EP1278502A2 - Inhibiteurs a protease - Google Patents

Inhibiteurs a protease

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Publication number
EP1278502A2
EP1278502A2 EP01970508A EP01970508A EP1278502A2 EP 1278502 A2 EP1278502 A2 EP 1278502A2 EP 01970508 A EP01970508 A EP 01970508A EP 01970508 A EP01970508 A EP 01970508A EP 1278502 A2 EP1278502 A2 EP 1278502A2
Authority
EP
European Patent Office
Prior art keywords
pyridine
carboxylic acid
azepan
ylcarbamoyl
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01970508A
Other languages
German (de)
English (en)
Other versions
EP1278502A4 (fr
Inventor
Maxwell D. Cummings
Robert W. Marquis, Jr.
Yu Ru
Scott K. Thompson
Daniel F. Veber
Dennis S. Yamashita
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication date
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Publication of EP1278502A2 publication Critical patent/EP1278502A2/fr
Publication of EP1278502A4 publication Critical patent/EP1278502A4/fr
Withdrawn legal-status Critical Current

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    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
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    • 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
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    • 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
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    • C07D405/14—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 three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
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    • 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
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • This invention relates in general to the use of 4-amino-azepan-3-one protease inhibitors, particularly such inhibitors of cathepsin S, in the treatment of diseases in which cathepsin S is implicated, especially treatment or prevention of autoimmune disease; treatment or prevention of a disease state caused by the formation of atherosclerotic lesions and complications arising therefrom; and diseases requiring inhibition, for therapy, of a class II MHC-restricted immune response, inhibition of an asthmatic response, inhibition of an allergic response, inhibition of immune response against a transplanted organ or tissue, or inhibition of elastase activity in atheroma; and novel compounds for use therewith.
  • Cathepsins are a family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins K, 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.
  • 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. See International Publication Number WO 94/04172, published on March 3, 1994, and references cited therein. See also European Patent Application EP 0 603 873 Al, and references cited therein. Two bacterial cysteine proteases from P.
  • gingivallis called gingipains
  • Cathepsin K is believed to play a causative role in diseases of excessive bone or cartilage loss. See International Publication Number WO 97/16433 , published on May 9, 1997, and references cited therein.
  • Pathological levels of cathepsin S have been implicated in a variety of disease states. For instance, mice treated with inhibitor exhibited attenuated antibody response indicating that selective inhibition of cathepsin S may provide a therapeutic strategy for asthma and autoimmune disease processes. Riese, Richard J., et al., J. Clin. Invest.
  • selective inhibition of cathepsin S may provide an effective treatment for diseases requiring, for therapy or prevention: inhibition of a class II MHC- restricted immune response; treatment and/or prevention of an autoimmune disease state such as rheumatoid arthritis, multiple sclerosis, juvenile-onset diabetes, sytemic lupus erythematosus, discoid lupus erythematosus, pemphigus vulgaris, pemphigoid, Grave's disease, myasthenia gravis, Hashimoto's thyroiditis, scleroderma, dermatomysositis, Addison's disease, pernicious anemia, primary myxoedema, thyrotoxicosis, autoimmune atrophic gastritis, stiff-man syndrome, Goodpasture's syndrome, sympathetic opthalamia, phacogenic uveitis, autoimmune haemolytic anaemia, idi
  • an autoimmune disease state such as r
  • cysteine protease inhibitors are known. Palmer et. al. (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, oc-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 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 etal, 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.
  • I. 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. Acta, , 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 S of Formula I and which are useful for treating diseases which may be therapeutically modified by altering the activity of cathepsin S.
  • the methods of this invention are especially useful for treatment or prevention of autoimmune disease; treatment or prevention of a disease state caused by the formation of atherosclerotic lesions and complications arising therefrom; and diseases requiring inhibition, for therapy, of a class II MHC-restricted immune response, inhibition of an asthmatic response, inhibition of an allergic response, inhibition of immune response against a transplanted organ or tissue, or inhibition of elastase activity in atheroma.
