WO1998048799A1 - Inhibiteurs de proteases - Google Patents

Inhibiteurs de proteases Download PDF

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Publication number
WO1998048799A1
WO1998048799A1 PCT/US1998/008740 US9808740W WO9848799A1 WO 1998048799 A1 WO1998048799 A1 WO 1998048799A1 US 9808740 W US9808740 W US 9808740W WO 9848799 A1 WO9848799 A1 WO 9848799A1
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Prior art keywords
ylcarbonyl
thiazol
hydrazide
leucinyl
naphthyl
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PCT/US1998/008740
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English (en)
Inventor
Stacie Marie Halbert
Evelyne Michaud
Scott Kevin Thompson
Daniel Frank Veber
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Smithkline Beecham Corporation
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Priority to BR9809333-9A priority Critical patent/BR9809333A/pt
Priority to CA002287989A priority patent/CA2287989A1/fr
Priority to JP54738998A priority patent/JP2002504097A/ja
Priority to EP98920926A priority patent/EP1019046A4/fr
Priority to IL13262998A priority patent/IL132629A0/xx
Priority to HU0001294A priority patent/HUP0001294A3/hu
Priority to AU73651/98A priority patent/AU7365198A/en
Publication of WO1998048799A1 publication Critical patent/WO1998048799A1/fr
Priority to NO995268A priority patent/NO995268L/no

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • This invention relates in general to heterocycleketohydrazide protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K.
  • Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
  • Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxy apatite are incorporated.
  • Type I Collagen represents the major structural protein of bone comprising approximately 90% of the structural protein. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
  • Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
  • Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage.
  • the osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
  • the low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed.
  • osteoblasts lay down a new protein matrix that is subsequently mineralized.
  • disease states such as osteoporosis and Paget's disease
  • the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle.
  • this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
  • inhibitors of cysteine proteases are effective at inhibiting osteoclast-mediated bone resorption, and indicate an essential role for a cysteine proteases in bone resorption. For example, Delaisse, et al., Biochem.
  • cystatin an endogenous cysteine protease inhibitor
  • cystatin an endogenous cysteine protease inhibitor
  • Other studies such as by Delaisse, et al, Bone, 1987, 8, 305, Hill, et al, J. Cell. Biochem., 1994, 56, 118, and Everts, et al, J. Cell. Physiol, 1992, 150, 221, also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al, J. Biol. Chem., 1994, 269, 1106, Inaoka, et al,
  • cathepsin K which has also been called cathepsin O
  • cathepsin O a cysteine protease
  • the abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption.
  • selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
  • Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
  • selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis.
  • Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix.
  • selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases. Palmer, et al., J. Med.
  • Chem., 1995, 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, a-ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases.
  • the synthesis of azatides (polyacylhydrazides) as peptide mimetics has recently been disclosed by Han and Janda, J. Am. Chem. Soc. 1996, 118, 2539.
  • N-phenyl-N'-(2-phenyloxazol-4-ylcarbonyl)hydrazide as well as its N-(2,4-dinitrophenyl) derivative, have been described in Afridi, A., et al., J. Chem. Soc, Perkin Trans. 1, 1976, 3, 315-20.
  • Benko, A.,et al., Justus LiebigsAnn. Chem., 1968, 717, 148-53 describes the preparation of N-(4-ethoxycarbonylthiazol-2-yl)-N'-[2-(4- pyridinyl)thiazol-4-ylcarbonyl]hydrazide.
  • cysteine protease inhibitors have been identified.
  • these known inhibitors are not considered suitable for use as therapeutic agents in animals, especially humans, because they suffer from various shortcomings. These shortcomings include lack of selectivity, cytotoxicity, poor solubility, and overly rapid plasma clearance.
  • An object of the present invention is to provide heterocycleketohydrazide protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases. Accordingly, in the first aspect, this invention provides a compound according to
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient.
  • this invention provides intermediates useful in the preparation of the compounds of Formula I.
  • this invention provides methods of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
  • proteases particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
  • the compounds of this invention are especially useful for treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis.
  • the present invention provides compounds of Formula I:
  • L is C 2 -6alkyl, Ar-C 0 . 6 alkyl, Het-C 0 -6alkyl, CH(R 4 )NR 5 R 6 , CH(R 4 )Ar, CH(R 4 )OAr', or NR 4 R 7 ;
  • Ar is phenyl or naphthyl, optionally independently substituted by one or more of Ph-Co-6 a lkyl, Het-Co-6alkyl, C ⁇ galkyl, Ci.galkoxy, Ph-C()-6 a lk° ⁇ y-- Het-Co-galkoxy,
  • Cj.galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring. Ph may be optionally substituted with one or more of Cj.galkyl, Ci.galkoxy, OH, (CH2) ⁇ _ 6 NR 8 R 9 , O(CH 2 )i-6NR 8 R 9 , CO 2 R ⁇ or halogen.
