Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates in general to the use of 4-amino-azepan-3-one protease inhibitors, particularly such inhibitors of cathepsin L, in the treatment of diseases in which cathepsin L is implicated, especially in the treatment or prevention of rheumatoid arthritis; treatment or prevention of cancer metastasis; treatment or prevention of diseases requiring inhibition of tissue destruction by macrophage, particularly lung macrophage, such as asthma, chronic obstructive pulmonary disease (COPD), and emphysema; treatment or prevention of diseases requiring, for therapy, inhibition of positive selection of CD4 + T " cells by cortical thymic epithelial cells.
• PPD chronic obstructive pulmonary disease
• Cathepsins are a family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature.
• Cathepsins function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have been implicated as causative agents in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like.
• cathepsin L Pathological levels of cathepsin L have been implicated in several disease states. Thus, selective inhibition of cathepsin L may provide an effective treatment for diseases requiring, for therapy or prevention: inhibition of rheumatoid arthritis (see Iwata et. al. Arthritis and Rheumatism 1997, 40, 499); inhibition of cancer metastasis (see K. Ishidoh and E. Kominami Biol. Chem.
• cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of compounds, such as aldehydes, nitriles, ⁇ -ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases. See Palmer, id, and references cited therein. U.S. Patent No. 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine protease. Published International Patent Application No. WO
• EP 94/04172, and European Patent Application Nos. EP 0 525 420 Al, EP 0 603 873 Al, and EP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L.
• International Patent Application No. PCT/US94/08868 and and European Patent Application No. EP 0 623 592 Al describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL- l ⁇ convertase. Alkoxymethyl and mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No. PCT/GB91/01479).
• Azapeptides which are designed to deliver the azaamino acid to the active site of serine proteases, and which possess a good leaving group, are disclosed by Elmore et al., Biochem. J., 1968, 107, 103, Garker et al, Biochem. J., 1974, 139, 555, Gray et al, Tetrahedron, 1977, 33, 837, Gupton et al., J. Biol. Chem., 1984, 259, 4279, Powers et al, J. Biol. Chem., 1984, 259, 4288, and are known to inhibit serine proteases.
• J. Med. Chem., 1992, 35, 4279 discloses certain azapeptide esters as cysteine protease inhibitors.
• Antipain and leupeptin are described as reversible inhibitors of cysteine protease in McConnell et al., J. Med. Chem., 33, 86; and also have been disclosed as inhibitors of serine protease in Umezawa et al., 45 Meth. Enzymol. 678. E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189, and Grinde, Biochem. Biophys. Ada, , 701, 328).
• 1,3-diamido-propanones have been described as analgesic agents in U.S. Patent Nos.4,749,792 and 4,638,010.
• An object of the present invention is to provide methods of treatment which use 4- amino-azepan-3-one carbonyl protease inhibitors of cathepsin L of Formula I and which are useful for treating diseases which may be therapeutically modified by altering the activity of cathepsin L.
• the methods of this invention are especially useful for treatment or prevention of rheumatoid arthritis; treatment or prevention of cancer metastasis; treatment or prevention of diseases requiring inhibition of tissue destruction by macrophage, particularly lung macrophage, such as asthma, chronic obstructive pulmonary disease (COPD), and emphysema; treatment or prevention of diseases requiring, for therapy, inhibition of positive selection of CD4 + T " cells by cortical thymic epithelial cells.