  • Another object of the present invention is to provide novel compounds for use in the present methods. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides a method of inhibiting cathepsin S 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:
  • R1 is selected from the group consisting of:
  • R2 is selected from the group consisting of: H, C ⁇ .galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-C 0 -6alkyl, Het-C 0 _6alkyl, R 9 C(0)-, R 9 C(S)-, R 9 SQ 2 -, R 9 OC(0)-,
  • R 3 is selected from the group consisting of: H, Ci-6alkyl, C3_gcycloalkyl-CQ_ galkyl, ⁇ r ' s ⁇ & ⁇ C2-6alkynyl, HetCo_6alkyl, ArC()-6 a lkyl Ar-ArCo_6alkyl, Ar-HetCo_ galkyl, Het-ArCrj- ⁇ alkyl, and Het-HetCo_6alkyl; R3 and R' may be connected to form a pyrrolidine, piperidine or morpholine ring;
  • R is selected from the group consisting of: H, Ci.galkyl, C3_gcycloalkyl-Co- 6 alkyl, Ar-C 0 -6alkyl, Het-C ⁇ galkyl, 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)-;
  • R5 is selected from the group consisting of: H, C j .galkyl, C2-6alkenyl, C - ⁇ alkynyl, C3_gcycloalkyl-Co_6alkyl, Ar-Co-6 a lkyl and Het-Crj-galkyl;
  • R6 is selected from the group consisting of: H, C j .galkyl, C3_6cycloalkyl-C ⁇ _ galkyl, Ar-C ⁇ -6alkyl, and Het-Cr j -6alkyl;
  • R is selected from the group consisting of: H, Ci.galkyl, C3_6cycloalkyl ⁇ Co_ galkyl, Ar-C 0 . 6 alkyl, Het-C 0 _6alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 14 N (O)-, and R 10 R 14 NC(S)-;
  • R ⁇ is selected from the group consisting of: H, Ci- ⁇ alkyl, C2-6alkenyl, C2-6alkynyl, HetC0_galkyl and ArC ⁇ _galkyl;
  • R 9 is selected from the group consisting of: Ci.galkyl, C3_gcycloalkyl-Co_6alkyl,
  • RIO is selected from the group consisting of: C galkyl, C3_gcycloalkyl-Co_6alkyl, Ar-CQ_galkyl and Het-Co-6 a lkyl;
  • R! 1 is selected from the group consisting of: H, Ci .galkyl, Ar-C ⁇ -6alkyl, and Het- C 0 . 6 alkyl;
  • Rl2 is selected from the group consisting of: H, Ci.galkyl, Ar-C ⁇ -6 a lkyl, and Het- C 0 -6alkyl;
  • R1 3 is selected from the group consisting of: H, C ⁇ .galkyl, Ar-Crj-6alkyl, and Het- C 0 -6alkyl
  • Rl4 is selected from the group consisting of: H, C j .galkyl, Ar-C()-6alkyl, and Het-
  • R' is selected from the group consisting of: H, Cj.galkyl, Ar-C ⁇ -6 a lky and Het- C 0 .6alkyl;
  • R" is selected from the group consisting of: H, C j .galkyl, Ar-C()-6 a lkyl, or Het-Crj. ⁇ alkyl;
  • R' is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-C _ galkyl, Ar-Co-6alkyl, and Het-Cf j -galkyl;
  • 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* is preferably .
  • R 3 is selected from the group consisting of: H, C ⁇ _6alkyl, C3_6cycloal yl-C()- 6alkyl,C2-6alkenyl, C2-6alkynyl, Het-Co_6al yl and Ar-Co-6alkyl, preferably C3.. 6cycloalkyl-Co_6 a lkyl and C ⁇ _6alkyl, especially selected from the group consisting of: cyclohexylmethyl and 2,2-dimethyl propyl, more preferably C3_6cycloalkyl-C ⁇ _6alkyl, most preferably cyclohexylmethyl;
  • R4 is selected from the group consisting of: H, C 1 .galkyl, C3_ cycloalkyl-Co_ 6 alkyl, Ar-C 0 -6alkyl, Het-C 0 _6alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 13 NC(0)-, and R 5 R 13 NC(S)-, preferably R 5 C(0)-.
