(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION
`
`TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`22 October 2009 (22.10.2009)
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`(43) International Publication Date
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`(10) International Publication Number
`WO 2009/129365 Al
`
`
`(51)
`
`International Patent Classification:
`AOIN 43/36 (2006.01)
`A61K 31/40 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/US2009/040754
`
`(22)
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`International Filing Date:
`
`(25)
`
`(26)
`
`(30)
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`(71)
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`(72)
`(75)
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`Filing Language:
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`Publication Language:
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`16 April 2009 (16.04.2009)
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`English
`
`English
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`Priority Data:
`61/046047
`
`18 April 2008 (18.04.2008)
`
`US
`
`Applicant (for all designated States except US): GLAXO
`GROUP LIMITED [GB/GB]; Glaxo Wellcome House,
`berkeley avenue, Greenford, Middlesex UB6 ONN (GB).
`
`Inventors; and
`Inventors/Applicants (for US only): LAINE, Dramane
`Ibrahim [FR/US]; 709 Swedeland Road, King of Prussia,
`PA 19406 (US). LIN, Guoliang [CN/US]; 709 Swede-
`land Road, King Of Prussia, PA 19406 (US). MCCLE-
`LAND, Brent, W. [US/US]; 709 Swedeland Road, King
`Of Prussia, PA 19406 (US). PALOVICH, Michael, R.
`[US/US]; 709 Swedeland Road, King of Prussia, PA
`19406 (US).
`
`(74)
`
`Agents: KANAGY, James, M. et al; GlaxoSmithKline,
`Corporate Intellectual Property, UW2220, 709 Swedeland
`Road, P.O. Box 1539, King of Prussia, PA 19406-0939
`(US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind gf national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ,
`EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU,ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO,
`NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG,
`SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA,
`UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind d regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 7M,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR),
`OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML,
`MR, NE, SN, TD, TG).
`Declarations under Rule 4.17:
`
`as to applicant's entitlement
`apatent
`(Rule 4.1 7(H))
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`to apply for and be granted
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`to claim the priority of
`as to the applicant's entitlement
`the earlier application (Rule 4.1 7(Hi))
`
`go inventorship (Rule 4.1 7(iv))
`Published:
`
`with international search report (Art. 21(3))
`
`(54) Title: CATITEPSIN C INHIBITORS
`
`—=2
`
`(1)
`
`(Ry),
`
`(57) Abstract: This invention relates to compounds of formula (J which are useful for treating chronic obstructive disease, and
`the like.
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`
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`wo2009/129365A1IMITINMINIIMTNAIATITIRAAITAAA
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`WO 2009/129365
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`PCT/US2009/040754
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`Cathepsin C Inhibitors
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`CROSS REFERENCE TO PRIOR APPLICATIONS
`
`This application claims the benefit to US provisional 61/046047 filed 18 April
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`2008.
`
`FIELD OF THE INVENTION
`
`This invention relates to certain ]-cyano-3-pyrrolidinyl-N-substituedsulfonamides
`
`that are cathepsin C inhibitors, and their use in the treatment of diseases mediated by the
`
`10
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`cathepsin C enzyme such as chronic obstructive pulmonary disease.
`
`BACKGROUND OF THE INVENTION
`
`Cathepsins are a family of enzymes included in the papain superfamily of cysteine
`
`proteases. Cathepsins B,C, F,H,K,L,8S, V, and X have been described in the scientific
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`15
`
`literature. Cathepsin C is also known in the literature as Dipeptidyl Peptidase I or "DPPI."
`
`A number of recently published studies have begun to describe the role cathepsin C
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`plays in certain inflammatory processes. See E.g. Adkison et al., The Journal dg Clinical
`
`Investigation 109:363-371 (2002); Tran et al., Archives d Biochemistry and Biophysics
`
`403:160-170 (2002); Thiele et al., The Journal fo Immunology 158: 5200-5210 (1997);
`
`20
`
`Bidere et al., The Journal d Biological Chemistry 277: 32339-32347 (2002); Mabeeetal.,
`
`The Journal dg Immunology 160: 5880-5885; McGuire et al., The Journal o Biological
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`Chemistry, 268: 2458-2467; and Paris et al., FEBS Letters 369: 326-330 (1995). From
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`these studies, it appears that cathepsin C is co-expressed with certain serine proteases,
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`which are released from inflammatory cells recruited to cites of inflammation, and acts as
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`25
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`a physiological activator of these proteases. Once activated, these proteases are capable of
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`degrading various extracellular matrix components, which can lead to tissue damage and
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`chronic inflammation.
