WO1999066925A1 - Inhibiteurs de proteases - Google Patents

Inhibiteurs de proteases Download PDF

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Publication number
WO1999066925A1
WO1999066925A1 PCT/US1999/014561 US9914561W WO9966925A1 WO 1999066925 A1 WO1999066925 A1 WO 1999066925A1 US 9914561 W US9914561 W US 9914561W WO 9966925 A1 WO9966925 A1 WO 9966925A1
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Prior art keywords
ylcarbonyl
thiazol
hydrazide
methylpropyl
amino
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PCT/US1999/014561
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English (en)
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Stacie Marie Halbert
Evelyne Michaud
Scott Kevin Thompson
Daniel Frank Veber
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Smithkline Beecham Corporation
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Priority to AU47237/99A priority Critical patent/AU4723799A/en
Priority to JP2000555611A priority patent/JP2002518444A/ja
Priority to EP99930779A priority patent/EP1093367A4/fr
Priority to CA002335876A priority patent/CA2335876A1/fr
Publication of WO1999066925A1 publication Critical patent/WO1999066925A1/fr

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    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates in general to diacyl hydrazine 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.
  • Cathepsins are a family of enzymes which are part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S. Patent No. 5,501,969 (called cathepsin O therein). Cathepsin K has been recently expressed, purified, and characterized. Bossard, M. J., et al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.
  • Cathepsin K has been variously denoted as cathepsin O or cathepsin 02 in the literature.
  • the designation cathepsin K is considered to be the more appropriate one.
  • Cathepsins function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease. Thus, cathepsins have been implicated as causative agents in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like.
  • Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated.
  • Type I collagen represents the major structural protein of bone comprising approximately 90% of the protein matrix. 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 remodelling at discrete foci throughout life. These foci, or remodelling 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, Biochem. Biophys. Res.
  • cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, 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.
  • cysteine protease inhibitors are known. Palmer, (1995) J. Med. Chem., 38, 3193, disclose certain vinyl sulfones which irreversibly inhibit cysteine proteases, such as the cathepsins B, L, S, 02 and cruzain. Other classes of compounds, such as aldehydes, nitriles, -ketocarbonyl compounds, halomethyl ketones, diazomethyl ketones, (acyloxy)methyl ketones, ketomethylsulfonium salts and epoxy succinyl compounds have also been reported to inhibit cysteine proteases. See Palmer, id, and references cited therein. U.S. Patent No.
  • 4,518,528 discloses peptidyl fluoromethyl ketones as irreversible inhibitors of cysteine protease.
  • Published International Patent Application No. WO 94/04172, and European Patent Application Nos. EP 0525 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 European Patent Application No. EP 0 623 592 Al describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL-lb 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, 707, 103, Garker et al, Biochem. J., 1974, 139, 555, Gray et al, Tetrahedron, 1977, 33, 837, Gupton et al, J. Biol. Chem., 1984, 259, 4279, Powers et al, J. Biol. Chem., 1984, 259, 4288, and are known to inhibit serine proteases.
  • 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 El
  • Diacyl carbohydrazides have recently been disclosed as inhibitors of cathepsin K by Thompson et al, Proc. Natl. Acad. ScL, U.S.A., 1997, 94, 14249 and in International Patent Application No. WO 97/16433.
  • 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).
  • 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 diacyl hydrazine 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 Formula I.
  • 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 a method 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 mat ⁇ x degradation, such as osteoarthritis and rheumatoid arthritis.