  • Ar' is phenyl or naphthyl, optionally independently substituted by one or more of Het-C()-6alkyl, Ci.galkyl, Cj.galkoxy, Ph-C ⁇ -galkoxy, Het-Co-galkoxy, OH, (CH2)I-6 NR8R9 > O(CH2)i-6N 8 R 9 , or halogen.
  • Ph may be optionally substituted with one or more of C ⁇ galkyl, C galkoxy, OH, (CH2) ⁇ _6NR 8 R 9 , 0(CH 2 )i-6NR 8 R 9 , CO2R', or halogen.
  • Two Cj-galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar' ring.
  • Het is a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four 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 quatemized, 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 the group consisting of Ph-C()-6 a lkyl, Het-C ⁇ -6 alkyl, Cj.galkyl, Cj. 6 ⁇ ° ⁇ ' Ph-C 0 . 6 alkoxy, Het-C 0 -6alkoxy, OH, (CH 2 ) ⁇ _6 NR R 9 , 0(CH 2 ) ⁇ _6NR 8 R9, CO2R'.
  • Two C ⁇ _6alkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Het ring.
  • Ph may be optionally substituted with one or more of C ⁇ _ 6 alkyl, C galkoxy, OH, (CH 2 )i-6NR 8 R 9 , 0(CH 2 ) ⁇ _6NR 8 R 9 , CO 2 R', or halogen.
  • such heterocycles are selected from the group consisting of the piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pryidazinyl, pyrimidinyl, triazinyl, tetrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isothiazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl,
  • W is C(O) or SO 2 ;
  • R ⁇ R 1 , R 2 , R 5 , R 8 , R 9 , R 10 , and R 12 are independently H, C galkyl, C 2 . galkenyl, Ar-Crj- ⁇ alkyl, or Het-C ⁇ _6alkyl;
  • R 3 is C 3 . 6 alkyl, Ar, Het, CH(R! ⁇ Ar, CH(R 1 -t)OAr, NR 1 ⁇ R 12 ,
  • R 4 , R - 11 , and R 15 are independently H, C j _ 6 alky 1, C 2 -6 a lkenyl, C 3 _6cycloalkyl-
  • R 7 is Cj.galkyl, C ⁇ galkenyl, C3_6cycloalkyl-Co_6-alkyl, Ar-C()-6alkyl, or Het- CQ-6 a lkyl;
  • R 4 and R 7 may be combined to form a 3-7 membered monocyclic or 7-10- membered bicyclic carbocyclic or heterocyclic ring, optionally independently substituted with 1-4 of C ⁇ alkyl, Ar-Co-e-alkyl, Het-Co-6 a lkyl, Ci .galkoxy, Ar-Cr ⁇ galkoxy, Het-C Q . 6 alkoxy, OH, (CH 2 )i-6NR 8 R 9 , or 0(CH 2 )i-6NR 8 R 9 ;
  • R 6 and R 13 are R 14 , R 14 C(0), R 14 C(S), R 14 OC(0), or R 14 OC(O)NR 9 CH(R 15 )(CO); and
  • R 14 is C2_6 a lkenyl, Ar-Co_6alkyl, or Het-C Q -6alkyl.
  • R 3 is:
  • Rl6 is H or C- galkyl, preferably H or Me;
  • R*7 is Ci.galkyl, C2-6 a lkenyl, and C3.