  • R-> is selected from the group consisting of: Cj.gaikyl, C2_6alkenyl, C2_6alkynyl, C3_6cycloalkyl-Co-6alkyl, Ar-Cr j _6alkyl or Het-Cg-galkyl.
  • R ⁇ is selected from the group consisting of: C ⁇ _galkyl, C3_6cycloalkyl-Co_6alkyl, Ar-Cn_6alkyl and Het-C ⁇ - galkyl.
  • R ⁇ is selected from the group consisting of: furanyl, especially furan-2-yl and furan-3-yl, more especially aryl substituted furanyl, even more especially 5-(4-chloro-phenyl)-furan-2-yl and 5-(3-trifluoromethyl- phenyl)-furan-2-yl; benzofuranyl, especially benzofuran-2-yl, more especially C ⁇ .galkoxy substituted benzofuranyl, particularly 5,6-dimethoxy-benzofuran-2-yl and 5-(2-morpholin-4-yl- ethoxy)benzofuran-2-y 1 ; thiophenyl, especially thiophene-3-yl and thiophene-2-yl, more especially Het-Cg.
  • galkyl-thiophenyl particularly 5-pyridin-2-yl-thiophene-2-yl, more especially C1 _galkyl- thiophenyl, particularly 5-methyl-thiophene-2-yl and 3-methyl-thiophene-2-yl; more especially C ⁇ .galkoxy -thiophenyl, particularly 3-ethoxy-thiophene-2-yl; furo[3,2-b]-pyridine-2-yl, especially C ⁇ _6alkyl-furo[3,2-b]-pyridine-2-yl, more especially 3-methyl-furo[3,2-b]-pyridine-2-yl; thiazolyl, especially thiazole-5-yl, more especially Het-Co-6alkyl-thiazolyl, particularly 4-methy l-2-pyridin-2-yl-thiazole-5-yl ; phenyl, especially halogen substituted phenyl, particularly bromophenyl, more particularly 4-bromophenyl; cycl
  • R' is selected from the group consisting of: H, C1.galkyl, Ar-C()-6alkyl, and Het-
  • Co-6 a l yl preferably H.
  • R" selected from the group consisting of: H, C ⁇ .galkyl, Ar-C()-6alkyl, and Het-C ⁇ - galkyl, preferably H.
  • R ⁇ is selected from the group consisting of: H, C 6 alkyl, C3_ 6 cycloalkyl-C 0 _ 6 alkyl, Ar-C 0 -6alkyl, Het-C 0 . 6 alkyl, R 9 C(0)-, R 9 C(S)-,
  • R ⁇ is selected from the group consisting of: R 9 S0 2 and C galkyl.
  • R2 is C j .galkyl
  • C galkyl is preferably propyl.
  • R ⁇ is most preferably R S0 2 .
  • R 9 is selected from the group consisting of: Ci.galkyl, C3_6cycloalkyl-Co_6 l yl, Ar-Cr j -6alkyl, and Het-Co-galkyl, preferably Het-Co-6 a lkyl, more preferably pyridinyl and 1-oxy-pyridinyl.
  • R ⁇ is R 9 S ⁇ 2
  • 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 pyridin-2-yl.
  • R 2 is R 9 S0 2 ;
  • R 3 is C3_6cycloalkyl-Cn_6alkyl
  • R 4 is R 5 C(0)
  • R 5 is Het-C 0 . 6 alkyl
  • R 9 is Het-Cn- ⁇ kyl
  • R' is H
  • R" is H; and R ⁇ is Cj ⁇ alkyl.
  • R 2 is R 9 S0 2 ;
  • R 3 is cyclohexylmethyl
  • R 4 is R 5 C(0);
  • R ⁇ is selected from the group consisting of: furanyl, especially furan-2-yl, and thiophenyl, especially thiophene-3-yl;
  • R 9 is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl, preferably pyridin-2-yl;
  • R' is H
  • R" is H
  • R'" is selected from the group consisting of: H and C j .galkyl.