• macrophage particularly lung macrophage, such as asthma, chronic obstructive pulmonary disease (COPD), and emphysema
• COPD chronic obstructive pulmonary disease
• emphysema emphysema
• the present invention provides a method of inhibiting cathepsin L comprising administering to an animal, particularly a mammal, most particularly a human being in need thereof, an effective amount of a compound of Formula I:
• R! is selected from the group consisting of:
• R2 is selected from the group consisting of: H, C galkyl, C3_gcycloalkyl-Co_ 6 alkyl, Ar-C 0 _6alkyl, Het-Co ⁇ alkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-,
• R3 is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-C ⁇ - galkyl, C2-6alkenyI, C2-6alkynyl, HetCo_6alkyl and ArC ⁇ _6alkyl;
• R 3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
• R4 is selected from the group consisting of: H, C galkyl, C3_6cycloalkyl-C()- galkyl, Ar-C 0 _6alkyl, Het-C 0 . 6 alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 13 NC(0) ⁇ , and R 5 R 13 NC(S)-;
• R ⁇ is selected from the group consisting of: H, C galkyl, C2-6 a lk en yl > C2- galkynyl, C3_gcycloalkyl-C ( )-6alkyl, Ar-C()-6alkyl and Het-Co- ⁇ alkyl;
• R6 is selected from the group consisting of: H, C galkyl, C3_gcycloalkyl-C ⁇ _ galkyl, Ar-C ⁇ -6alkyl, and Het-Co_6alkyl;
• R ⁇ is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-C 0 -6alkyl, Het-C 0 . 6 alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 14 NC(O)-, and R 10 R 14 NC(S)-; R ⁇ is selected from the group consisting of: H, Ci- ⁇ alkyl, C2-6 a lkenyl,
• R 9 is selected from the group consisting of: C ⁇ galkyl, C3_6cycloalkyl-C ⁇ -6 lkyl, Ar-Co_6alkyl and Het-Co-6alkyl;
• RIO is selected from the group consisting of: C galkyl, C3_gcycloalkyl-Co_6alkyl, Ar-C 0 .6alkyl and Het-C 0 _6alkyl;
• RU is selected from the group consisting of: H, C ⁇ .galkyl, Ar-C()-6alkyl, and Het- Co- ⁇ alkyl;
• Rl i selected from the group consisting of: H, C j .galkyl, Ar-Co-6 a lkyl, and Het- Co_6alkyl
• R!3 is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6alkyl, and Het-
• R!4 is selected from the group consisting of: H, C ⁇ galkyl, Ar-C ⁇ -6 a lkyl, and Het- C 0 . 6 alkyl;
• R' is selected from the group consisting of: H, C galkyl, Ar-C()-6alkyl, and Het- Co-galkyl
• R" is selected from the group consisting of: H, Cj.galkyl, Ar-C ⁇ -6alkyl, or Het-CQ. galkyl
• R' is selected from the group consisting of: H, C .galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-Co_6 a Ikyl, and Het-Co- ⁇ alkyl;
• X is selected from the group consisting of: CH2, S, and O; Z is selected from the group consisting of: C(O) and CH2; and pharmaceutically acceptable salts, hydrates and solvates thereof.
• R S preferably .
• R 3 is selected from the group consisting of: H, Ci-galkyl, C3_6cycloalkyl-Co_ galkyl, C2-6alkenyl, C2-6alkynyl, Het-Co_6alkyl and Ar-Co_6alkyl, preferably Ci- ⁇ alkyl and Ar-Co- ⁇ alkyl, most preferably isobutyl, napthalen-2-ylmethyl, benzyl, and benzyloxymethyl;
• R 4 is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl- C 0 -6alkyl, Ar-C 0 _ 6 alkyl, Het-C 0 -6alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-,
• R ⁇ is selected from the group consisting of: C galkyl, C2_6alkenyl, C2-6alkynyl, C3_ cycloalkyl-C Q _,5alkyl, Ar-C Q _galkyl or Het-Co_6alkyl.
• R ⁇ is selected from the group consisting of: C ⁇ galkyl, Ar-Co-6alkyl and Het-Co-6alkyl.
• R ⁇ is selected from the group consisting of: quinolinyl, especially quinolin-2-yl, quinolin-4-yl and quinolin-8-yl; isoquinolinyl, especially isoquinolin-1-yl; naphthalenyl, especially naphthalen-1-yl; and benzofuranyl, especially benzofuran-2-yl.
• R' is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het-
• R" selected from the group consisting of: H, C galkyl, Ar-C ⁇ -6 a lkyl, and Het-C ⁇ - galkyl, preferably H.
