in the inhibition of proteases by covalent interaction of enzyme with inhibitors. For example, aldehydes, semicarbazones, nitriles and ketones usually lead to reversible inhibition, whereas halomethylketones, epoxides and Michael acceptors are among the functionalities used for irreversible inhibition.
  • the invention provides compounds and pharmaceutical compositions thereof, which may be useful as inhibitors for cathepsin proteases.
  • the present invention provides compounds of Formula (1):
  • X is O or S
  • R 1 is OR 2 , halo, (CR 2 ) n R 3 , nitro, cyano, amino, amido, sulfonamide, or an optionally substituted Ci_6alkyl, C 2 -6 alkenyl, or C3-6 alkynyl;
  • R 2 is H, (CR 2 ) n R 3 , or an optionally substituted Ci_6alkyl, C 2 -6 alkenyl or C3_6 alkynyl;
  • R 3 is an optionally substituted aryl, heteroaryl, carbocyclic ring or heterocyclic ring; m is 1-3; and n is 0-4.
  • m is 1.
  • R 1 is halo or OR 2 , wherein R 2 may be an optionally substituted phenyl, benzyl or Ci_ 6 alkyl.
  • compounds having Formula (1) have a cis stereoconformation. In other examples, compounds having Formula (1) have a trans stereoconformation.
  • the invention provides pharmaceutical compositions comprising compounds having Formula (1) and a pharmaceutically acceptable excipient.
  • the invention provides methods for inhibiting a cathepsin protease, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of Formula (1), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby inhibiting said cathepsin protease.
  • the present invention also provides methods for treating a condition or disease mediated by cathepsin protease activity, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of Formula (1), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby treating said cathepsin protease-mediated condition or disease.
  • the invention provides methods for treating a condition or disease mediated by papain-like cathepsin protease, including but not limited to cellular homeostasis, apoptosis, tumor invasion and metastasis, bone resorption and antigen presentation.
  • the compounds of the invention may be used to treat osteoporosis, arthritis, asthma, auto-immune disease and tumors.
  • the invention provides the use of compounds having Formula (1) for the manufacture of a medicament for treating a disease mediated by cathepsin protease, more particularly papain-like cathepsin protease.
  • a compound having Formula (1) may be administered to a system comprising cells or tissues. In other embodiments, a compound having Formula (1) may be administered to a human or animal subject.
  • Alkyl refers to a moiety and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, and may be straight-chained or branched.
  • An optionally substituted alkyl, alkenyl or alkynyl as used herein may be optionally halogenated (e.g., CF 3 ), or may have one or more carbons that is substituted or replaced with a heteroatom, such as NR, O or S (e.g., -OCH 2 CH 2 O-, alkylthiols, thioalkoxy, alkylamines, etc).
  • Aryl refers to a monocyclic or fused bicyclic aromatic ring containing carbon atoms.
  • aryl may be phenyl or naphthyl.
  • Arylene means a divalent radical derived from an aryl group.
  • Heteroaryl as used herein is as defined for aryl above, where one or more of the ring members are a heteroatom.
  • heteroaryls include but are not limited to pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.
  • Examples of carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.
  • a "heterocyclic ring” as used herein is as defined for a carbocyclic ring above, wherein one or more ring carbons is a heteroatom.
  • heterocyclic rings include but are not limited to morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.
  • substituent is a group that may be substituted with one or more group(s) individually and independently selected from, for example, an optionally halogenated alkyl, alkenyl, alkynyl, alkoxy, alkylamine, alkylthio, alkynyl, amide, amino, including mono- and di-substituted amino groups, aryl, aryloxy, arylthio, carbonyl, carbocyclic, cyano, cycloalkyl, halogen, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heterocyclic, hydroxy, isocyanato, isothiocyanato, mercapto, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S
  • co-administration or “combined administration” or the like as used herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • the term "pharmaceutical combination” as used herein refers to a product obtained from mixing or combining active ingredients, and includes both fixed and non-fixed combinations of the active ingredients.