  • the present invention provides compounds of Formula I:
  • L is selected from the group consisting of:C2_6alkyl, Ar-C()-6 a lkyl, Het-Co_6alkyl,
  • R', R 1 , R 2 , R 5 , R 10 , R 12 , R 16 and R 17 are independently selected from the group consisting of: H, Ci ⁇ alkyl, C2_6alkenyl, Ar-C ⁇ -6alkyl, and Het-C()-6alkyl;
  • R is selected from the group consisting of: C3_6alkyl, Ar, Het, CH(Rl *)Ar, CH(R 1 1 )OAr, NR 1 1 R 12 , CH(R 1 1 )NR 12 R 13 ; and
  • R" and R*3 are independently selected from the group consisting of R 4 , R I4 C(0), R 14 C(S), R 14 OC(0), and R 14 OC(0)NR 9 CH(R 15 )(CO);
  • R' is selected from the group consisting of: C j . ⁇ alkyl, Cj.galkenyl, C3. 6cycloalkyl-Co_6-alkyl, Ar-Cr j _6alkyl, and Het-Co_6alkyl; R 4 and R' may be combined to form a 3-7 membered monocyclic or 7-10- membered bicyclic carbocyclic or heterocyclic ring, optionally substituted with 1-4 of C ⁇ _ galkyl, Ar-Crj- ⁇ alkyl, Het-Cr j - ⁇ alkyl, C j .galkoxy, Ar-Cr j -galkoxy, Het-C Q - ⁇ alkoxy, OH, (CH 2 ) ⁇ . 6 NR 8 R 9 , 0(CH 2 ) I. 6 NR R9;
  • R 8 and R 9 are independently selected from the group consisting of: H, C j .galkyl, C 2- 6alkeny 1, Ar-C 0 -6alkyl, Het-C 0 -6alkyl, and R J 6 R 17 NC 2- 6alkyl ;
  • RI 4 is selected from the group consisting of: Ci.galkyl, C2_6alkenyl, A ⁇ -CQ_ 6alkyl, and Het-C Q -galkyl, and pharmaceutically acceptable salts, hydrates and solvates thereof.
  • R ⁇ is:
  • R!6 s selected from the group consisting of:
  • L is preferably:
  • 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.
  • 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-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.
  • Any Ci-galkyl group may be optionally substituted independently by one to five halogens, S R ⁇ , O R ⁇ , N(R ⁇ )2, C(0)N(Rl6)2, carbamyl or Ct_4alkyl, where R ⁇ is Ci-6alkyl.
  • C ⁇ alkyl means that no alkyl group is present in the moiety.
  • Ar-CQalkyl 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.
  • 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.
  • C2-6alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C2-6alkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C2-6 alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • Halogen means F, Cl, Br, and I.
  • Ar represents phenyl or naphthyl, optionally substituted by one or more of Ph-Crj-6alkyl, Het-Crj-6 alkyl, Ci .galkyl, Cj.galkoxy, Ph-Co- ⁇ alkoxy, Het-Crj- 6 alkoxy, OH, NR 8 R 9 , Het-S-C 0 . 6 alkyl, (CH 2 ) ⁇ _60H, (CH 2 ) ⁇ .6NR 8 R 9 , 0(CH 2 ) ⁇ .
  • 6NR 8 R 9 (CH 2 )o-6C0 2 R', 0(CH 2 )i-6C0 2 R', (CH 2 ) ⁇ _6S0 2 , CF 3 , OCF3 or halogen; Ph and Het may be optionally substituted with one or more of C1.galkoxy, OH, (CH 2 ) ⁇ _6NR 8 R 9 , 0(CH 2 ) 1 _6NR 8 R 9 , C0 2 R', CF3, or halogen; two C ⁇ alkyl or C ⁇ galkoxy groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring;
  • Ar' represents phenyl or naphthyl, optionally substituted by one or more of Ph-Co_6alkyl, Het-Co-6 a lkyl, Cj.galkyl, C j .galkoxy, Ph-Crj_6alkoxy, Het-Crj.
  • Ph may be optionally substituted with one or more of Ci.galkyl, C ⁇ _ 6 alkoxy, OH, (CH ) ⁇ _6NR 8 R 9 , 0(CH2) ⁇ _ gNR 8 R 9 , CO2R', or halogen; two Cj. ⁇ alkyl groups may be combined to form a 5-7 membered ring, saturated or unsaturated, fused onto the Ar' ring;
  • 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 be optionally substituted as with Ar (including on the nitrogens)
  • heterocycles include piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4- piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, mo ⁇ holinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl
  • 5-7 membered ring, saturated or unsaturated, fused onto the Ar ring means a fused bicyclic ring system such as indane, 1,2,3,4-tetrahydrodecalin, methylenedioxyphenyl, 1,2-ethylenedioxyphenyl and 1,3-propylenedioxyphenyl.
  • C ⁇ denotes the absence of the substituent group immediately following; for instance, in the moiety ArC ⁇ -6 a lkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArC ⁇ -6 au ⁇ yl * s identified as a specific aromatic group, e.g., phenyl, it is understood that C is 0.
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxy carbonyl radical.