• R 2 is selected from the group consisting of: H, Cj_ galkyl, C 3 . 6 cycloalkyl-C 0 . 6 alkyl, Ar-C 0 -6alkyl, Het-C 0 _6alkyl, R 9 C(0)-, R 9 C(S)-,
• R 2 is R 9 S ⁇ 2-
• R 9 is selected from the group consisting of: Cj.galkyl, C3_gcycloalkyl-Co_6alkyl, Ar-C Q -6alkyl, and Het-C ⁇ -galkyl, preferably Het-CQ-galkyl, more preferably pyridinyl and 1-oxy-pyridinyl.
• R 9 is even more preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl. Most preferably, R 9 is l-oxy-pyridin-2- yi.
• R 2 is R 9 S0 2 ;
• R 3 is selected from the group consisting of: isobutyl, napthalen-2-ylmethyl, benzyl, and benzyloxymethyl;
• R 4 is R 5 C(0);
• R ⁇ is selected from the group consisting of: quinolin-2-yl, quinolin-4-yl, quinolin-8- yl, isoquinolin-1-yl, naphthalen-1-yl, and benzofuran-2-yl;
• R 9 is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl, preferably l-oxy-pyridin-2-yl.
• R' is H
• R" is H
• R'" is H;
• Compounds of Formula I selected from the following group are particularly preferred embodiments for use in the present invention:
• the 7 membered ring compounds used in the present invention are configurationally more stable at the carbon center alpha to the ketone.
• the present invention also uses deuterated analogs of the inventive compounds.
• a representative example of such a deuterated compound is set forth in Example 12.
• a representative synthetic route for the deuterated compounds of the present invention is set forth in Example 12, below.
• the deuterated compounds used in the present invention exhibit superior chiral stability compared to the protonated isomer.
• the compounds used in the present invention include all hydrates, solvates, complexes and prodrugs.
• Prodrugs are any covalently bonded compounds which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound used in the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
• Compounds used in the present methods containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
• proteases are enzymes that catalyze the cleavage of amide bonds of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis.
• proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases.
• the compounds of the present invention are capable of binding more strongly to the enzyme than the substrate and in general are not subject to cleavage after enzyme catalyzed attack by the nucleophile. They therefore competitively prevent proteases from recognizing and hydrolyzing natural substrates and thereby act as inhibitors.
• amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
• C ⁇ -6alkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n- pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
• R* 2 is selected from the group consisting of: H, C ⁇ _galkyl, Ar-C ⁇ -6alkyl, and Het-Co-6alkyl; "C3_6cycloalkyl” as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane.
• C2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
• C2-6 a lkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
• C2-6alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
• C2-6 alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
• Hydrogen means F, Cl, Br, and I.
• Ar or “aryl” means phenyl or naphthyl, optionally substituted by one or more of Ph-Co-6 alk y J ; Het-C 0 _6 a lkyl; Cj.galkoxy; Ph-CQ ⁇ ko y; Het-Co_6 al koxy; OH, (CH 2 ) ⁇ _ 6 NR 15 R 16 ; 0(CH 2 ) ⁇ _6NR 15 R 16 ; C ⁇ _6alkyl, OR 17 , N(R 17 ) 2 , SR 17 , CF 3 , N0 2 , CN, C0 2 R 17 , CON(R 17 ), F, Cl, Br or I; where R 15 and R 16 are H, C galkyl, Ph-C 0 -6alkyl, naphthyl-Co_6alkyl or Het-Co- ⁇ alkyl; and R ⁇ is phenyl, naphthyl, or Cj.galkyl.
• Het represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C 0 _6Ar, Ci-6alkyl, OR 17 , N(R 17 ) 2 , SR 17 , CF 3 , N0 2 , CN, C0 2 R 17 , C0N(R1 7 ), F, Cl, Br and I, where R ⁇ 7 is phenyl, naphthyl, or C ⁇ _6alkyl.
• heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzoimid
• CQ denotes the absence of the substituent group immediately following; for instance, in the moiety ArCQ-galkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCo_5alkyl is identified as a specific aromatic group, e.g., phenyl, it is understood that the value of C is 0.
