WO2009129370A1 - Inhibiteurs de la cathepsine c - Google Patents

Inhibiteurs de la cathepsine c Download PDF

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Publication number
WO2009129370A1
WO2009129370A1 PCT/US2009/040771 US2009040771W WO2009129370A1 WO 2009129370 A1 WO2009129370 A1 WO 2009129370A1 US 2009040771 W US2009040771 W US 2009040771W WO 2009129370 A1 WO2009129370 A1 WO 2009129370A1
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WIPO (PCT)
Prior art keywords
cyano
pyrrolidinyl
mmol
thiophenesulfonamide
ring
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PCT/US2009/040771
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English (en)
Inventor
Jianghe Deng
Dramane Ibrahim Laine
Brent W. Mccleland
Michael R. Palovich
Emile Veronique Petitjean
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Glaxo Group Limited
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Publication of WO2009129370A1 publication Critical patent/WO2009129370A1/fr

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    • 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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—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 no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to certain l-cyano-3-pyrrolidinyl-benzenesulfonamides that are cathepsin C inhibitors, and their use in the treatment of diseases mediated by the cathepsin C enzyme such as chronic obstructive pulmonary disease.
  • Cathepsins are a family of enzymes included in the papain superfamily of cysteine proteases. Cathepsins B, C, F, H, K, L, S, V, and X have been described in the scientific literature. Cathepsin C is also known in the literature as Dipeptidyl Peptidase I or "DPPI.”
  • cathepsin C is co-expressed with certain serine proteases, which are released from inflammatory cells recruited to cites of inflammation, and acts as a physiological activator of these proteases. Once activated, these proteases are capable of degrading various extracellular matrix components, which can lead to tissue damage and chronic inflammation.
  • COPD Chronic Obstructive Pulmonary Disease
  • the American Thoracic Society defines COPD as "a disease characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and may be partially reversible.”
  • Chronic bronchitis is generally characterized by a chronic productive cough, whereas emphysema is generally characterized by permanent enlargement of the airspaces distal to the terminal bronchioles and airway wall destruction.
  • Chronic bronchitis and emphysema usually occur together in COPD patients.
  • Cigarette smoking is a significant risk factor for developing COPD. Exposure to cigarette smoke and other noxious particles and gases may result in chornic inflammation of the lung. In response to such exposure, inflammatory cells such as CD8+ Tcells, macrophages, and neutrophils are recruited to the area. These recruited inflammatory cells release proteases, which are believed to play a major role in the disease etiology by degrading airway walls. Proteases believed to be involved in this process include the serine proteases neutrophil elastase ("NE"), chymase ("CY”), cathepsin G, proteinase 3 and granzymes A and B. Cathepsin C appears to be involved in activating these enzymes.
  • NE neutrophil elastase
  • CY chymase
  • Cathepsin C appears to be involved in activating these enzymes.
  • RA Rheumatoid arthritis
  • Cathepsin C appears to play a role.
  • Neutrophils are recruited to the site of joint inflammation and release cathepsin G, NE, and proteinase 3, which are believd to be responsible for cartilage destruction associated with RA.
  • Cathepsin C appears to be involved in activating these enzymes.
  • cathepsin C may play a role
  • Other conditions where cathepsin C may play a role include osteoarthritis, asthma, and Multiple Sclerosis.
  • Matsui K. Yuyama N. Akaiwa M. Yoshida NL. Maeda M. Sugita Y. Izuhara K. Identification of an alternative splicing variant of cathepsin C/dipeptidyl-peptidase I, Gene. 293(1-2): 1-7, 2002 Jun 26; Wolters PJ.
  • Laig- Webster M. Caughey GH. Dipeptidyl peptidase I cleaves matrix-associated proteins and is expressed mainly by mast cells in normal dog airways, American Journal of Respiratory Cell & Molecular Biology. 22(2): 183-90, 2000.