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`For example, Chronic Obstructive Pulmonary Disease ("COPD") is a chronic
`
`inflammatory disease where cathepsin C appears to play arole. The American Thoracic
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`30
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`Society defines COPD as "a disease characterized by the presence of airflow obstruction
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`due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive,
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`may be accompanied by airway hyperreactivity, and may be partially reversible."
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`American Journal fo Respiratory and Critical Care Medicine 152: S$77-S120 (1995).
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`WO 2009/129365
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`Chronic bronchitis is generally characterized by a chronic productive cough, whereas
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`emphysemais generally characterized by permanent enlargement of the airspaces distal to
`
`the terminal bronchioles and airway wall destruction. Chronic bronchitis and cmphyscma
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`usually occur together in COPDpatients.
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`Cigarette smoking is a significant risk factor for developing COPD. Exposure to
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`cigarette smoke and other noxious particles and gases may result in chornic inflammation
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`of the lung.
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`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
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`10
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`degrading airway walls. Proteases believed to be involved in this process include the
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`scrinc protcascs ncutrophil clastasc ("NE"), chymase ("CY"), cathcpsin G, protcinase 3
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`and granzymes A and B. Cathepsin C appearsto be involved in activating these enzymes.
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`Rheumatoid arthritis ("RA") is another chronic inflammatory disease where
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`cathepsin C appears to play arole. Neutrophils are recruited to the site ofjoint
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`15
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`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.
`
`Other conditions where cathepsin C may play arole include osteoarthritis, asthma,
`
`and Multiple Sclerosis. See E.g. Matsui K. Yuyama N.Akaiwa M. Yoshida NL. Maeda
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`20
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`M. Sugita Y. Izuhara K., Identification of an alternative splicing variant of cathepsin
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`C/dipeptidyl-peptidase LL. Gene. 293(1-2): 1-7, 2002 Jun 26; Wolters PJ. Laig- Webster M.
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`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 &
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`Molecular Biology. 22(2): 183-90, 2000.
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`25
`
`One approachto treating these conditions is to inhibit the activity of the serine
`
`proteases involved in the inflammatory process, especially NE activity. See E.g.,
`
`Ohbayashi, "Neutrophil elastase inhibitors as treatment for COPD", Expert Opin. Investig.
`
`Drugs 11(7): 965-980 (2002); Shapiro, "Neutrophil Elastase: Path Clearer, Pathogen
`
`Killer, or Just Pathologic?", Am. J. Respir. Cell Mol. Biol. 26: 266-268 (2002).
`
`In light of
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`30
`
`the role cathepsin C plays in activating certain serine proteases, especially NE,it is
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`desirable to prepare compoundsthat inhibit its activity, which thereby inhibit serine
`
`protease activity. Thus, there is a need to identify compounds that inhibit cathepsin C,
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`which can be used in the treatment of a variety of conditions mediated by cathepsin C.