  • the term "fixed combination” means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • the term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula (1) and a co-agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the active ingredients in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • terapéuticaally effective amount means the amount of the subject compound that will elicit a biological or medical response in a cell, tissue, organ, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • administering should be understood to mean as providing a compound of the invention including a pro-drug of a compound of the invention to the individual in need of treatment.
  • the invention provides compounds and compositions for inhibiting cathepsin proteases, more particularly papain-like cathepsin proteases.
  • the present invention also provides methods for treating a condition or disease mediated by cathepsin protease activity, particularly a condition or disease mediated by papain-like cathepsin protease, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of Formula (1), or pharmaceutically acceptable salts or pharmaceutical compositions thereof, thereby treating said papain-like cathepsin protease-mediated condition or disease.
  • Papain-like cysteine proteases have been identified as key proteolytic activities in degenerative, invasive, and immune system related disorders. (Lecaille et al., Chem. Rev. 2002, 102:4459-4488; Bromine et al., Curr. Pharm. Des. 2002, 8:1639-1658).
  • cathepsin K is the major bone-degrading activity in osteoclasts, and its selective inhibition may be beneficial for treating osteoporosis and certain forms of arthritis.
  • Cathepsin S plays an important role in MHC class II dependent antigen presentation; inhibition of cathepsin S significantly decreases the response to antigens, rendering cathepsin S as a drug target for asthma and certain auto-immune diseases.
  • Cathepsins also have been implicated in tumor invasion and metastasis, and in tumors of the central nervous systems, such as astrocytoma, glioblastoma and meningioma. (Berquin et al., Perspect. Drug Discovery Design 1995, 2:371-388; Levicar et al., J. Neurooncol. 2002, 58:21- 32).
  • the compounds of the invention have Formula (1):
  • X is O or S
  • R 1 is OR 2 , halo, (CR 2 ⁇ R 3 , nitro, cyano, amino, amido, sulfonamide, or an optionally substituted Ci_6alkyl, C 2 -6 alkenyl, or C3_6 alkynyl;
  • R 2 is H, (CR 2 ) n R 3 , or an optionally substituted Ci_6alkyl, C 2 -6 alkenyl or C3_6 alkynyl;
  • R 3 is an optionally substituted aryl, heteroaryl, carbocyclic ring or heterocyclic ring; m is 1-3; and n is 0-4.
  • the compounds of the invention may be used to inhibit papain- like cathepsin proteases.
  • Cyclic carbamates 8 and 12-16 showed inhibitory activity across the board of papain- like cathepsin proteases. Within this protease family, the apparent K 1 values are lowest for cathepsin B, followed by cathepsins S, C, L, and K. Moderate activities are seen against cathepsins V, X, F and H. The compounds are shown to be inactive against other families of cysteine proteases such as caspases and against members of the serine protease family such as hepsin, thrombin, MT-SPl or trypsin.
  • cysteine proteases such as caspases and against members of the serine protease family such as hepsin, thrombin, MT-SPl or trypsin.
  • cathepsin B is first incubated at 37 0 C with 0.2 ⁇ M of compound 12 (20Ox K 1 ) for complete suppression of catalytic activity (2.9 rfu/sec for inhibitor treated versus 121 rfu/sec for vehicle control). Then the mixtures are dialyzed extensively at 4 0 C to remove unbound inhibitor before the cathepsin activities are re-measured at 37 0 C (51 rfu/sec for inhibitor treated versus 71 rfu/sec for vehicle control).
  • cathepsin B The potential adduct formation between cathepsin B and inhibitor (compound 12) is analyzed by mass spectrometry following tryptic/chymotryptic digestion.
  • Two active site fragments of the test enzyme (cathepsin B) are identified as 79 EIRDQGSCGSC * W 30 and 22 DQGSCGSC W 30 from the untreated cathepsin B sample.
  • EIRDQGSCGSC * W 30 and 22 DQGSCGSC W 30 Two active site fragments of the test enzyme (cathepsin B) are identified as 79 EIRDQGSCGSC * W 30 and 22 DQGSCGSC W 30 from the untreated cathepsin B sample.
  • For inhibitor treated cathepsin B both fragments gained a mass of 247, corresponding to a single covalent conjugation of 12 to the catalytic cysteine residues (C ).
  • C catalytic cysteine residues
  • the invention provides compounds of Formula (1) that are selective for the cathepsin family, with subtype selectivities following the order B > S > C,L,K > V,X,F,H.