  • this invention relates to compounds of formula (I)
  • Ar is a monocyclic heteroaromatic ring, a bicyclic heteroaromatic ring or a bicyclic heterocycloalkylaromatic ring wherein the monocyclic ring or one or both rings of a bicyclic heteroaromatic ring or bicyclic heterocycloalkylaromatic contains one or more of N, O, or S; any ring carbon being optionally substituted by at least one substituent X which is selected from the group consisting of: Ci-C ⁇ alkyl; C 2 -Cealkenyl; C 2 -C6alkynyl; halo; halo-substituted Ci-C ⁇ alkyl; C(O)R 2 ; a monocyclic heteroaromatic ring containing one or more of N, O or S; aryl unsubstituted or substituted by Ci-C 6 alkyl, halo, halo-substituted Ci-C ⁇ alkyl, or C(O)R 2 ; aryl
  • this invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the prevention, management or treatment of a respiratory or inflammatory disease, such as chronic obstructive pulmonary disease or rhinitis.
  • a respiratory or inflammatory disease such as chronic obstructive pulmonary disease or rhinitis.
  • this invention relates to a pharmaceutically acceptable formulation
  • a pharmaceutically acceptable formulation comprising a compound of forumula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups the selected groups may be the same or different.
  • independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • An "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • the term "therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • alkyl refers to a saturated straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms.
  • the terms "Ci-C 6 alkyl” and “Ci_Cio alkyl” refers to such a group having at least 1 and up to 6 or 10 carbon atoms respectively.
  • Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, and n-decyl, and branched analogs of the latter 5 normal alkanes.
  • Ci-Cio-alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 , or more, carbon-carbon double bonds. Examples include ethenyl (or ethenylene) and propenyl (or propenylene).
  • Ci-Cioalkynyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1, or more, carbon-carbon triple bonds. Examples include ethynyl (or ethynylene) and propynyl (or propynylene).
  • Cs-C ⁇ Cycloalkyl refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. So, for example, the term “C3_C ⁇ cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to eight carbon atoms.
  • Exemplary "C3-C6 cycloalkyl” groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C4-C6cycloalkenyl refers to a non-aromatic monocyclic carboxycyclic ring having the specified number of carbon atoms and up to 3 carbon-carbon double bonds.
  • Cycloalkenyl includes by way of example cyclopentenyl and cyclohexenyl.
  • Halo means the halogen radical fluoro, chloro, bromo, or iodo.
  • Haloalkyl means a Ci-Cioalkyl, Ci-Cio-alkenyl, or Ci-Cioalkynyl group that is substituted with one or more halo substituents. Haloalkyl includes trifluoromethyl.
  • C3-C6 heterocycloalkyl means a non-aromatic heterocyclic ring containing the specified number of ring atoms being, saturated or having one or more degrees of unsaturation and containing one or more heteroatom substitutions selected from O, S and/or N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s).
  • heterocyclic moieties include, but are not limited to, aziridine, thiirane, oxirane, azetidine, oxetane, thietane, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, 2,4- piperazinedione, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, and the like.
  • Aryl refers to optionally substituted monocyclic and polycarbocyclic unfused or fused groups having 6 to 14 carbon atoms and having at least one aromatic ring that complies with H ⁇ ckel's Rule.
  • aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl and the like.
  • “Monocyclic heteroaromatic ring” means an optionally substituted aromatic monocyclic ring wherein the ring complies with H ⁇ ckel's Rule, has the specified number of ring atoms, and that ring contains at least one heteratom selected from N, O, and/or S.
  • Examples of these groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, and indazolyl.
  • a "bicyclic heteroaromatic ring” is a polycarbocyclic fused ring system having 2 rings, both of which comply with H ⁇ ckel's Rule and at least one ring contains at least one heteratom which is N, O, and/or S.