  • jcycloalkyl-Ci.galkyl preferably n- propyl, wo-propyl, wo-pentyl, tert-butylmethyl, cyclopropylmethyl, iso-butyl, n-butyl, or allyl; and
  • R 18 is C3_6alkyl, OC3_6alkyl, Ar, Het, O(CH2) ⁇ -3Ar, or O(CH2) ⁇ -3Het, preferably 2-pyridinylmethoxy, 3-pyridinylmethoxy, 4-pyridinylmethoxy, tert-butoxy, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrazinyl, 4-tert- butoxycarbonylbenzyloxy, 4-carboxybenzyloxy, 3-tert-butoxycarbonylbenzyloxy, 3- carboxybenzyloxy, 2-methyl-3-pyridinylmethoxy, 6-methyl-3-pyridinylmethoxy, benzyloxy, 2-quinolino, 3-quinolino, 4-quinolino, 5-quinolino, 6-quinoIino, 7-quinolino, 8- quinolino, 1-isoquinolino, 3-isoquinolino, piperidinyl,
  • L is 4-(cis-2,6-dimethyl)-4- morpholinyl, N-cyclopropylmethyl-N-(2-methylpropyl)amino, 4-methyl-l -naphthyl, N- methyl-N-(2-methylpropyl)amino, 1 -naphthyl, 5-acena ⁇ hthyl, N-cyclopropyl-N- cyclopropylmethylamino, N,N-bis-(2-methylpropyl)amino, l-(l,2,3,4-tetrahydroquinolino, N-cyclopropylmethyl-N-propylamino, N-(2-methylpropyl)-N-phenylamino, 2-methoxy-l- naphthyl, 2-benzyloxyphenyl, 2-benzyloxy-l -naphthyl, 9
  • Most particularly preferred compounds of the present invention include: N-[2-[N-cyclopropylmethyl-N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[N-(4- pyridinylmethoxycarbonyl)-L-leucinyl]hydrazide;
  • the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
  • 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 of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Inventive compounds 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.
  • any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
  • Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).
  • 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.
  • Ci-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.
  • Any Ci-6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R')2, C(0)N(R')2, carbamyl or Ci_4alkyl, where R' is C ⁇ _6alkyl.
  • C ⁇ alkyl means that no alkyl group is present in the moiety.
  • Ar-C ⁇ alkyl is equivalent to Ar.
  • C3- ⁇ cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cycloundecane.
  • substituents are defined as for "Ci-6alkyl", above.
  • 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 l enyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and die 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.
  • Halogen means F, Cl, Br, and I.
  • Ar or “aryl” or “Ar”' or “aryl”' means phenyl or naphthyl, optionally independently substituted by one or more of Ph-C ⁇ .galkyl, Het-C ⁇ -galkyl, Cj.galkyl, C ⁇ _ 6 alkoxy, Ph-C 0 . 6 alkoxy, Het-C 0 . 6 alkoxy, OH, (CH 2 ) ⁇ _6NR 8 R 9 , O(CH 2 ) ⁇ .6NR 8 R 9 , CO2R', or halogen.
  • Two C ⁇ .galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring.
  • Ph may be optionally substituted with one or more of C ⁇ alkyl, C ⁇ 6 alkoxy, OH, (CH 2 )i-6NR 8 R 9 , O(CH 2 ) ⁇ _6 R 8 R 9 , C0 2 R', or halogen.
  • Het represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic 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 quatemized, 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 the group consisting of Ph- Co_galkyl, Het-C ⁇ .g alkyl, Cj.galkyl, Cj.galkoxy, Ph-C ⁇ .galkoxy, Het-C ⁇ .galkoxy, OH, (CH 2 )i-6 NR 8 R 9 , 0(CH 2 )i-6NR 8 R 9 , C0 2 R'.
  • TWO C galkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Het ring.
  • Ph may be optionally substituted with one or more of Cj.galkyl, C j .galkoxy, OH, (CH2) ⁇ _6NR 8 R9, O(CH2)i-6-N R 9 > CO2 ', or halogen.
  • heterocycles include the piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrr ' olidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidiny
  • 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.
  • EDC refers to N-ethyl- N'(dimethylaminopropyl)-carbodiimide.
  • HOBT refers to 1 -hydroxy benzotriazole
  • DMF refers to dimethyl formamide
  • BOP refers to benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate
  • Lawesson's reagent is 2,4-bis(4- methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide
  • NMM is N-methylmorpholine
  • TFA refers to trifluoroacetic acid
  • THF refers to tetrahydrofuran.
  • An acid chloride (such as cyclopropanecarbonyl chloride or isobutyryl choride) (A Scheme 1) is treated with a primary amine (such as aniline, cyclopropylamine, isobutylamine or propylamine) and pyridine in an aprotic solvent (such as methylene chloride) to provide 2-Scheme 1. which is treated with lithium aluminum hydride in THF to afford 3-Scheme 1.
  • 3-Scheme 1 may be prepared by treatment of an aldehyde (such as cyclopropanecarboxaldehyde or isobutyraldehyde) (8-Scheme 1 " ) with an amine (such as cyclopropylamine) in methylene chloride to provide 9-Scheme 1. which is treated with a reducing agent (such as lithim aluminum hydride in ether or sodium triacetoxyborohydride in methylene chloride). Treatment of 3-Scheme 1 with thiophosgene and pyridine in methylene chloride, followed by treanment with ammonia in methanol provides 4-Scheme 1.