  • a preference for hydrophobic R-groups in cis configuration relative to the carbamate oxygen is observed, with apparent K 1 values for Cathepsin B in the single digit nanomolar range.
  • the carbamate functionality in the scaffold is substantially destabilized, and offers a weak point for nucleophilic attack by the active site cysteine thiol.
  • the bicycle subsequently undergoes ring- opening and covalently binds to the catalytic cysteine, leading to inhibition of the enzyme. This hypothesis is in accordance with the mass spectrometric analysis of digested enzyme.
  • compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5 mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg active ingredient.
  • Compounds of the invention may be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions may be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets, together with c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; and if desired, d) disintegrants, e.g., starches,
  • compositions may be aqueous isotonic solutions or suspensions, and suppositories may be prepared from fatty emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier may include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations may also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, may be aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Compounds of the invention may be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations). Where the compounds of the invention are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.
  • the compounds of the invention may be used in combination with a chemotherapeutic agent to treat a cell proliferative disorder and tumors.
  • chemotherapeutic agents which may be used in the compositions and methods of the invention include but are not limited to anthracyclines, alkylating agents (e.g., mitomycin C), alkyl sulfonates, aziridines, ethylenimines, methylmelamines, nitrogen mustards, nitrosoureas, antibiotics, antimetabolites, folic acid analogs (e.g., dihydrofolate reductase inhibitors such as methotrexate), purine analogs, pyrimidine analogs, enzymes, podophy Ho toxins, platinum- containing agents, interferons, and interleukins.
  • alkylating agents e.g., mitomycin C
  • alkyl sulfonates e.g., aziridines, ethylenimines, methylmelamines, nitrogen
  • chemotherapeutic agents which may be used in the compositions and methods of the invention include, but are not limited to, busulfan, improsulfan, piposulfan, benzodepa, carboquone, meturedepa, uredepa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolomelamine, chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, aclacinomycin
  • Synergistic effects may also occur with other immunomodulatory or antiinflammatory substances, for example when used in combination with cyclosporin, rapamycin, or ascomycin, or immunosuppressant analogues thereof, for example cyclosporin A (CsA), cyclosporin G, FK-506, rapamycin, or comparable compounds, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolate mofetil, 15-deoxyspergualin, immunosuppressant antibodies, especially monoclonal antibodies for leukocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD45, CD58 or their ligands, or other immunomodulatory compounds, such as CTLA41g.
  • CsA cyclosporin A
  • FK-506, rapamycin or comparable compounds
  • corticosteroids
  • the invention also provides for a pharmaceutical combinations, e.g. a kit, comprising a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit may comprise instructions for its administration.
  • the reagents and conditions are: (a) CbzCl, 0.5 M Na 2 C ⁇ 3 /dioxane 5:2, rt, 5h; (b) mCPBA, DCM, O 0 C-It, 7h; (c) ROH, 2 M NaOH/MeCN 1:4, reflux, 48h; (d) 1 atm H 2 , Pd/C (cat), EtOH, rt, 3h; (e) triphosgene, NEt 3 , DCM, O 0 C, Ih; (f) NaH, rt, 18h; (g) PPh 3 , DEAD, p-nitrobenzoic acid, THF, 5O 0 C, 48h; (h) NaOH, MeOH, rt, Ih; (i) 1 atm H 2 , Pd/C (cat), EtOH, rt, 3h; Q) OsO 4 , NMO, citric acid, tBuOH
  • the regioisomers are chromatographic ally separated and hydrogenolytically deprotected to give the open forms 6 and 7.
  • the cyclization of 6 requires a two step procedure. First the piperidine-nitrogen is selectively carbonylated to the corresponding chloroformate using triphosgene and triethylamine, then the 3 -hydroxy group is deprotonated using sodium hydride, which leads to spontaneous intramolecular cyclization to give racemic ?r «n5-4-(2,3-dimethyl-phenoxy)-6-oxa-l-aza-bicyclo[3.2.1]octan-7-one 8. Attempts to cyclize the chloroformate intermediate of 7 to the bicycle 9 are unsuccessful, probably due to the unfavorable boat conformation of the piperidine ring required for intramolecular ring closure.