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`SUMMARY OF THE INVENTION
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`In a first instance this invention relates to compounds of formula (1)
`
`or a salt thereof wherein
`
`R, is Ci-C ,alkyl; or aryl or arylCi-C ,alkyl where aryl is unsubstituted or
`
`substituted by halo, Ci-C ,alkyl, halo-substituted-Ci-C ¢alkyl, Ci-C alkoxy optionally
`substituted with halo, or S(O), where y is 0-2;
`nis 1-5,
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`10
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`each Riis independently halo; OR2; Ci-Cioalkyl unsubstituted or substituted by
`
`halo; CN; C(O)NR 3R,; NO,; NHC(O)NR 5R,; NR{Rg; a heteraromatic ring containing 1-3
`
`heteroatoms selected from the group consisting of N, O or S; aryl, unsubstituted or
`
`substituted by halo or Ci-C¢ alkyl; C3-Cecycloalkyl; C4-Cecycloalkenyl
`
`;Ci-Cioalkenyl; C,-
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`15
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`Cioalkynyl; or C(O)OR ,;
`
`R, is H, Cci-C 6 alkyl, haloCi-C 6 alkyl, C(O)Ro;
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`R3 is H; Ci-C, alkyl; C,-C,cycloalkyl,; or C,-C,heterocycloalkyl containing N, O or
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`S and where when the ring heteroatom is N it is optionally substituted by CN;
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`R, is H, or Ci-C, alkyl;
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`20
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`Rs and R, are independently H; Ci-C, alkyl; aryl unsubstituted or substituted by
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`halo, Ci-C ,alkoxy, Ci-C ,alkyl, or OR,; Ci-Ci , alkyl unsbustituted or substituted by halo or
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`Ci-C ,alkoxy;, C,-C,cycloalkyl; C,-C,cycloalkylalkyl; Ci-Cioalkenyl; Ci-Cioalkynyl; C,-
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`C,heteroycloalkyl; C,-C,heteroycloalkyl Ci-C alkyl, heteroarylCi-C alkyl or heteroaryl
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`wherein the heteroaryl ring is unstubstituted or substituted by halo, Ci-C,¢ alkyl or halo-
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`25
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`substituted-Ci-C , alkyl; or arylCi-C ,alkyl wherein the aryl group is unsubstituted or
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`substituted by halo, OR,, or C(O);
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`WO 2009/129365
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`R, and R gare independently H; Ci-Cioalkyl; arylCi-C¢alkyl wherein the aryl group
`
`is unsubstituted or substituted by R9, halo, or Ci-Cealkyl; Ci-Cioalkyl substituted by C,-
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`Cecycloalkyl, onc or more OH groups, halo; hetcroarylCi-C ¢alkyl; or hetcroaryl; or
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`Rg is OH, Ci-C¢ alkyoxy or NR2R3., wherein R,, or R, are independently H or Ci-
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`Cealkyl.
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`In a second instance, this invention relates to the use of a compound of formula (1)
`
`or a pharmaceutically acceptable salt thereof in the prevention, management or treatment
`
`of arespiratory or inflammatory disease, such as chronic obstructive pulmonary disease or
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`rhinitis.
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`10
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`In a further aspect, this invention relates to apharmaceutically acceptable
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`formulation comprising a compound of formula (D or a pharmaceutically acceptable salt
`
`thercof and a pharmaccutically acceptable cxcipicnt.
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`15
`
`Terms and Definitions
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`DETAILED DESCRIPTION OF THE INVENTION
`
`For the avoidance of doubt, unless otherwise indicated, the term "substituted"
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`means substituted by one or more defined groups.
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`In the case where groups may be
`
`selected from a numberofalternative groups the selected groups may be the same or
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`different.
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`20
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`The term "independently" means that where more than one substituent is selected
`
`from a number ofpossible substituents, those substituents may be the same or different.
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`For the avoidance of doubt, unless otherwise indicated, the term "substituted" means
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`substituted by one or more defined groups.
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`In the case where groups may be selected from
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`anumber of alternative groups the selected groups may be the same or different.
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`25
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`The term "independently" means that where more than one substituent is selected
`
`from a number of possible substituents, those substituents may be the same or different.
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`An "effective amount” means that amount of a drug or pharmaceutical agent that
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`will elicit the biological or medical response of a tissue, system, animal or humanthat is
`
`being sought, for instance, by aresearcher or clinician. Furthermore, the term
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`30
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`"therapeutically effective amount" means any amount which, as compared to a
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`corresponding subject who has not received such amount, results in improved treatment,
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`healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in
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`the rate of advancement of a disease or disorder. The term also includes within its scope
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`amounts effective to enhance normal physiological
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`function.
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`As.used herein the term "alkyl" refers to a saturated straight- or branched-chain
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`hydrocarbon radical having the specified number of carbon atoms. As used herein,
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`the
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`terms "Ci-Cg alkyl" and "Ci_Cio alkyl" refers to such a group having at least
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`1 and up to 6
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`or 10 carbon atoms respectively. Examples of such branched or straight-chained alkyl
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`groups useful in the present invention include, but are not limited to, methyl, ethyl, n-
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`propyl,
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`isopropyl,
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`isobutyl, n-butyl,
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`t-butyl, n-pentyl,
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`isopentyl, n-hexyl, n-heptyl, n-octyl,
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`n-nonyl, and n-decyl, and branched analogs of the latter 5 normal alkanes.