  • an aldehyde such as cyclopropanecarboxaldehyde or isobutyraldehyde
  • an amine such as cyclopropylamine
  • a reducing agent such as lithim aluminum hydride in ether or sodium triacetoxyborohydride in methylene chloride.
  • 4-Scheme 1 may be prepared by treatment of __ Scheme 1 with benzoyl isothiocyanate, followed by treatment of the intermediate benzoyl thiourea with potassium carbonate in methanol/water. 4-Scheme 1 is treated with hydrazine hydrate in ethanol to give 5-Scheme 1.
  • Ethyl bromopyruvate __ Scheme 2 is treated with thiourea in refluxing ethanol to provide 2-Scheme 2. which is treated successively with sodium nitrite and copper (I) bromide in 16% aqueous HBr, and die product was heated in ethanol with a catalytic amount of HBr to give 3-Scheme 2.
  • arylboronic acid such as 2-benzyloxyphenylboronic acid, 1 -naphthy lboronic acid, 4-methyll -naphthy lboronic acid, 5-acenaphthylboronic acid, 2-methoxy-l -naphthy Iboronic acid, 2-methoxymethoxy-l -naphthy lboronic acid, 9- anthraceny lboronic acid, 9-phenantheny lboronic acid, 2-(4-tert- butoxycarbonylbenzyloxy)phenylboronic acid, 4-methoxymethoxynaphthylboronic acid or 8-quinolineboronic acid), tetrakis(txiphenylphosphine)palladium(0) and sodium bicarbonate in refluxing toluene/ethaonl water provides 4-Scheme 2.
  • 2-benzyloxyphenylboronic acid such as 2-benzyloxyphenylbor
  • 5-Scheme 2 Treatment of 4-Scheme 2 with hydrazine hydrate in ethanol provides 5-Scheme 2. which is treated with a carboxylic acid (such as N-(2-pyridinylmethoxycarbonyl)-L-leucine, N-(3-pyridinylmethoxycarbonyl)-L- leucine, N-(4-pyridinylmethoxycarbonyl)-L-leucine, N-methyl-N-(3- pyridinylmethoxycarbonyl)-L-leucine, N-benzyloxycarbonyl-L-leucine, 4-methyl-2-(3- phenylphenyl)pentanoic acid, 4-methyl-2-(3-phenoxyphenyl)pentanoic acid, 4-methyl-2-(4- phenoxyphenyl)pentanoic acid, N-benzyloxycarbonyl-L-b-tert-butylalanine, N- benzyloxycarbonyl
  • a carboxylic acid (such as N-benzyloxycarbonyl-L-leucine) (1 -Scheme 3) is converted to 2-Scheme 3 by treatment with isobutyl chloroformate, N-methylmo ⁇ holine and ammonia in THF.
  • 2-Scheme 3 is treated with Lawesson's reagent in THF to provide the thioamide 3-Scheme 3.
  • This material is converted to the thiazole by condensation with an a-ketoester followed by treatment with trifluoroacetic anhydride and pyridine in methylene chloride to afford 4-Scheme 3 which is converted to 5-Scheme 3 by treatment with hydrazine monohydrate.
  • This material is treated with a carboxylic acid (such as (1S)- l-benzyloxycarbonylamino-l-(4-carboxythiazol-2-yl)-3-methylbutane) and a peptide coupling reagent (such as EDC- ⁇ C1/1-HOBT) in an aprotic solvent (such as DMF) to provide 6-Scheme 3 where W is C(O).
  • W SO2
  • 5-Scheme 3 is treated with a corresponding sulfonyl chloride, R 3 SU2C1, and n-mediylmo ⁇ holine (NMM) in methylene chloride.
  • This material is treated with a carboxylic acid (such as pryazinecarboxylic acid, picolinic acid, 2-quinolinecarboxylic acid, 3-quinolinecarboxylic acid, 4- quinolinecarboxylic acid, 5-quinolinecarboxylic acid, 6-quinolinecarboxylic acid, 7- quinolinecarboxylic acid, 8-quinolinecarboxylic acid, 1-isoquinolinecarboxylic acid, 3- isoquinolinecarboxylic acid, N-methylpiperidinecarboxlic acid 4-methylimidazole-5- carboxylic acid, N-benzylproline, N-methy lproline, l-benzyl-5-methylimidazole-4- carboxylic acid, 6-methylnicotinic aicd, 2-methylnicotinic acid, 2-methylisonicotinic acid, 4-dimethyaminomethylbenzoic acid, 4-(4-mo ⁇ holino)benzoic acid, 5- hydroxymethylimidazole-4-carboxy
  • 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 PRAC ⁇ CE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEP ⁇ DES, 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 inco ⁇ orated herein by reference.
  • amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives diereof 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" 1"1" , Mg -1"1- and NH4 "1" 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.
  • compositions of 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.
  • 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 mglo 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 protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K.
  • the present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.
  • the present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia of malignancy, and metabolic bone disease.
  • Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
  • the present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human, in need thereof an effective amount of a compound or combination of compounds of the present invention.
  • proteases particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family
  • the present invention especially provides metiiods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, particularly a mammal, most particularly a human, in need thereof an effective amount of an inhibitor of cathepsin K, including a compound or combination of compounds of the present invention.
  • an effective amount is meant that amount of a compound or combination of compounds of the present invention sufficient to ameliorate or cure the clinically undesirable manifestations of disease (e.g. brittle and weakened bone in osteoporosis) caused by said pathological levels of target enzyme, e.g., cathepsin K, by inhibition of the target enzyme.
  • the present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease.
  • diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata;
  • This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to an animal, particularly a mammal, most particularly a human in need thereof an effective amount of a compound or combination of compounds of Formula I, alone or in combination with other inhibitors of bone reso ⁇ tion, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • a compound of this invention and an anabolic agent such as bone mo ⁇ hogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.
  • 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 K.
  • 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.
  • an inventive compound which is therapeutically effective 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 diis invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone reso ⁇ tion 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 of the present invention may be tested in one of several biological assays to determine the concentration of compound which is required to provide a given pharmacological effect.
  • 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. Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants. 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. Inhibition studies
  • v is the velocity of the reaction with maximal velocity V m
  • A is the concentration of substrate with Michaelis constant of KQ
  • / is the concentration of inhibitor.
  • [AMC] v ss t + (vo - v ss ) [1 - exp (-k ⁇ b s t)J / k 0 bs (2)
  • the cells were washed x2 with cold RPMI-1640 by centrifugation (1000 ⁇ m, 5 min at 4°C) and then transferred to a sterile 15 mL centrifuge tube. The number of mononuclear cells were enumerated in an improved Neubauer counting chamber.
  • Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium.
  • the beads were mixed with the cells and die suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube. Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts. This wash process was repeated xlO. The bead-coated cells were discarded.
  • the osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample.
  • the cells were pelleted by centrifugation and the density of osteoclasts adjusted to l.SxK ⁇ mL in EMEM medium, supplemented with 10% fetal calf serum and Ug/litre of sodium bicarbonate. 3 mL aliquots of the cell suspension ( per treatment) were decanted into 15 mL centrifuge tubes. These cells were pelleted by centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium).
  • a positive control (87MEM1 diluted to 100 ug/ L) and an isotype control (IgG2a diluted to 100 ug/mL).
  • the tubes were incubate at 37°C for 30 min.
  • 0.5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37°C for 2 h. Each treatment was screened in quadruplicate.
  • the slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 h.
  • the slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C.
  • the slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
  • the TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication. Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope.
  • 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 tetramethylsilane.
  • Cis-2,6-dimethylmo ⁇ holine (1.40 g, 12.17 mmol, 1.5 mL) was dissolved in chloroform (20 mL) and benzoyl isothiocyanate (2.0 g, 12.17 mmol, 1.75 mL) was added. After stirring 45 minutes at room temperature, the solution was concentrated to giv the title compound as a yellow solid (3.94 g, 100%). MS (ESI): 279.2 (M+H)+. b) cis-2,6-dimethy ⁇ -4-mo ⁇ holinothiourea
  • Example 1(a) The compound of Example 1(a) (3.38 g, 12.17 mmol) was dissolved in methanol (40 mL) and water (40 mL), potassium carbonate (8.4 g, 60.84 mmol) was added and the solution was heated at reflux overnight. The reaction mixture was concentrated, redissolved in ethyl acetate, washed with sodium bicarbonate and water, then dried (MgSO4), filtered and concentrated to afford the title compound as a beige solid (1.7 g, 80%). MS (ESI): 174.9 (M+H)+.
  • Example 1(f) To a stirring solution the compound of Example 1(f) (1.98g, 7.06 mmol) in THF (7 mL) was added 7 mL of water followed by LiOH ⁇ O (325 mg, 7.76 mmol). The mixture was stirred for 30 minutes and then concentrated. The residue was redissolved in water (10 mL) and 3 NHC1 was added (2.6 mL). The solution was lyophilized to yield a white solid (2.015 g, 6.44 mmol). MS (ESI): 267.2 (M+H) + .