  • these groups include rings that have 7-9 carbon atoms and at least one of N, O or S in 1 of the rings; one or both rings may have 2 or more of N, O or S in any combination with a concomitant reduction in carbon atoms. Examples include quinolines, benzothiadiazoles, benzothiophenes, and the like.
  • a "bicyclic heterocycloalkylaromatic ring” is one which has 2 rings wherein 1 ring is an aryl ring as defined above and the other is a fused C 3 -C 6 heterocycloalkyl ring, as defined above.
  • Monocyclic or bicyclic groups of particular interest in this invention include the following rings where the floating bond on the left side of the ring means the (O) 2 S-C bond is to any carbon in the ring, except where noted:
  • Enantiomerically enriched refers to products whose enantiomeric excess is greater than zero.
  • enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.
  • Enantiomeric excess or "ee” is the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).
  • Enantiomerically pure means products whose enantiomeric excess is 99% ee or greater.
  • Halo means the halogen radical fluoro, chloro, bromo, or iodo.
  • Haloalkyl means an alkyl group that is substituted with one or more halo substituents. Haloalkyl includes trifluoromethyl.
  • Some compounds of formula (I) have a nitrogen which is basic enough to form pharmaceutically-acceptable acid addition salts by treatment with a suitable acid.
  • Suitable acids include pharmaceutically-acceptable inorganic acids amd pharmaceutically-acceptable organic acids.
  • Representative pharmaceutically-acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxy
  • salts include pharmaceutically- acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically-acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
  • pharmaceutically- acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts
  • carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc
  • the compounds according to formula I may contain one or more asymmetric center, also referred to as a chiral center, and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers may also be present in a substituent such as an alkyl group.
  • the stereochemistry of a chiral center present in formula I, or in any chemical structure illustrated herein, is not specified the structure is intended to encompass any stereoisomer and all mixtures thereof.
  • compounds according to formula I containing one or more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.
  • Individual stereoisomers of a compound according to formula I which contain one or more asymmetric center may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer- specif ⁇ c reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral enviornment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form.
  • specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically-acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water. The invention includes all such solvates.
  • polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymophs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the compounds of the invention inhibit the cathepsin C enzyme and can be useful in the treatment of conditions wherein the underlying pathology is (at least in part) attributable to cathepsin C involvement or in conditions wherein cathepsin C inhibition offers some clinical benefit even though the underlying pathology is not (even in part) attributable to cathepsin C involvement.
  • Examples of such conditions include COPD, rheumatoid arthritis, osteoarthritis, asthma, and multiple sclerosis. Accordingly, in another aspect the invention is directed to methods of treating such conditions.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound of the invention to a patient in need thereof.
  • treatment in reference to a condition means: (1) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.
  • prevention of a condition includes prevention of the condition.
  • prevention is not an absolute term.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safety and effective amount and “therapeutically effective amount” in reference to a compound of formula I, or a pharmaceutically acceptable salt of it, means an amount of sufficient to significantly induce a positive modification in the condition to be treated but low enough to avoid serious side effects at a reasonable benefit/risk ratio within the scope of sound medical judgment.
  • a safe and effective amount of a compound of the invention will vary with the particular compound chosen, e.g.
  • patient refers to a human or animal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the amount administered and the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the particular route of administration chosen, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Typical daily dosages range from 10 mg to 1000 mg.
  • the compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.
  • the pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds. Conversely, the pharmaceutical compositions of the invention typically contain more than one pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one pharmaceutically-acceptable excipient.
  • pharmaceutically-acceptable excipient means a material, composition or vehicle involved in giving form or consistency to the composition and which is safe when administered to a patient.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsif ⁇ ers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsif ⁇ ers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chel
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
  • the invention is directed to a dosage form adapted for administration to a patient by inhalation.
  • the compound of the invention may be inhaled into the lungs as a dry powder, an aerosol, a suspension, or a solution.
  • Dry powder compositions for delivery to the lung by inhalation typically comprise a compound of the invention as a finely divided powder together with one or more pharmaceutically-acceptable excipients as finely divided powders.