• t-Bu refers to the tertiary butyl radical
• Boc refers to the t-butyloxycarbonyl radical
• Fmoc refers to the fluorenylmethoxycarbonyl radical
• Ph refers to the phenyl radical
• Cbz refers to the benzyloxycarbonyl radical.
• m-CPBA refers to 3-chloroperoxybenzoic acid
• EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide
• DMF refers to dimethyl formamide
• DMSO refers to dimethyl sulfoxide
• TEA triethylamine
• TFA trifluoroacetic acid
• THF tetrahydrofuran
• Nucleophilic ring opening of epoxide 4 may be effected with a reagent such as sodium azide to provide the azido alcohol 5 which may be reduced to the amino alcohol 6 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or triphenylphosphine in THF and water.
• the amine of compound 6 may be protected with with di-terf-butyl dicarbonate to provide derivative 7 (Scheme 2). Removal of the benzyloxycarbonyl protecting group may be effected by treatment of 7 with hydrogen gas in the presence of a catalyst such as 10% Pd/C to provide the amine 8.
• amine 8 Treatment of amine 8 with a sulfonyl chloride such as 2-pyridinesulfonyl chloride in the presence of a base such as triethylamine provides the sulfonamide derivative 9.
• a base such as triethylamine
• Removal of the tert-butoxycarbonyl protecting group may be effected with an acid such as hydrochloric acid to provide intermediate 10.
• Coupling of 10 with an acid such as N-Boc-phenylalanine in the presence of a coupling agent common to the art such as HBTU or polymer supported EDC provides the alcohol intermediate 11. Removal of the tert-butoxycarbonyl protecting group under acidic conditions provides 12.
• Coupling of 12 with an acid such as benzofuran-2-carboxylic acid in the presence of a coupling agent such as HBTU or polymer supported EDC provides alcohol 13.
• Alcohol 13 may be oxidized with an oxidant common to the art such as pyridine sulfur trioxide complex in DMSO and triethylamine or the Dess-Martin periodinane to provide the ketone 14.
• the diastereomers of 14 may be separated by HPLC.
• Reagents and conditions (a) NaH, 5-bromo-l-pentene, NaH; (b) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, CH 2 C1 2 , reflux; (c) m-CPBA, CH 2 C1 2 ; (d) NaN 3 , NH 4 CI, CH 3 OH, H 2 0; (e) TEA, 1,3-propanedithiol, CH 3 OH.
• Reagents and conditions (a) Di-ferf-butyl dicarbonate, THF; (b) H 2 , 10% Pd/C, EtOAc; (c) 2- pyridinesulfonyl chloride, TEA, CH.C1.; (d) HCl, EtOAc; (e) N-Boc-phenylalanine, P-EDC, CH 2 C1 2 ; (f) HCl, CH 2 C1 2 ; (g) benzofuran-2-carboxylic acid, P-EDC, CH 2 C1 2 ; (h) Dess-Martin periodinane, methylene chloride.
• Reagents and conditions (a) N-Boc-leucine, EDC, HOBt, TEA, CH 2 C1 2 ; (b) H 2 , 10% Pd/C, EtOAc; (c) 2-pyridinesulfonyl chloride, TEA, CH 2 C1 2 ; (d) HCl, methanol; (e) quinoline-8-carboxylic acid, EDC, HOBt, TEA, CH 2 C1 2 ; (f) pyridine sulfur trioxide complex, TEA, DMSO.
• the deuterated compound of the Example 12 may be conveniently prepared according to Scheme 4. The skilled artisan will understand from Example 12 and Scheme 4 how to make any of the the deuterated compounds of the present invention.
• Coupling methods to form amide bonds herein are generally well known to the art.
• the methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally illustrative of the technique and are incorporated herein by reference. Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions.
• amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
• Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
• Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
• Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH4+ are specific examples of cations present in pharmaceutically acceptable salts.
• Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
• the methods of the present invention may be practiced by administering a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
• a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
• the compounds of Formula I may be used in the manufacture of a medicament.
• Pharmaceutical compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
• the liquid formulation may be a buffered, isotonic, aqueous solution.
• Suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
• Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
• these compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
• Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
• Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
• Liquid carriers include syrup, peanut oil, olive oil, saline and water.