  • Both stereoisomers 8 and 12 are isolated as white, stable solids. The compounds are also stable in aqueous basic or neutral solutions, while spontaneous ring opening is observed under fairly acidic conditions (pH ⁇ 2).
  • Analogs 13-16 (Table 1, supra) are synthesized in a similar fashion to the synthesis of 12. In the case of analog 13, thiophosgene is used instead of phosgene in the cyclization step; for analogs 15 and 16, the corresponding alcohol (benzylalcohol for 15, isopropanol for 16) is used as solvent together with NaH in the opening of epoxide 3.
  • An alternative synthetic route via dihydroxylation leads to the protected tetrahydropyridine 17.
  • Compounds of the present invention that have acidic groups may be converted into salts with pharmaceutically acceptable bases, e.g., an aqueous alkali metal hydroxide, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol.
  • Resulting salts may be converted into the free compounds, e.g., by treatment with acids.
  • These or other salts may also be used for purification of the compounds obtained.
  • Ammonium salts may be obtained by reaction with the appropriate amine, e.g., diethylamine, and the like.
  • compounds of the present invention having basic groups may be converted into acid addition salts, especially pharmaceutically acceptable salts.
  • inorganic acids such as mineral acids (e.g., sulfuric acid, a phosphoric or hydrohalic acid); organic carboxylic acids (e.g., Ci-C 4 alkyl carboxylic acids such as acetic acid, which may be unsubstituted or substituted by halogen; saturated or unsaturated dicarboxylic acids, such as oxalic, succinic, maleic or fumaric acid; hydroxycarboxylic acids, such as glycolic, lactic, malic, tartaric or citric acid); amino acids, such as aspartic or glutamic acid); organic sulfonic acids (e.g., Ci-C 4 alkylsulfonic acids such as methanesulfonic acid); or arylsulfonic acids which may be unsubstituted or substituted (for example, by halogen).
  • inorganic acids such as mineral acids (e.g
  • the compounds of the present invention that comprise free hydroxyl groups may also exist in the form of pharmaceutically acceptable, physiologically cleavable esters, and as such may be included within the scope of the invention.
  • Such pharmaceutically acceptable esters may be preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiological conditions to the corresponding compounds of the present invention which comprise free hydroxyl groups.
  • Suitable pharmaceutically acceptable prodrug esters may be those derived from a carboxylic acid, a carbonic acid monoester or a carbamic acid, preferably esters derived from an optionally substituted lower alkanoic acid or an arylcarboxylic acid.
  • 1,2,3,6-Tetrahydropyridine (1.1 mL, 12 mmol) is dissolved in dioxane (10 mL). An aqueous solution of 0.5 M sodium carbonate (25 mL, 12.5 mmol) is added followed by benzyl chloroformate (1.8 mL, 12 mmol). The mixture is stirred for 3 h at rt, then diluted with ethyl acetate (50 mL). The organic layer is separated, washed with water and dried over magnesium sulfate. The solvents are removed in vacuo to give 3,6-dihydro-2H-pyridine-l-carboxylic acid benzyl ester as a colorless liquid.
  • trans-4-(2,3-Dimethyl-phenoxy)-3-hydroxy-piperidine-l-carboxylic acid benzyl ester 4 (700 mg, 2.0 mmol) is dissolved in EtOH (10 mL) and a catalytic amount of palladium (10% on charcoal) is added. After stirring for 3 h at rt under 1 atm hydrogen, the mixture is filtered over CELITE® and washed with EtOH.
  • cis-4-(2,3-Dimethyl-phenoxy)-6-oxa-l-aza-bicyclor3.2.11octan-7-one (12) [0060] cis-4-(2,3-Dimethyl-phenoxy)-piperidin-3-ol 11 (50 mg, 0.23 mmol) is dissolved in DCM (10 mL). Triphosgene (45 mg, 0.15 mmol) is added and the mixture is cooled to O 0 C. Then triethylamine (96 ⁇ L, 0.69 mmol) is added slowly in increments over 50 min. After warming to rt, sodium hydride (30 mg, 0.75 mmol) is added, and the mixture is stirred at rt overnight.
  • LC-MS analysis of samples is performed using an LCQ Deca XP Plus mass spectrometer modified with a home-built nanospray source configured for online desalting as described in Licklider et al., Anal. Chem. 74:3076-3083 (2002).
  • the peptide digests are loaded onto a 100 ⁇ m i.d. precolumn packed with 2 cm of Monitor, 5 ⁇ m, C18 (Column Engineering, Ontario, Canada), and desalted for 5 min at 5 ⁇ L/min with 0.1 M HOAc. After desalting, the precolumn is placed in line with a 75 ⁇ m i.d.