  • Pharmaceutically- acceptable excipients particularly suited for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-, and polysaccharides.
  • the dry powder may be administered to the patient via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (un-metered doses) of medicament in dry powder form.
  • RDPIs typically include a means for metering each medicament dose from the reservoir to a delivery position.
  • the metering means may comprise a metering cup, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation.
  • the dry powder may be presented in capsules (e.g. gelatin or plastic), cartridges, or blister packs for use in a multi-dose dry powder inhaler (MDPI).
  • MDPIs are inhalers wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof) of medicament.
  • the dry powder is presented as a blister pack, it comprises multiple blisters for containment of the medicament in dry powder form.
  • the blisters are typically arranged in regular fashion for ease of release of the medicament therefrom.
  • the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the blisters may be elongate in form, for example comprising a strip or a tape.
  • Each capsule, cartridge, or blister may, for example, contain between 20 ⁇ g-10mg of the compound of the invention.
  • Aerosols may be formed by suspending or dissolving a compound of the invention in a liquified propellant.
  • Suitable propellants include halocarbons, hydrocarbons, and other liquified gases.
  • Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA- 134a), 1,1-difluoroethane (HFA- 152a), difluoromethane (HFA-32), pentafluoroethane (HFA- 12), heptafluoropropane (HFA- 227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane. Aerosols comprising a compound of the invention will typically be administered to a
  • the aerosol may contain additional pharmaceutically-acceptable excipients typically used with multiple dose inhalers such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
  • additional pharmaceutically-acceptable excipients typically used with multiple dose inhalers such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
  • Suspensions and solutions comprising a compound of the invention may also be administered to a patient via a nebulizer.
  • the solvent or suspension agent utilized for nebulization may be any pharmaceutically-acceptable liquid such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc. or mixtures thereof.
  • Saline solutions utilize salts which display little or no pharmacological activity after administration.
  • organic salts such as alkali metal or ammonium halogen salts, e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose.
  • organic acids e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc.
  • Other pharmaceutically-acceptable excipients may be added to the suspension or solution.
  • the compound of the invention may be stabilized by the addition of an inorganic acid, e.g., hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid; an organic acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., a complexing agent such as EDTA or citric acid and salts thereof; or an antioxidant such as antioxidant such as vitamin E or ascorbic acid.
  • Preservatives may be added such as benzalkonium chloride or benzoic acid and salts thereof.
  • Surfactant may be added particularly to improve the physical stability of suspensions. These include lecithin, disodium dioctylsulphosuccinate, oleic acid and sorbitan esters.
  • the compounds of formula (I) may be obtained by using synthetic procedures illustrated in the Schemes below or by drawing on the knowledge of a skilled organic chemist.
  • the synthesis provided in these Schemes are applicable for producing compounds of the invention having a variety of different Ri groups employing appropriate precursors, which are suitable protected if needs be, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, where needs be, and then affords compounds of the nature generally disclosed. While the Schemes are shown with compounds only of formula (I), they are illustrative of processes that may be used to make the compounds of the invention.
  • Reagents and conditions a) ArSO 2 Cl, TEA, DCM; b) 4 N HCl, Dioxane ; c) BrCN, DIEA, DCM.
  • LC-MS analysis Liquid Chromatograph: System: Shimadzu LC system with SCL-IOA Controller and dual UV detector
  • the eluent was a mixture composed of solvents A and B: o Solvent A: 0.1% trifluoroacetic acid in water o Solvent B: 0.1% trifluoroacetic acid in acetonitrile
  • PS-trisamine A tris-(2-aminoethyl)amine polystyrene resin (Argonaut®, p/n 800230)
  • the compounds according to formula I are cathepsin C inhibitors, which indirectly inhibit the activity of serine proteases that are activated by cathepsin C, such as NE.