• the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
• the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 g per dosage unit.
• the pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
• a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension.
• Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.
• the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository.
• the compounds of Formula I are useful as inhibitors of cathepsin L.
• the present invention provides methods of treatment of diseases caused by pathological levels of cathepsin L, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof a therapeutically effective amount of an inhibitor of cathepsin L, including a compound of the present invention.
• the present invention particularly provides methods for treating the following diseases in which cathepsin L is implicated: diseases which require for therapy: inhibition of rheumatoid arthritis; inhibition of cancer metastasis; inhibition of tissue destruction by macrophage, particularly, lung macrophage, in diseases such as asthma, chronic obstructive pulmonary disease (COPD), and emphysema; and inhibition of positive selection of CD4 + T"cells by cortical thymic epithelial cells.
• diseases which require for therapy inhibition of rheumatoid arthritis
• cancer metastasis inhibition of tissue destruction by macrophage, particularly, lung macrophage, in diseases such as asthma, chronic obstructive pulmonary disease (COPD), and emphysema
• COPD chronic obstructive pulmonary disease
• emphysema emphysema
• the present methods contemplate the use of one or more compounds of Formula I, alone or in combination with other therapeutic agents.
• parenteral administration of a compound of Formula I is preferred.
• the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin S.
• the compounds are administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
• the precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
• the compounds of Formula I may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit rheumatoid arthritis or to achieve any other therapeutic indication as disclosed herein.
• a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
• the oral dose would be about 0.5 to about 20 mg kg.
• the compounds used in the present methods may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
• cathepsin L proteolytic catalytic activity
• Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA.
• Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 uM final substrate concentration in the assays. All assays contained 10% DMSO. All assays were conducted at ambient temperature.
• Product fluorescence excitation at 360 nM; emission at 460 nM
• Product progress curves were generated over 20 to 30 minutes following formation of AMC product.
• v is the velocity of the reaction with maximal velocity V m
• A is the concentration of substrate with Michaelis constant of K a
• I is the concentration of inhibitor.
• [AMC] v ss t + (vp - v ss ) [1 - exp (-k 0 b s t)] / k 0 bs (2)
• Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.
• CDCI3 is deuteriochloroform
• DMSO-d ⁇ is hexadeuteriodimethylsulfoxide
• CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramefhylsilane.
• Example lj-k Following the procedures of Example lj-k except substituting quinoline-4- carboxylic acid for quinoline-8-carboxylic acid of Example lj the title compound was prepared: ⁇ NMR (CDC1 3 ): ⁇ 1.0 (m, 6H), 1.5-2.1 (m, 5H), 2.2 (m, 2H), 2.7 (m, IH), 3.1 (d, IH).
• the diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer; MS(EI): 538 (M+H + ,100%), and the slower eluting diastereomer; MS(EI): 538 (M+H + ,100%).
• Example 5 Following the procedure of Example Ik except substituting the compound of Example 4g the title compound was prepared: MS 622 (M+H + ). Example 5
• Example 4e-h Following the procedures of Example 4e-h except substituting N-Boc-phenylalanine for N-(t-butoxycarbonyl)-3-(2-naphthyl)-L-alanine of Example 4e the title compound was prepared: MS 572 (M+H + ).
• Example 4e-h Following the procedures of Example 4e-h except substituting N-Boc-phenylalanine for N-(t-butoxycarbonyl)-3-(2-naphthyl)-L-alanine of Example 4e and naphthoic acid for quinoline-8-carboxylic acid of Example 4g the title compound was prepared: MS 571 (M+H*).
• Example 4e-h Following the procedures of Example 4e-h except substituting N-Boc-phenylalanine for N-(t-butoxycarbonyl)-3-(2-naphthyl)-L-alanine of Example 4e and quinoline-2- carboxylic acid for quinoline-8-carboxylic acid of Example 4g the title compound was prepared. Purification of the diastereomers by HPLC provided the two diastereomers of the title compound as solids (first: 40 mg: second: 43mg): MS(ESI) 537.8 (M+H) + .

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