  • MS-MS are acquired in a data-dependent scanning mode with one full scan followed by three MS-MS scans on the three most intense precursor ions. The dynamic exclusion of previously selected precursors is set to 1 min. Tandem MS data are analyzed with TurboSequest (Thermo Electron). A custom database containing 8 proteins is searched using the following parameters: variable methionine oxidation, carboxamidomethyl adduct on cysteine, and carbamate adduct on cysteine (+247) or histidine (+247).
  • Example 11 Peptides identified by LC-MS/MS from inhibitor treated cathepsin B
  • Cathepsin B is digested with trypsin and chymotrypsin.
  • Peptides are identified by nano-LC-MS/MS as described in the methods section.
  • " ⁇ denotes carboxymethylated cysteines and "#” indicates modification by the strained carbamate compound.
  • the unmodified peptide is present at an amount 118-fold less than the modified peptide.
  • Q-Tof analysis of the intact protein there is an additional cleavage of the pro-enzyme upon auto-activation to yield the active enzyme with alternative N-terminal sequence starting points. The cleavage at position -4 relative to the expected major cleavage product is noted in Table 2.
  • Samples of cathepsin B are inhibited with compound 12 followed by overnight dialysis in order to remove any non-cathepsin bound compound. Dialyzed samples are then analyzed by LC-MS for the presence of the dissociation product 11. Prior to LC-MS analysis, the samples are incubated for 2 h on ice or at 37°C. The temperature effect on carbamate inhibited cathepsin B samples is evaluated using LC-MS with multiple reaction monitoring (MRM) on an Applied Biosystems/MDS SCIEX 4000 Q TRAP. MRM transitions for the open form of the carbamate are determined by infusion of a synthetic standard. Collision energy and exit cell potential are individually optimized for each of the selected transitions.
  • MRM multiple reaction monitoring
  • Cathepsin B samples are loaded on a Phenomenex Luna C5 column (30 x 2mm) in 2% ACN, 0.1M HOAc and eluted using a 5 min linear gradient to 70% ACN, 0.1M HOAc and flow rate of 300 ⁇ L/min. Effluent from the column is introduced into the 4000 QTRAP using a TurboV ion source.
  • Source parameters are: Cur, 10; IS, 4500; TEM, 450; GSl, 30; GS2, 15.
  • Cathepsin B is inhibited with compound 12 and dialyzed overnight.
  • Compound 11 is detected using LC-MS with MRM post dialysis (panel A) and after incubation for 2 hours on ice (panel B) or at 37C (panel C).
  • MRM transitions are chosen from collisionally activated dissociation of a synthetic standard of compound 11 (inset). Five MRM transitions are monitored for the detection of compound 11 (222.1 to 100.0, 71.1, 69.0, 81.9, and 55.0) and only the most intense transition is graphed for clarity (222.1 to 100.0).
  • MRM MRM transitions are selected and optimized using a synthetic analog of a metabolite (compound 11).
  • the abundance of the compound 11 increased four-fold after incubation at 37°C for 2 hrs.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des composés (I) et des compositions pharmaceutiques de ceux-ci et plus particulièrement des carbamates bicycliques, lesquels sont utiles en tant qu'inhibiteurs des cathepsines ; et des procédés d'utilisation de tels composés ou de sels acceptables du point de vue pharmaceutique de ceux-ci. [Dans la formule (I), X est O ou S ; R1 est OR2, un halogéno, (CR2)nR3, un nitro, un cyano, un amino, un amido, un sulfonamide ou un alkyle en C1-6, alcényle en C2-6 ou alcynyle en C3-6 éventuellement substitué ; R2 est H, (CR2)nR3 ou un alkyle en C1-6, alcényle en C2-6 ou alcynyle en C3-6 éventuellement substitué ; R3 est un aryle, hétéroaryle, cycle carbocyclique ou hétérocycle éventuellement substitué; m vaut 1-3 ; et n vaut 0-4.]
PCT/US2007/081635 2006-10-23 2007-10-17 Inhibiteurs de protéases de type cathepsines WO2008051763A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
BRPI0717348-2A2A BRPI0717348A2 (pt) 2006-10-23 2007-10-17 Composições e processos para inibir captecina proteases
CA002667816A CA2667816A1 (fr) 2006-10-23 2007-10-17 Inhibiteurs de proteases de type cathepsines
MX2009004290A MX2009004290A (es) 2006-10-23 2007-10-17 Inhibidores de proteasas de catepsina.
JP2009534774A JP2010507681A (ja) 2006-10-23 2007-10-17 カテプシンプロテアーゼ阻害剤
AU2007309195A AU2007309195A1 (en) 2006-10-23 2007-10-17 Cathepsin proteases inhibitors
EP07844341A EP2078027A1 (fr) 2006-10-23 2007-10-17 Inhibiteurs de protéases de type cathepsines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86250006P 2006-10-23 2006-10-23
US60/862,500 2006-10-23