  • the biological activity of the compounds according to formula (IA) or (IB) can be determined using any suitable assay for determining the activity of a candidate compound as a cathepsin C inhibitor or for determining the ability of a candidate compound to prevent the cathepsin C mediated activation of certain serine proteases, as well as suitable tissue and in vivo models. All examples were found to be cathepsin C inhibitors.
  • Cathepsin C has been shown to catalyze the transpeptidation of dipeptidyl methyl- O -esters within the lysosome of cell frm the monocytic lineage like HL60, U937 or THPl causing a membranolythic effects that results in cell death ( DL. Thiele P. Lipsky PNAS 1990 Vol. 87, pp. 83-87). This phenomenon was used to assess cellular Cathepsin C activity in the presence of our compounds. Reagents:
  • Iscove's Modified Dulbecco's Medium with L-Glutamine with 25mMolar HEPES buffer (GSK Media Prep Lab)
  • GSK media prep lab HL60 (ATCC, CCL-240) Dimethyl Sulfoxide (DMSO) (Sigma, D8418)
  • IM HEPES buffer solution Gibco, 15630-080
  • CellTiter-Glo Luminescent Cell Viability Assay Promega, G7572, G7573
  • Count HL60 cells with Hemocytometer Spin cells down at 1200K for 5 min.
  • Dispense lOOul/well of re-suspended cells in sterile black clear bottom polystyrene 96- well plate (Costar #3603).
  • LLOM is Vi serial diluted in IMDM with
  • Blood is collected, and each 25 mL of blood is layered over 15 mL Ficol-Paque Plus and centrifuged at 40Og at room temperature for 30 min. (brake is OFF). Discard everything above the red cell fraction.
  • Red blood cell (RBC) pellets are resuspended to 35 mL in PBS w/o.
  • Mix Dextran tubes by inversion, and add 12 mL to each blood tube.
  • Mix RBC tubes by inversion and allow to stand undisturbed at room temperature for about 40 minutes ( a clearly defined Richleau layer appears).
  • the layer above the RBC is collected, adjusted to 50 mL with PBS w/o, and centrifuged at 800 g at room temperature for 5 min. ( brake can be on). The sups are decanted and discarded down to about 3 rnL, then the cells are gently dislodged and resuspended ( in remaining supt.).
  • Lyse the RBC by adding 18 rnL sterile water for 30 seconds at room temperature followed by 2 mL 1OX PBS w/o.
  • the cell suspensions are adjusted to 50 mL with PBS w/o and centrifuged at 800 g for 5 min. at room temperature. Decant and discard sup.
  • PBS Dulbecco's Phosphorus Buffered Saline without calcium and magnesium
  • PBS/gelatin Dulbecco's Phosphorus Buffered Saline without calcium and magnesium with 0.1% gelatin made from a stock of 3% gelatin (Sigma) which is boiled and frozen in aliquots.
  • a 96-welled v-bottom plate polypropylene: 2OuL stock compound solution (1OmM in DMSO) added to wells in top row. DMSO added to alternating rows at 20 and 23uL. Dilutions are made by placing 10 uL to the row below, mixing then repeating serially until reaching the bottom row using a multichannel pipettor. Resuspend PMN in PBS/gelatin to a final concentration of 200,000 cells per mL.
  • Recombinant Cathepsin C in vitro assay The activity of recombinant human cathepsin C is measured by the cleavage of a fluorogenic substrate, H-Ser-Tyr-AMC. Briefly, 20 pM cathepsin C is incubated with test compound (e.g. inhibitor) in a buffer consisting of 50 mM sodium acetate, 30 mM sodium chloride, 1 mM CHAPS, 1 mM dithiothreitol, 1 mM EDTA, pH 5.5 at room temperature for one hour.
  • test compound e.g. inhibitor
  • the activity assay is initiated by the addition of an equal volume of 0.010 mM H-Ser-Tyr-AMC in the same buffer. After one hour, the activity assay is stopped by the addition of 1/10 volume of 10 mM 2-Aldrithiol.