  • R'" is: especially selected from the group consisting of: methyl, ethyl, propyl, butyl, pentyl and hexyl, more especially methyl; preferably selected from the group consisting of: 5-, 6- or 7- Ci .galkyl, especially selected from the group consisting of: 5-, 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and -hexyl, more especially selected from the group consisting of: 5-, 6- or 7-methyl; more preferably selected from the group consisting of: 6- or 7- C ⁇ _galkyl, especially selected from the group consisting of: 6- or 7-methyl, -ethyl, -propyl, -butyl, -pentyl and - hexyl, more especially selected from the group consisting of: the group consisting of: 6- or 7
  • R'" is C galkyl, especially selected from the group consisting of: methyl, ethyl, propyl, butyl, pentyl and hexyl; most preferably cis-7- methyl, as shown in Formula la wherein R'" is methyl.
  • Compounds of Formula I selected from the following group are particularly preferred for use in the present invention:
  • furan-2-carboxylic acid ⁇ (S)-2-cyclohexyl-l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-ethyl ⁇ -amide;
  • cyclobutanecarboxyhc acid ⁇ (S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-ethyl ⁇ -amide
  • cyclopentanecarboxylic acid ⁇ (S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-ethyl ⁇ -amide
  • furan-3-carboxylic acid ⁇ (S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-ethyl ⁇ -amide;
  • furan-2-carboxylic acid ⁇ (S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-ethyl ⁇ -amide;
  • furan-2-carboxylic acid [(S)-2-cyclohexyl- l-((4S,7R)-7-methyl-3-oxo- l-propyl-azepan-4- ylcarbamoyl)-ethyl]-amide;
  • furan-2-carboxylic acid ⁇ (S)-3,3-dimethyl-l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-butyl ⁇ -amide;
  • furan-2-carboxylic acid ⁇ (S)-2-cyclohexyl-l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-ethyl ⁇ -amide;
  • the present invention provides the following novel compounds:
  • furan-2-carboxylic acid ⁇ (S)-2-cyclohexyl-l-[3-oxo-l-(pyridine-2-sulfonyl)-azepan-4- ylcarbamoyl]-ethyl ⁇ -amide;
  • furan-2-carboxylic acid ⁇ (S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-ethyl ⁇ -amide;
  • furan-3-carboxylic acid ⁇ (S)-2-cyclohexyl-l-[3-oxo-l-(l-oxy-pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl] -ethyl ⁇ -amide;
  • 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. Representative examples of such deuterated compounds are set forth in Examples 7 and 41. A representative synthetic route for the deuterated compounds of the present invention are set forth in Scheme 3 and Examples 7 and 41, below. The deuterated compounds used in the present invention exhibit superior chiral stability compared to the protonated isomer. Definitions
  • 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.
  • “Hydrogen” or “H” includes all of its possible isotopes, including “deuterium” or “D” or “ 2 H”; and “tritium” or “T” or “3H”.
  • “Cx.galkyl” 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.
  • 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.
  • C2-6 lkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C2-6 alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • Halogen means F, Cl, Br, and I.
  • Ar or “aryl” means phenyl or naphthyl, optionally substituted by one or more of Ph-C 0 -6alkyl; Het-C 0 _6alkyl; C ⁇ galkoxy; Ph-C 0 _6alkoxy; Het-Co_6 a lkoxy; OH, (CH 2 ) ⁇ _ 6 NR 15 R 16 ; 0(CH 2 ) ⁇ _6NR 15 R 16 ; Ci-6alkyl, OR 17 , N(R 17 ) 2 , SR 17 , CF3, N0 2 , CN, C0 2 R 17 , CON(R 17 ), F, Cl, Br or I; where R 15 and R 16 are H, C1 _ 6 alkyl, Fh-Co-galkyl, naphthyl-Co- ⁇ alkyl or Het-Co- ⁇ alkyl; and R 7 is phenyl, naphthyl, or C _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, ORI , N(R 17 ) 2 , SR 17 , CF 3 , N0 2 , CN, C0 2 R 17 , CON(R1 7 ), F, Cl, Br and I, where Rl is phenyl, naphthyl, or C1 -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 ArCo_ f 5alkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCo-6 a l yl is identified as a specific aromatic group, e.g., phenyl, it is understood that the value of C is 0. Certain radical groups are abbreviated herein.