Publications (1)

Publication Number Publication Date
WO2008051763A1 true WO2008051763A1 (fr) 2008-05-02

Family

ID=39091868

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/081635 WO2008051763A1 (fr) 2006-10-23 2007-10-17 Inhibiteurs de protéases de type cathepsines

Country Status (9)

Country Link
EP (1) EP2078027A1 (fr)
JP (1) JP2010507681A (fr)
KR (1) KR20090064463A (fr)
CN (1) CN101589047A (fr)
AU (1) AU2007309195A1 (fr)
BR (1) BRPI0717348A2 (fr)
CA (1) CA2667816A1 (fr)
MX (1) MX2009004290A (fr)
WO (1) WO2008051763A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9982257B2 (en) 2012-07-13 2018-05-29 Wave Life Sciences Ltd. Chiral control
US10017463B2 (en) 2014-07-21 2018-07-10 Brandeis University Inhibitors of deubiquitinating proteases
US10144933B2 (en) 2014-01-15 2018-12-04 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator
US10149905B2 (en) 2014-01-15 2018-12-11 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having antitumor effect and antitumor agent
US10160969B2 (en) 2014-01-16 2018-12-25 Wave Life Sciences Ltd. Chiral design
US10167309B2 (en) 2012-07-13 2019-01-01 Wave Life Sciences Ltd. Asymmetric auxiliary group
US10280192B2 (en) 2011-07-19 2019-05-07 Wave Life Sciences Ltd. Methods for the synthesis of functionalized nucleic acids
US10307434B2 (en) 2009-07-06 2019-06-04 Wave Life Sciences Ltd. Nucleic acid prodrugs and methods of use thereof
US10329318B2 (en) 2008-12-02 2019-06-25 Wave Life Sciences Ltd. Method for the synthesis of phosphorus atom modified nucleic acids
US10428019B2 (en) 2010-09-24 2019-10-01 Wave Life Sciences Ltd. Chiral auxiliaries

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002010172A1 (fr) * 2000-08-01 2002-02-07 Aventis Pharma Sa Composes azabicycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens
WO2003063864A2 (fr) * 2002-01-28 2003-08-07 Aventis Pharma S.A. Composes heterocycliques, actifs comme inhibiteurs de beta-lactamases
WO2005039496A2 (fr) * 2003-10-21 2005-05-06 Irm Llc Inhibiteurs de la cathepsine s

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002010172A1 (fr) * 2000-08-01 2002-02-07 Aventis Pharma Sa Composes azabicycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens
WO2003063864A2 (fr) * 2002-01-28 2003-08-07 Aventis Pharma S.A. Composes heterocycliques, actifs comme inhibiteurs de beta-lactamases
WO2005039496A2 (fr) * 2003-10-21 2005-05-06 Irm Llc Inhibiteurs de la cathepsine s

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EPPLE ET AL: "Bicyclic carbamates as inhibitors of papain-like cathepsin proteases", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 17, no. 5, 14 February 2007 (2007-02-14), pages 1254 - 1259, XP005888459, ISSN: 0960-894X *
HERDEIS C ET AL: "Synthesis of Nonracemic 2,3,6-Trisubstituted Piperidine Derivatives from Sugar Lactones via Tandem Wittig [2+3] Cycloaddition Reaction. A Novel Entry to Prosopis and Cassia Alkaloids", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 55, no. 4, 22 January 1999 (1999-01-22), pages 1043 - 1056, XP004151327, ISSN: 0040-4020 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10329318B2 (en) 2008-12-02 2019-06-25 Wave Life Sciences Ltd. Method for the synthesis of phosphorus atom modified nucleic acids
US10307434B2 (en) 2009-07-06 2019-06-04 Wave Life Sciences Ltd. Nucleic acid prodrugs and methods of use thereof
US10428019B2 (en) 2010-09-24 2019-10-01 Wave Life Sciences Ltd. Chiral auxiliaries
US10280192B2 (en) 2011-07-19 2019-05-07 Wave Life Sciences Ltd. Methods for the synthesis of functionalized nucleic acids
US9982257B2 (en) 2012-07-13 2018-05-29 Wave Life Sciences Ltd. Chiral control
US10167309B2 (en) 2012-07-13 2019-01-01 Wave Life Sciences Ltd. Asymmetric auxiliary group
US10590413B2 (en) 2012-07-13 2020-03-17 Wave Life Sciences Ltd. Chiral control
US10144933B2 (en) 2014-01-15 2018-12-04 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator
US10149905B2 (en) 2014-01-15 2018-12-11 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having antitumor effect and antitumor agent
US10160969B2 (en) 2014-01-16 2018-12-25 Wave Life Sciences Ltd. Chiral design
US10017463B2 (en) 2014-07-21 2018-07-10 Brandeis University Inhibitors of deubiquitinating proteases