  • the reaction product is measured on a fluorescence reader set at an excitation wavelength of 360 nm and emission wavelength of 460 nm and equipped with a 400 nm dichroic mirror.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés représentés par la formule suivante (I), ou un sel de ceux-ci. Dans la formule, Ar représente un anneau hétéroaromatique monocyclique, un anneau hétéroaromatique bicyclique ou un anneau hétérocycloalkylaromatique bicyclique.
PCT/US2009/040771 2008-04-18 2009-04-16 Inhibiteurs de la cathepsine c WO2009129370A1 (fr)

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Cited By (15)

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WO2012119941A1 (fr) 2011-03-04 2012-09-13 Prozymex A/S Composés de peptidylnitrile à titre d'inhibiteurs de peptidases
WO2018060742A1 (fr) * 2016-09-30 2018-04-05 Mission Therapeutics Limited Dérivés de cyanopyrrolidine ayant une activité en tant qu'inhibiteurs de l'usp 30
WO2018220355A1 (fr) * 2017-05-31 2018-12-06 Mission Therapeutics Limited Cyanopyrrolidines substituées par sulfonamide ayant une activité en tant qu'inhibiteurs de dub
WO2020212351A1 (fr) 2019-04-16 2020-10-22 Mission Therapeutics Limited Cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30
WO2020212350A1 (fr) 2019-04-16 2020-10-22 Mission Therapeutics Limited Cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30
US10927110B2 (en) 2016-09-29 2021-02-23 Mission Therapeutics Limited Cyano-subtituted heterocycles with activity as inhibitors of USP30
WO2021043870A1 (fr) 2019-09-04 2021-03-11 Mission Therapeutics Limited Cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30
US11059809B2 (en) 2017-06-20 2021-07-13 Mission Therapeutics Limited Substituted cyanopyrrolidines with activity as DUB inhibitors
US11091488B2 (en) 2015-11-30 2021-08-17 Mission Therapeutics Limited 1-cyano-pyrrolidine derivatives as inhibitors of USP30
WO2021204856A1 (fr) 2020-04-08 2021-10-14 Mission Therapeutics Limited N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'usp30
WO2021239863A1 (fr) 2020-05-28 2021-12-02 Mission Therapeutics Limited N-(1-cyano-pyrrolidin-3-yl)-5-(3- (trifluorométhyl)phényl)oxazole-2-carboxamide et dérivés d'oxadiazole correspondants utilisés en tant qu'inhibiteurs d'usp30 pour le traitement d'un dysfonctionnement mitochondrial
WO2021245186A1 (fr) 2020-06-04 2021-12-09 Mission Therapeutics Limited N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'usp30
WO2021249909A1 (fr) 2020-06-08 2021-12-16 Mission Therapeutics Limited 1-(5-(2-cyanopyridin-4-yl)oxazole-2-carbonyl)-4-méthylhexahydropyrrolo[3,4-b]pyrrole-5(1h)-carbonitrile utilisé en tant qu'inhibiteur d'usp30 pour le traitement d'un dysfonctionnement mitochondrial, d'un cancer et d'une fibrose
WO2022084479A1 (fr) 2020-10-22 2022-04-28 Mission Therapeutics Limited N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'usp30
WO2023099561A1 (fr) 2021-12-01 2023-06-08 Mission Therapeutics Limited N-cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30

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WO2012119941A1 (fr) 2011-03-04 2012-09-13 Prozymex A/S Composés de peptidylnitrile à titre d'inhibiteurs de peptidases