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP 2,6-dimethylaminopyridine
  • EDC refers to N-ethyl-N'(dimethylaminopropyl)- carbodiimide
  • HOBT 1-hydroxybenzotriazole
  • DMF refers to dimethyl formamide
  • BOP refers to benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
  • DMAP is dimethylaminopyridine
  • NMM is N-methylmo ⁇ holine
  • TFA refers to trifluoroacetic acid
  • THF refers to tetrahydrofuran.
  • Jones reagent is a solution of chromium trioxide, water, and sulfuric acid well-known in the art.
  • R 3 C ⁇ 2H was a N-tert- butoxycarbonyl protected amino acid
  • treatment of 8-Scheme 1 with trifluoroacetic acid in dichloromethane provided 9-Scheme 1 , which was treated with a carboxylic acid (such as 6-phenylnicotinic acid, 4-(2-pyridinyl)benzoic acid, 6-methylpicolinic acid, 3,4- difluorobenzoic acid, 4-methylimidazole-5-carboxylic acid, 5-butylpicolinic acid, 6-(l- pyrrolyl)nicotinic acid.
  • a carboxylic acid such as 6-phenylnicotinic acid, 4-(2-pyridinyl)benzoic acid, 6-methylpicolinic acid, 3,4- difluorobenzoic acid, 4-methylimidazole-5-carboxylic acid, 5-butylpicolinic acid, 6-(l- pyrrolyl)nicotinic acid.
  • W en R 14 C ⁇ 2H is 2-(4-tert- butoxycarbonyl-l-piperazinyl)pyrimidine-4-carboxylic acid, 2-(4-rerr-butoxycarbonyl-l- piperazinyl)pyrimidine-5-carboxylic acid, 5- rr-butoxycarbonylmethoxybenzofuran-2- carboxylic acid, 7-ferr-butoxycarbonylmethoxybenzofuran- 2-carboxylic acid or 5-tert- butoxycarbonylbenzofuran-2-carboxylic acid, the tert-butyl protecting groups were removed from 10-Scheme 1 by treatment with trifluoroacetic acid in dichloromethane.
  • 5-Scheme 2 Treatment of 5-Scheme 2 with a carboxylic acid (such as N-rerf-butoxycarbonyl-L-leucine, (1S)-1- (benzy loxycarbony l)amino- 1 -(4-carboxythiazol-2-yl)-3-methy lbutane, N-(5-butyl-2- pyridinylmethoxycarbonyl)-L-leucine or 2-(l-naphthyl)thiazole-4-carboxylic acid) and a peptide coupling reagent (such as EDC HC1/ l-HOBT) in an aprotic solvent (such as DMF) provided 6-Scheme 2.
  • a carboxylic acid such as N-rerf-butoxycarbonyl-L-leucine, (1S)-1- (benzy loxycarbony l)amino- 1 -(4-carboxythiazol-2-yl)-3-meth
  • the present invention includes all novel intermediates required to make the compounds of Formula I. More specifically, the present invention includes the following compounds:
  • N-benzoyl-N'-cyclopropyl-N'-cyclopropylmethylthiourea N-cyclopropyl-N-cyclopropy lmethy Ithiourea
  • ethyl 2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazole-4-carboxylate N-benzoyl-N'-cyclopropyl-N'-cyclopropylmethylthiourea
  • N-cyclopropyl-N-cyclopropylmethy Ithiourea ethyl 2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazole-4-carboxylate
  • 6-phenylnicotinic acid N-cyclopropyl-N-(2-methylpropyl)amine
  • 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 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 inco ⁇ orated herein by reference.
  • 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.
  • 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 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 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.
  • 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 as inhibitors of 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 a compound of the present invention.
  • the present invention especially provides methods 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 inhibitor of cathepsin K, including a compound of the present invention.
  • 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 a patient of an effective amount of a compound 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 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.
  • treatment with 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 g/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.
  • 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 this 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. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
  • the compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have 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
  • Product progress curves were generated over 20 to 30 minutes following formation of AMC product.
  • [AMC] v ss t + (vo - v ss ) [1 - exp (-k 0 b s t)] /k oos (2)
  • the cells were washed x2 with cold RPMI-1640 by centrifugation (1000 ⁇ ra, 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 the 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.SxlCr mL in EMEM medium, supplemented with 10% fetal calf serum and 1.7g/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 rube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug mL) 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.