  • Triethylamine (1.53 g, 15.09 mmol, 2.1 mL) and isobutylamine (1.10 g, 15.09 mmol, 1.5 mL) were dissolved in methylene chloride (15 mL), cooled to 0°C, and cyclopropane carbonyl chloride (1.58 g, 15.09 mmol, 1.4 mL) was added dropwise. After stirring at 0°C for one hour the mixture was diluted with methylene chloride (60 mL) and washed with NaOH (1M), then with saturated brine, dried (MgS04), filtered and concentrated. The residue was washed with ether and dried to give the title compound as a beige solid (2.1 g, 100%). MS (ESI): 141.9 (M+H)+.
  • Example 1(b) The compound of Example 1(b) was heated at reflux in EtOH (1 L) for lh, then filtered. To the filtrate was added 64 drops of 48% (aq) HBr. After stirring at reflux for 24 h the solution was concentrated and redissolved in EtOAc (1 L). The solution was washed successively with saturated aqueous NaHC ⁇ 3 (1 L) and brine (1 L), dried (MgSO4), filtered, decolorized with charcoal, filtered through Celite, and concentrated to a pale yellow solid (16.95 g, 56%). l H NMR (400 MHz, CDC1 3 ) d 8.14 (s, IH), 4.46, (q, 2H), 1.43 (t, 3H). d) 4-methyl-l -naphthalene boronic acid
  • Example 3(a) The compound of Example 3(a) (2.9 g, 8.99 mmol) was dissolved in THF (40 mL) and metiiyl iodide (2.24 mL, 35.98 mmol) was added. The reaction mixture was cooled to 0°C in a flask protected from moisture. Sodium hydride dispersion (1.214 mg, 13.49 mmol) was added cautiously and the suspension was stirred for 5 h at room temperature. Ethyl acetate was then added (to consume die sodium hydroxide formed from the excess of sodium hydride), followed by water, dropwise, to destroy the excess of sodium hydride. The solution was concentrated in vacuo, and the oily residue partitioned between ether and water.
  • Example 3(b) To the compound of Example 3(b) (2.07 g, 6.15 mmol) in methylene chloride (20 mL) was added trifluoroacetic acid (3 mL). After stirring one hour at room remperature the solution was concentrated and the residue was redissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried (MgSU4) and concentrated to afford the title compound as a white solid (1.72 g, 100%). MS (ESI): 281.3 (M+H) + .
  • Example 45 Following the procedure of Example 1(d) and 1(h), except substituting ethyl 2-[2- (4-tert-butoxycarbonylbenzyloxy)phenyl]thiazole-4-carboxylate for ethyl 2-(cis-2,6- dimed ⁇ yl-4-mo ⁇ holino)thiazole-4-carboxylate in step (d) and N-benzyloxycarbonyl-L- leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (0.102 g, 68%). MS (ESI): 673.2 (M+H)+.
  • Example 45 Following the procedure of Example 1(d) and 1(h), except substituting ethyl 2-[2- (4-tert-butoxycarbonylbenzyloxy)phenyl]thiazole-4-carboxylate for ethyl 2-(cis-2,6- dimed ⁇ yl-4
  • Example 48 Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmo ⁇ holine in step (a) and N- benzyloxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as a white solid (156 mg, 75%). MS (ESI): 500.3 (M+H)+.
  • Example 48 Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting N- cyclopropylmethyl cyclopropylamine for cis-2,6-dimethylmo ⁇ holine in step (a) and N- benzyloxycarbonyl-L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as
  • step (g) the title compound was prepared as a pale yellow solid (179.1 mg,
  • Example 69 Following the procedure of Example 59(a)-59(d), except substituting 7- quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.106 g, 75%). MS (ESI): 538.2 (M+H) + .
  • Example 69
  • Example 75(a) The compound of Example 75(a) (0.300 g, 2.5 mmol) was dissolved in concentrated hydrochloric acid (3 mL). After stirring at reflux for 18 h, the solution was concentrated to yield the title compound as a white solid (0.342 g, 100%). MS (ESI): 137.8 (M+H)+.
  • Example 81 Following the procedure of Example 4(a)-4(d), except substituting 2- pyridylcarbinol for 4-pyridylcarbinol in step (a) and N-cyclopropyl isobutylamine for N- methyl isobutylamine in step (d), the title compound was prepared as a white solid (85 mg, 32%). MS (ESI): 517.3 (M+H)+. Example 81
  • Diazomethane (4.8 mmol in 18 ml Et2 ⁇ ) was added to a solution of the compound of Example 92(a) (0.210 g, 0.48 mmol) in 1 ml Et2 ⁇ at room temperature and was stirred for 5 minutes. Then Pd(OAc)2 (2 mg) was added and the reaction was stirred overnight, filtered through silica gel, concentrated in vacuo, and was used in the next reaction without further purification (205 mg, 95%). MS (ESI): 300.1 (M+Na) + .