US11091488B2 (en) 2015-11-30 2021-08-17 Mission Therapeutics Limited 1-cyano-pyrrolidine derivatives as inhibitors of USP30
US10927110B2 (en) 2016-09-29 2021-02-23 Mission Therapeutics Limited Cyano-subtituted heterocycles with activity as inhibitors of USP30
WO2018060742A1 (fr) * 2016-09-30 2018-04-05 Mission Therapeutics Limited Dérivés de cyanopyrrolidine ayant une activité en tant qu'inhibiteurs de l'usp 30
JP2019532950A (ja) * 2016-09-30 2019-11-14 ミッション セラピューティクス リミティド Ｕｓｐ３０の阻害剤としての活性を有するシアノピロリジン誘導体
US11084821B2 (en) 2016-09-30 2021-08-10 Mission Therapeutics Limited Cyanopyrrolidine derivatives with activity as inhibitors of USP30
JP7084918B2 (ja) 2016-09-30 2022-06-15 ミッション セラピューティクス リミティド Ｕｓｐ３０の阻害剤としての活性を有するシアノピロリジン誘導体
CN110678176B (zh) * 2017-05-31 2023-03-14 特殊治疗有限公司 具有dub抑制剂活性的磺酰胺取代的氰基吡咯烷
JP7221217B2 (ja) 2017-05-31 2023-02-13 ミッション セラピューティクス リミティド Ｄｕｂ阻害剤としての活性を有するスルホンアミド置換シアノピロリジン
US11414402B2 (en) 2017-05-31 2022-08-16 Mission Therapeutics Limited Sulfonamide-substituted cyanopyrrolidines with activity as DUB inhibitors
JP2020521730A (ja) * 2017-05-31 2020-07-27 ミッション セラピューティクス リミティド Ｄｕｂ阻害剤としての活性を有するスルホンアミド置換シアノピロリジン
CN110678176A (zh) * 2017-05-31 2020-01-10 特殊治疗有限公司 具有dub抑制剂活性的磺酰胺取代的氰基吡咯烷
WO2018220355A1 (fr) * 2017-05-31 2018-12-06 Mission Therapeutics Limited Cyanopyrrolidines substituées par sulfonamide ayant une activité en tant qu'inhibiteurs de dub
US11059809B2 (en) 2017-06-20 2021-07-13 Mission Therapeutics Limited Substituted cyanopyrrolidines with activity as DUB inhibitors
WO2020212350A1 (fr) 2019-04-16 2020-10-22 Mission Therapeutics Limited Cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30
WO2020212351A1 (fr) 2019-04-16 2020-10-22 Mission Therapeutics Limited Cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30
WO2021043870A1 (fr) 2019-09-04 2021-03-11 Mission Therapeutics Limited Cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30
WO2021204856A1 (fr) 2020-04-08 2021-10-14 Mission Therapeutics Limited N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'usp30
WO2021239863A1 (fr) 2020-05-28 2021-12-02 Mission Therapeutics Limited N-(1-cyano-pyrrolidin-3-yl)-5-(3- (trifluorométhyl)phényl)oxazole-2-carboxamide et dérivés d'oxadiazole correspondants utilisés en tant qu'inhibiteurs d'usp30 pour le traitement d'un dysfonctionnement mitochondrial
WO2021245186A1 (fr) 2020-06-04 2021-12-09 Mission Therapeutics Limited N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'usp30
WO2021249909A1 (fr) 2020-06-08 2021-12-16 Mission Therapeutics Limited 1-(5-(2-cyanopyridin-4-yl)oxazole-2-carbonyl)-4-méthylhexahydropyrrolo[3,4-b]pyrrole-5(1h)-carbonitrile utilisé en tant qu'inhibiteur d'usp30 pour le traitement d'un dysfonctionnement mitochondrial, d'un cancer et d'une fibrose
WO2022084479A1 (fr) 2020-10-22 2022-04-28 Mission Therapeutics Limited N-cyanopyrrolidines ayant une activité en tant qu'inhibiteurs de l'usp30
WO2023099561A1 (fr) 2021-12-01 2023-06-08 Mission Therapeutics Limited N-cyanopyrrolidines substituées ayant une activité en tant qu'inhibiteurs de l'usp30

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