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`10
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`The term "Ci-Cio-alkenyl" refers to straight or branched hydrocarbon chains
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`containing the specified number of carbon atoms andat Icast 1, or morc, carbon-carbon
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`double bonds. Examples include ethenyl (or ethenylene) and propenyl (or propenylene).
`
`When the term "Ci-Cioalkynyl" (or "alkynylene")
`
`is used it refers to straight or
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`branched hydrocarbon chains containing the specified number of carbon atoms and at least
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`15
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`1, or more, carbon-carbon triple bonds. Examples include ethynyl (or ethynylene) and
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`propynyl
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`(or propynylene).
`
`When "Cs-C5Cycloalkyl" is used it refers to a non-aromatic,
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`saturated, cyclic
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`hydrocarbon ring containing the specified number of carbon atoms. So, for example,
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`the
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`term "C3_Cs cycloalkyl" refers to anon-aromatic cyclic hydrocarbon ring having from
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`20
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`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,
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`cycloheptyl and cyclooctyl.
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`The term "C4-C6cycloalkenyl” refers to a non-aromatic monocyclic carboxycyclic
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`ring having the specified number of carbon atoms and up to 3 carbon-carbon double bonds.
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`25
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`"Cycloalkenyl"
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`includes by way of example cyclopentenyl and cyclohexenyl.
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`"Halo" means the halogen radical fluoro, chloro, bromo, or iodo.
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`"Haloalkyl" means a Ci-Cioalkyl, Ci-Cio-alkenyl, or Ci-Cioalkynyl group that is
`
`substituted with one or more halo substituents. Haloalkyl
`
`includes trifluoromethyl.
`
`Where "C.-C; heterocycloalkyl"
`
`is used, it means a non-aromatic heterocyclic ring
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`30
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`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 aring may be optionally fused to one or more other "heterocyclic"
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`ring(s) or cycloalkyl ring(s). Examples of “heterocyclic” moieties include, but are not
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`limited to, aziridine, thiirane, oxirane, azetidine, oxetane, thietane, tetrahydrofuran, pyran,
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`1,4-dioxane, 1,3-dioxane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine,
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`imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran,
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`tetrahydrothiophene, and the like.
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`"Aryl" refers to optionally substituted monocyclic and polycarbocyclic unfused or
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`fused groups having 6 to 14 carbon atoms and having at least one aromatic ring that
`
`complies with HUckKel’s Rule. Examples of aryl groups are phenyl, biphenyl, naphthyl,
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`anthracenyl, phenanthreny] and the like.
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`"Heteroaromatic ring" means an optionally substituted aromatic monocyclic ring or
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`10
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`polycarbocyclic fused ring system wherein at least one ring complies with HUckel’s Rule,
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`has the specified number of ring atoms, and that ring containsat least one heteratom
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`selected from N, O, and/or S. Examples ofthese groups include furanyl, thiopheny],
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`pytrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,
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`oxadiazolyl, oxo-pyridyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl,
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`15
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`pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, and
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`indazolyl.
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`"Enantiomerically enriched" refers to products whose enantiomeric excess is
`
`greater than zero. For example, enantiomerically enriched refers to products whose
`
`enantiomeric excess 1s greater than 50% ee, greater than 75% ee, and greater than 90% ee.
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`20
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`"Enantiomcric cxccss" or "cc" is the excess of one cnantiomer over the other
`
`expressed as a percentage. As aresult, since both enantiomers are present in equal
`
`amounts in aracemic mixture, the enantiomeric excess is zero (0% ee). However, if one
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`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
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`25
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`of the other enantiomer, 5%).
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`"Enantiomerically pure" means products whose enantiomeric excess is 99% ee or
`
`greater.
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`"Halo" means the halogen radical fluoro, chloro, bromo, or iodo.