  • Example 96 Following the procedure of Example 1(a)- 1(d) and 1(h), except substituting bis- (cyclopropylmethyl)amine for cis-2,6-dimethylmo ⁇ holine in step (a) and N- bejnzyloxycarbonyl L-leucine for N-(4-pyridinylmethoxycarbonyl)-L-leucine in step (h), the title compound was prepared as as a yellow solid (140 mg, 69%). MS (ESI): 514.3 (M+H) + .
  • Example 96 Example 96
  • Example 28(d) Following the procedure of Example 28(d), except substituting ethyl 2-(4-hydroxy- 1 -naphthy l)thiazole-4-carboxy late for ethyl 2- (2-hydroxy-l -naphthy l)thiazole-4- carboxylate and 2-(N,N-dimethylamino)ethanol for benzyl alcohol, the title compound was prepared as a white solid (0.097 g, 52%). MS (ESI): 371.3 (M+H)+.
  • Example 136 Following the procedure of Example 59(a)-59(d), except substituting N-tgrt- butoxycarbonyl-L-b-cyclopropylalanine for N-tert-butoxycarbonyl-L-leucine in step (b) and 2-quinolinecarboxylic acid for 8-quinolinecarboxylic acid in step (d), the title compound was prepared as a white solid (0.151 g, 86%). MS (ESI): 536.3 (M+H)+.
  • Example 136 Example 136

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Abstract

Composés de formule (I) qui inhibent les protéases, dont la cathepsine K, compositions pharmaceutiques contenant lesdits composés et méthodes de traitement de maladies se traduisant par une perte osseuse excessive ou une dégradation du cartilage ou de la matrice, telles que l'ostéoporose, de maladies gingivales telles que la gingivite et la parodontite, de l'arthrite, plus spécifiquement de l'ostéoarthrite et de la polyarthrite rhumatoïde, de la maladie de Paget, de l'hypercalcémie ou de la malignité et de maladies métaboliques des os à l'aide desdites compositions.
PCT/US1998/008740 1997-04-29 1998-04-29 Inhibiteurs de proteases WO1998048799A1 (fr)

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JP54738998A JP2002504097A (ja) 1997-04-29 1998-04-29 プロテアーゼ阻害剤
EP98920926A EP1019046A4 (fr) 1997-04-29 1998-04-29 Inhibiteurs de proteases
IL13262998A IL132629A0 (en) 1997-04-29 1998-04-29 Protease inhibitors
HU0001294A HUP0001294A3 (en) 1997-04-29 1998-04-29 Heterocycleketo hydrazide derivatives having protease inhibitor activity, process for their preparation and their use
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WO1999053039A1 (fr) * 1998-04-09 1999-10-21 Smithkline Beecham Corporation Traitement de maladies parasitaires par l'inhibition des cysteine-proteases de la superfamille de la papaine
WO2000029408A1 (fr) * 1998-11-13 2000-05-25 Smithkline Beecham P.L.C. Inhibiteurs de morpholino-ethoxybenzofuran protease
US6344562B1 (en) * 1998-01-02 2002-02-05 Hoffmann-La Roche Inc. Thiazole derivatives
EP1234821A1 (fr) * 1999-12-03 2002-08-28 Ono Pharmaceutical Co., Ltd. Derives de 1.3.4-oxadiazoline et medicaments contenant ces derives utiles comme ingredients actifs
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
US6548503B1 (en) 1998-11-04 2003-04-15 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
US6583137B1 (en) 1999-11-10 2003-06-24 Smithkline Beecham Corporation Protease inhibitors
US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
WO2004007477A1 (fr) * 2002-07-04 2004-01-22 Aventis Pharma S.A. Nouveaux derives acyl hydrazino du thiophene, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation
US6730683B2 (en) 1997-12-19 2004-05-04 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses
US6797720B2 (en) 1999-12-03 2004-09-28 Ono Pharmaceutical Co., Ltd. 1,3,4-oxadiazoline derivative and an agent comprising its derivative as active ingredient
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7342027B2 (en) 2002-07-26 2008-03-11 Yuhan Corporation 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
WO2011015524A3 (fr) * 2009-08-03 2011-05-19 Bayer Cropscience Ag Dérivés d'hétérocycles fongicides