  • 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
  • P-EDC refers to polymer supported EDC
  • DMF refers to dimethyl formamide
  • DMSO refers to dimethyl sulfoxide
  • NMM is N-methylmorpholine
  • TEA refers to triethylamine
  • TFA trifluoroacetic acid
  • THF refers to tetrahydrofuran.
  • Nucleophilic epoxide ring opening 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-tert- butyldicarbonate to provide the N-Boc 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 N-methylmorpholine or triethylamine provides the sulfonamide derivative 9.
  • a base such as N-methylmorpholine or 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 amine 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.
  • 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 C1, CH 3 OH, H 2 0; (e) TEA, 1,3-propanedithiol, CH 3 OH.
  • Scheme 2 (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 C1, CH 3 OH, H 2 0; (e) TEA, 1,3-propanedithiol, CH
  • Reagents and conditions (a) Di-tert-butyldicarbonate, THF; (b) H 2 , 10% Pd/C, EtOAc; (c) 2-pyridylsulfonyl chloride, TEA, DMF; (d) HCl, EtOAc; (e) N-Boc-cylohexylalanine, 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.
  • the deuterated compound of the Example 7 may be conveniently prepared according to Scheme 3. The skilled artisan will understand from Example 7 and Scheme 3 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- Veriag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally illustrative of the technique and are incorporated herein by reference. Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions.
  • amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
  • Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
  • Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH4 + are specific examples of cations present in pharmaceutically acceptable salts.
  • Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
  • the methods of the present invention may be practiced by administering a pharmaceutical composition which comprises one or more compounds 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. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternately, 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 S.
  • the present invention provides methods of treatment of diseases caused by pathological levels of cathepsin S, 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 S, including one or more compounds of the present invention.
  • the present invention particularly provides methods for treating the following diseases in which cathepsin S is implicated: treatment and/or prevention of an autoimmune disease state such as rheumatoid arthritis, multiple sclerosis, juvenile-onset diabetes, sytemic lupus erythematosus, discoid lupus erythematosus, pemphigus vulgaris, pemphigoid, Grave's disease, myasthenia gravis, Hashimoto's thyroiditis, scleroderma, dermatomysositis, Addison's disease, pernicious anemia, primary myxoedema, thyrotoxicosis, autoimmune atrophic gastritis, stiff-man syndrome, Goodpasture's syndrome, sympathetic opthalamia, phacogenic uveitis, autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura, idiopathic leucopenia, primary bili
  • 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
  • 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 bone resorption 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.
  • cathepsin S proteolytic catalytic activity All assays for cathepsin S were carried out with human recombinant enzyme. Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Val-Val-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) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader. Product progress curves were generated over 20 to 30 minutes following formation of AMC product.
  • Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Val-Val-Arg
  • [AMC] v ss t + (vo - v ss ) [1 - exp (-k 0 b s t)] / k 0 bs (2)
  • Example Id To a solution of the azido alcohol of Example Id (1.1 g, 3.79 mmol) in methanol was added triethylamine (1.5 mL, 11.37 mmol) and 1,3-propanedithiol (1.1 mL, 11.37 mL).
  • Example 7 Following the procedure of Example 1(h) - l(m), except 5,6-dimethoxy- benzofuran-2-carboxylic acid in step 1(1) and 2-pyridine-N-oxide sulfonyl chloride for pyridine-2-sulfonyl chloride in step 1(h), the title compound was purified to yield two diastereomers as solids: -NMR (400Hz, CDCI3): ⁇ 8.25-7.37(m), 7.07(d), 5.02(m), 4.88(m), 4.12(d), 3.96(s), 3.94(s), 3.84(d), 3J3(s), 2.86(t), 2.20(m), 1.94-1.02(m).
  • -NMR 400Hz, CDCI3
  • the diastereomeric mixture was separated by HPLC to provide the faster eluting diastereoemer: MS(EI): 530 (M+H + ,100%) and the slower eluting diastereomer: MS(EI): 530 (M+H + ,100%).
  • Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g, ⁇ 184 mmol) in CH 2 C1 2 (231 ml), then was cooled to 0 degrees C. Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reaction mixture turned yellow, then faintly brown. After 5 minutes ((R)-2-hydroxy-l-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was warmed to RT then stirred for 3 h.
  • Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of (2R,5S,6S)-5- azido-6-hydroxy-2-methyl-azepane-l -carboxylic acid benzyl ester (0.193 g, 0.635 mmol) in THF (10 ml) and H 2 0 (0.04 ml), then was heated to 45 degrees C overnight. The reaction mixture was then diluted with toluene (100 ml x 2) and was azeotroped in vacuo by rotary evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et 2 0 and the resulting salt was collected following filtration and was used in the next reaction without further purification (0.27 g, 90%).
  • Dess-Martin periodinane (0.15 g, 0.35 mmol) was added to a solution of Furan-2-carboxylic acid ⁇ (S)-2-cyclohexyl-l -[(3S,4S,7R)-7-methyl-3-hydroxy- 1 -(pyridine-2-sulfonyl)-azepan- 4-ylcarbamoyl]-ethyl ⁇ -amide (0.15 g, 0.28 mmol) in CH 2 C1 2 (2.0 ml) and was stirred at RT for 1 h. The solution was washed with 10% aq. Na 2 S 2 0 3 , then aq. sat. NaHC0 3 , then brine.
  • Furan-2-carboxylic acid ⁇ (S)-2-cyclohexyl-l-[(4S,7R)-7-methyl-3-oxo-l-(pyridine-2- sulfonyl)-azepan-4-ylcarbamoyl]-ethyl ⁇ -amide is dissolved in d4-methanol (CD 3 OD) and D 2 0 (10:1), then triethyl amine is added and the reaction mixture is stirred for 3 days. Azeotroping with toluene by concentrating in vacuo provides the title compound.

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Abstract

Cette invention se rapporte à des procédés qui utilisent des inhibiteurs de 4-amino-azépan-3-one protéase, en particulier des inhibiteurs de cathepsine S, pour traiter des maladies dans lesquelles la cathepsine S est impliquée, notamment pour traiter ou prévenir des maladies auto-immunes, pour traiter ou prévenir un état pathologique causé par la formation de lésions athéroscléreuse et par des complications dues à ces lésions, et des maladies nécessitant, à des fins thérapeutiques, l'inhibition d'une réaction immunitaire limitée par MHC de classe II, l'inhibition d'une réaction asthmatique, l'inhibition d'une réaction allergique, l'inhibition d'une réaction immunitaire contre un organe ou un tissu transplanté ou l'inhibition de l'activité de l'élastase dans l'athérome, cette invention concernant en outre de nouveaux composés à utiliser dans ces procédés.
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EP1401453A4 (fr) * 2001-05-17 2005-04-06 Smithkline Beecham Corp Inhibiteurs de protease
US20050030912A1 (en) * 2002-08-22 2005-02-10 Enikia L.L.C. Use of hybrid (HW/DSP/MCU/SW) architectures for powerline OFDM communication field
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JPWO2009054454A1 (ja) * 2007-10-24 2011-03-03 国立大学法人 東京医科歯科大学 カテプシン阻害剤を有効成分として含有するＴｏｌｌ様受容体のシグナル伝達の調整剤
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CZ20023460A3 (en) 2004-03-17
CO5280088A1 (es) 2003-05-30
IL151087A0 (en) 2003-04-10
EP1278502A4 (fr) 2003-05-21
KR20020089482A (ko) 2002-11-29
CN1431904A (zh) 2003-07-23
HK1053785A1 (zh) 2003-11-07
NO20025005L (no) 2002-12-06
JP2004526662A (ja) 2004-09-02
PL366040A1 (en) 2005-01-24
BR0108954A (pt) 2006-05-09
HUP0301781A2 (hu) 2003-09-29
WO2001089451A3 (fr) 2002-04-04
NO20025005D0 (no) 2002-10-17
AR032319A1 (es) 2003-11-05
WO2001089451A2 (fr) 2001-11-29
AU9050701A (en) 2001-12-03
CA2406829A1 (fr) 2001-11-29
MXPA02010276A (es) 2003-04-25

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