`
`"Haloalkyl" means an alkyl group that is substituted with onc or morc halo
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`30
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`substituents. Haloalkyl includes trifluoromethyl] andtrifluoroethyl.
`
`Certain compounds of formula (D have a basic nitrogen group and are therefore
`
`capable of forming pharmaceutically-acceptable acid addition salts by treatment with a
`
`suitable acid. Suitable acids include pharmaceutically-acceptable inorganic acids amd
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`pharmaceutically-acceptable organic acids. Representative pharmaceutically-acceptable
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`acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate,
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`bisulfate, sulfamate, phosphate., acetate, hydroxyacetate, phenylacetate, propionate,
`
`butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate,
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`tartrate, citrate, salicylate, /?-aminosalicyclate, glycollate, lactate, heptanoate, phthalate,
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`oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate,
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`dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate,
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`stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate,
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`glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-
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`10
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`hydroxy ethanesulfonate, benzenesulfonate (besylate), /?-aminobenzenesulfonate,p -
`
`tolucncsulfonate (tosylate), and napthalcnc-2-sulfonate.
`
`Certain other compounds of formula (1) have an acidic functional group, one acidic
`
`enough to form salts. Representative salts include pharmaceutically-acceptable metal salts
`
`such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts;
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`15
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`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,
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`20
`
`cthanolamine, dicthanolamine, and cyclohexylaminc.
`
`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. Where the
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`25
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`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. Thus, 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.
`
`30
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`Individual stereoisomers of a compound according to formula I which contain one
`
`or more asymmetric center may be resolved by methods knownto those skilled in theart.
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`For example, such resolution may be carried out (1) by formation of diastereoisomeric
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`salts, complexes or other derivatives; (2) by selective mixture with a stereoisomer-specific
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`reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid
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`chromatography in a chiral enviornment, for example, on a chiral support such assilica
`
`with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will
`
`appreciate that where the desired 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. Alternatively, specific stereoisomers may be synthesized by asymmetric
`
`synthesis using optically active reagents, substrates, catalysts or solvents, or by converting
`
`one enantiomerto the other by asymmetric transformation.
`
`The compoundsof the invention may exist in solid or liquid form.
`
`In the solid
`
`10
`
`state, the compoundsof the invention may exist in crystalline or noncrystalline form, or as
`
`a mixture thercof. For compoundsof the invention that are in crystalline form, the skilled
`
`artisan will appreciate that pharmaccutically-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
`
`15
`
`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.
`
`20
`
`The skilled artisan will further appreciate that ccrtain compoundsofthe invention
`
`that exist in crystalline form, including the various solvates thereof, may exhibit
`
`polymorphism, i.e. the capacity to occur in different crystalline structures. These different
`
`crystalline forms are typically known as polymorphs. The invention includes all such
`
`polymorphs. Polymorphs typically exhibit different melting points, IR spectra, and X-ray
`
`25
`
`powder diffraction patterns, which may be used for identification. The skilled artisan will
`
`appreciate that different polymorphs may be produced, for example, by changing or
`
`adjusting the mixture conditions or reagents, used in making the compound. For example,
`
`changes in temperature, pressure, or solvent may result in polymophs.
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`In addition, one
`
`polymorph may spontaneously convert to another polymorph under certain conditions.
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`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)
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`attributable to cathepsin C involvement or in conditions wherein cathepsin C inhibition
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`offers some clinical benefit even though the underlying pathology is not (even in part)
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`attributable to cathepsin C involvement. Examples of such conditions include COPD,
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`rheumatoid arthritis, osteoarthritis, asthma, and multiple sclerosis. Accordingly, in another
`
`aspect the invention is directed to methods oftreating such conditions.
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`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.
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`As used herein, "treatment" in reference to a condition means: (1) the amelioration
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`or prevention of the condition being treated or one or more of the biological manifestations
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`of the condition being treated, (2) the interference with (a) one or more points in the
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`biological cascade that leads to or is responsible for the condition being treated or (b) one
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`or more of the biological manifestations of the condition being treated, or (3) the
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`alleviation of one or more of thc symptomsor cffccts associated with the condition being
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`treated.