Also Published As

Publication number Publication date
CN101589047A (zh) 2009-11-25
BRPI0717348A2 (pt) 2013-10-15
KR20090064463A (ko) 2009-06-18
CA2667816A1 (fr) 2008-05-02
EP2078027A1 (fr) 2009-07-15
JP2010507681A (ja) 2010-03-11
MX2009004290A (es) 2009-07-27
AU2007309195A1 (en) 2008-05-02

Similar Documents

Publication Publication Date Title
WO2008051763A1 (fr) Inhibiteurs de protéases de type cathepsines
AU2004204692B2 (en) Macrocyclic beta-secretase inhibitors for treatment of Alzheimer's disease
EP2903998B1 (fr) Antagonistes d'iap
EP2882740B1 (fr) Antagonistes de iap
KR102128232B1 (ko) 매크로사이클릭 프롤린 유도된 ｈｃｖ 세린 프로테아제 억제제
TW502020B (en) Arylsulfonyl hydroxamic acid derivatives
US20070167409A1 (en) Compounds and Methods for Treating Toll-Like Receptor 2-Related Diseases and Conditions
JP2002518368A (ja) メタロプロテイナーゼ阻害剤としての環式ヒドロキサム酸類
OA11594A (en) Hydroxy pipecolate hydroxamic acid derivatives as MMP inhibitors.
EA012810B1 (ru) Димерные ингибиторы ингибиторов белков апоптоза (iap)
JP2002536373A (ja) スルファメトヒドロキサム酸メタロプロテアーゼ阻害剤
JP2011521911A (ja) Ｃ型肝炎ウイルス阻害剤
JP2011506472A (ja) 大環状オキシミルｃ型肝炎セリンプロテアーゼ阻害剤
JP7130873B2 (ja) バニン阻害剤としてのヘテロ芳香族化合物
AU2006222232A1 (en) 3,4,5-substituted piperidine compounds
DE10322191B4 (de) N-sulfonylierte Aminosäurederivate, Verfahren zu ihrer Herstellung und ihre Verwendung
US20160229839A1 (en) Factor XIa Inhibitors
EP2864296A1 (fr) Composés 2h-imidazol-4-amine et leur utilisation en tant qu'inhibiteurs de bace
WO2011156220A1 (fr) Nouveaux inhibiteurs de prolylcarboxypeptidase
KR20170002407A (ko) C형 간염 바이러스의 강력하고 선택적인 저해제
CN115835907A (zh) 用于靶向pd-l1的方法和组合物
KR20150064736A (ko) 아자인돌린
KR20150042792A (ko) Bir2 및/또는 bir3 억제제로서 아자헤테로사이클
AU2014214325A1 (en) Substituted carboxylic acid derivatives as aggrecanase inhibitors for the treatment of osteoarthritis
EP2132174B1 (fr) Amides d'aminoacides secondaires de phénylsulfonylamide méta-substitué, leur production et leur utilisation comme inhibiteurs de la matriptase

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200780039462.2

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07844341

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2451/DELNP/2009

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2007844341

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: MX/A/2009/004290

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 2009534774

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2007309195

Country of ref document: AU

Ref document number: 2667816

Country of ref document: CA

Ref document number: 1020097008318

Country of ref document: KR

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2007309195

Country of ref document: AU

Date of ref document: 20071017

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2009119362

Country of ref document: RU

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: PI0717348

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20090422