WO2014031784A1 (fr) * 2012-08-23 2014-02-27 Alios Biopharma, Inc. Composés pour le traitement d'infections virales par paramyxovirus
US10358453B2 (en) 2015-02-25 2019-07-23 Alios Biopharma, Inc. Antiviral compounds
US11021444B2 (en) 2013-08-21 2021-06-01 Janssen Biopharma, Inc. Antiviral compounds

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US6730683B2 (en) 1997-12-19 2004-05-04 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses
US6344562B1 (en) * 1998-01-02 2002-02-05 Hoffmann-La Roche Inc. Thiazole derivatives
WO1999053039A1 (fr) * 1998-04-09 1999-10-21 Smithkline Beecham Corporation Traitement de maladies parasitaires par l'inhibition des cysteine-proteases de la superfamille de la papaine
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
US6548503B1 (en) 1998-11-04 2003-04-15 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
WO2000029408A1 (fr) * 1998-11-13 2000-05-25 Smithkline Beecham P.L.C. Inhibiteurs de morpholino-ethoxybenzofuran protease
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
US6583137B1 (en) 1999-11-10 2003-06-24 Smithkline Beecham Corporation Protease inhibitors
US6596715B1 (en) 1999-11-10 2003-07-22 Smithkline Beecham Corporation Protease inhibitors
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
EP1234821A4 (fr) * 1999-12-03 2002-10-28 Ono Pharmaceutical Co Derives de 1.3.4-oxadiazoline et medicaments contenant ces derives utiles comme ingredients actifs
EP1234821A1 (fr) * 1999-12-03 2002-08-28 Ono Pharmaceutical Co., Ltd. Derives de 1.3.4-oxadiazoline et medicaments contenant ces derives utiles comme ingredients actifs
US6797720B2 (en) 1999-12-03 2004-09-28 Ono Pharmaceutical Co., Ltd. 1,3,4-oxadiazoline derivative and an agent comprising its derivative as active ingredient
US7563784B2 (en) 2000-03-21 2009-07-21 Smithkline Beecham Corporation Protease inhibitors
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
WO2004007477A1 (fr) * 2002-07-04 2004-01-22 Aventis Pharma S.A. Nouveaux derives acyl hydrazino du thiophene, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation
US7342027B2 (en) 2002-07-26 2008-03-11 Yuhan Corporation 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof
WO2011015524A3 (fr) * 2009-08-03 2011-05-19 Bayer Cropscience Ag Dérivés d'hétérocycles fongicides
WO2014031784A1 (fr) * 2012-08-23 2014-02-27 Alios Biopharma, Inc. Composés pour le traitement d'infections virales par paramyxovirus
US9724351B2 (en) 2012-08-23 2017-08-08 Alios Biopharma, Inc. Compounds for the treatment of paramoxyvirus viral infections
AU2013305759B2 (en) * 2012-08-23 2017-09-28 Janssen Biopharma, Inc. Compounds for the treatment of paramoxyvirus viral infections
AU2013305759C1 (en) * 2012-08-23 2018-01-18 Janssen Biopharma, Inc. Compounds for the treatment of paramoxyvirus viral infections
US11014935B2 (en) 2012-08-23 2021-05-25 Janssen Biopharma, Inc. Compounds for the treatment of paramyxovirus viral infections
US11021444B2 (en) 2013-08-21 2021-06-01 Janssen Biopharma, Inc. Antiviral compounds
US10358453B2 (en) 2015-02-25 2019-07-23 Alios Biopharma, Inc. Antiviral compounds

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CO4940477A1 (es) 2000-07-24
CA2287989A1 (fr) 1998-11-05
JP2002504097A (ja) 2002-02-05
AU7365198A (en) 1998-11-24
HUP0001294A3 (en) 2001-06-28
NO995268D0 (no) 1999-10-28
EP1019046A4 (fr) 2002-11-27
ZA983522B (en) 1998-10-29
PE69099A1 (es) 1999-09-26
MA26487A1 (fr) 2004-12-20
KR20010020391A (ko) 2001-03-15
NO995268L (no) 1999-11-15
EP1019046A1 (fr) 2000-07-19
CN1261276A (zh) 2000-07-26
TR199902703T2 (xx) 2000-02-21
BR9809333A (pt) 2000-07-04
AR012622A1 (es) 2000-11-08
PL337725A1 (en) 2000-08-28
HUP0001294A2 (hu) 2001-04-28
IL132629A0 (en) 2001-03-19

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