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`As indicated above, "treatment" of a condition includes prevention of the
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`condition. The skilled artisan will appreciate that "prevention" is not an absolute term.
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`In
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`medicine, "prevention" is understood to refer to the prophylactic administration of a drug
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`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
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`thereof.
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`As used herein, "safe and effective amount" and "therapeutically effective amount”
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`20
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`in reference to a compound of formula I, or a pharmaccutically acccptable salt of it, mcans
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`an amountof sufficicnt to significantly inducc a positive modification in the condition to
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`be treated but low enoughto avoid serious side effects at a reasonable benefit/risk ratio
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`within the scope of sound medical judgment. A safe and effective amount of a compound
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`of the invention will vary with the particular compound chosen, e.g. consider the potency,
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`25
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`efficacy, and half-life of the compound; the route of administration chosen; the condition
`
`being treated; the severity of the condition being treated; the age, size, weight, and
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`physical condition of the patient being treated; the medical history of the patient to be
`
`treated; the duration of the treatment; the nature of concurrent therapy; the desired
`
`therapcutic cffect; and like factors, but can nevertheless be routincly determined by the
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`skilled artisan.
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`As used herein, "patient" refers to a human or animal.
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`The compounds of the invention may be administered by any suitable route of
`
`administration, including both systemic administration and topical administration.
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`Systemic administration includes oral administration, parenteral administration,
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`transdermal administration, rectal administration, and administration by inhalation.
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`Parcntcral administration rcfcrs to routes of administration othcr than enteral, transdcrmal,
`
`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
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`10
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`dosing regimen wherein a number of doses are administered at varying intervals of time
`
`for a given period of time. For cxamplc, doscs may be administcred 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
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`15
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`that compound, such as absorption, distribution, and half-life, which can be determined by
`
`the skilled artisan.
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`In addition, suitable dosing regimens, including the amount
`
`administered and the duration such regimens are administered, for a compound ofthe
`
`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
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`20
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`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.
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`It will be further understood by suchskilled 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
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`25
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`range from 10 mg to 1000 mg.
`
`Compositions
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`The compounds of the invention will normally, but not necessarily, be formulated
`
`into a pharmaceutical composition prior to administration to a patient. Accordingly, in
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`30
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`another aspect the invention is directed to pharmaceutical compositions comprising a
`
`compound of the invention and a pharmaceutically-acceptable excipient.
`
`The pharmaceutical 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
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`extracted and then given to the patient such as with powders, syrups, and solutions for
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`injection. Alternatively, 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. When prepared in unit dosage
`
`form, 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
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`10
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`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 onc or more additional pharmaccutically active compounds.
`
`Conversely, the pharmaceutical compositions of the invention typically contain more than
`
`one pharmaceutically-acceptable excipient. However, in certain embodiments, the
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`15
`
`pharmaceutical compositions of the invention contain one pharmaceutically-acceptable
`
`excipient.
`
`As used herein, "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
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`20
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`other ingredients of the pharmaceutical composition when commingled such that
`
`interactions which would substantially reduce the efficacy of the compound ofthe
`
`invention when administered to a patient and interactions which would result in
`
`pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
`
`In
`
`addition, each excipient must of course be of sufficiently high purity to render it
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`25
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`pharmaceutically-acceptable.
`
`The compounds of the invention and the pharmaceutically-acceptable excepient or
`
`excepients will typically be formulated into a dosage form adapted for administration to
`
`the patient by the desired route of administration. For example, dosage forms include
`
`those adapted for (1) oral administration such as tablcts, capsules, caplcts, pills, troches,
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`30
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`powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2)
`
`parenteral administration suchas 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)
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`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.
`
`In addition, suitable pharmaceutically-acceptable
`
`excipients may be chosen for a particular function that they may serve in the composition.
`
`For example, 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 fortheir ability to facilitate the production of stable
`
`dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their
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`10
`
`ability to facilitate the carrying or transporting the compound or compoundsof 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
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`15
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`excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents,
`
`coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers,
`
`sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents,
`
`hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants,
`
`preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will
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`20
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`appreciate that certain pharmaceutically-acceptable excipients may serve more than one
`
`function and may serve alternative functions depending on how much of the excipient is
`
`present in the formulation and what ot