  • Example 1(f) The compound of Example 1(f) (6.10 g, 54.86 mmol) was dissolved in chloroform (100 mL) and benzoyl isothiocyanate (8.95 g, 54.86 mmol, 8.00 mL) was added. After stirring 45 minutes at room temperature, the solution was concentrated to give the title compound as an orange solid (15.05 g, 100%). MS (ESI): 275.1 (M+H)+.
  • Example 1(g) The compound of Example 1(g) (15.05 g, 54.86 mmol) was dissolved in methanol (100 mL) and water (100 mL), potassium carbonate (22.7 g, 164.6 mmol) was added and the solution was heated at reflux overnight. The reaction mixture was concentrated, redissolved in ethyl acetate, washed with sodium bicarbonate, water and dried (MgS ⁇ 4), filtered and concentrated to afford the title compound as a yellow solid (9.34 g. 100%). MS (ESI): 170.9 (M).
  • Example 1(h) The compound of Example 1(h) (9.34 g, 54.86 mmol) was dissolved in 50 mL of ethanol upon heating. The solution was cooled to room temperature and ethylbromopyruvate (10.7 g, 54.86 mmol, 6.8 mL) was added. The reaction mixture was heated at reflux for 30 minutes, then concentrated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated brine, dried (MgS04), filtered and concentrated to give an orange oil.
  • Example l(i) The compound of Example l(i) (13.53 g, 50.80 mmol) was dissolved in 100 mL ethanol and hydrazine monohydrate (25.4 g, 508 mmol, 24.6 mL) was added. The solution was heated at reflux for 2 hours, then concentrated. The crude product was passed trough silica gel eluting with 10% methanol in methylene chloride to give the title compound as a yellow solid (11.04 g, 86%).
  • Example 1(e) 160 mg, 0.48 mmol
  • Example l(j) 120 mg, 0.48 mmol
  • 1- hydroxybenzotriazole 6.0 mg, 0.05 mmol
  • l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride 91 mg, 0.48 mmol
  • the solution was partitioned between ethyl acetate and water.
  • the aqueous layer was extracted with ethyl acetate.
  • the combined organic layers were washed with saturated brine, dried (MgS04), filtered and concentrated.
  • the crude product was purified by column chromatography on silica gel (6% methanol in methylene chloride) to afford the title compound as a white solid (200 mg, 80%).
  • Palladium acetate (450 mg, 2.0 mmol) was dissolved in toluene (50 mL) and treated with tris(o-tolyl)phosphine (800 mg, 2.63 mmol). The solution was heated to 50°C for three minutes and cooled to room temperature. The solution was reduced to a quarter of its volume and, after addition of hexane (50 mL). the precipitate was filtered off and dried under vacuum to give the title compound as a yellow solid (670 mg, 71%), which was dissolved in dimethylacetamide (8.4 mL) and the catalyst solution was degassed and purged with argon several times before use.
  • Example 8(b) The compound of Example 8(b) was heated at reflux in EtOH (1 L) for lh then filtered. To the filtrate was added 48% (aq) HBr (3.2 mL). The solution was returned to reflux for 24h. After concentrating the solution, it was redissolved in EtOAc ( 1 L) and washed successively with saturated aqueous NaHC03 (1 L) and brine (1 L). The organic layer was dried (MgS ⁇ 4), filtered, decolorized with charcoal, filtered through Celite, and concentrated to give the title compound as a pale yellow solid ( 16.95 g, 56% from aminothiazole). iHNMR (400MHz, CDC1 3 ) ⁇ 8.13 (s, 1H), 4.41 (q, 2H), 1.40 (t, 3H).
  • Example 2(f) Following the procedure of Example 2(f), except substituting N-(N-tert- butoxycarbony l-L-leucinyl)-N '-[2-( 1 -naphthyl)thiazol-4-ylcarbonyl]hydrazide for N-(N-rerr- butoxycarbonyl-L-leucinyl)-N'-[2-[N-cyclopropyl-N-(2-methylpropyl)amino]thiazol-4- ylcarbonyl]hydrazide, the title compound was prepared as an off-white solid (8.02 g, 98%).
  • Tetrakis(triphenylphosphine)palladium(0) (0.65 g, 057 mmol) was added and heating at 85 °C was continued for 5 h.
  • the mixture was diluted with water (60 mL) and extracted with ethyl acetate (2 x 120 mL). The combined extracts were washed with saturated aqueous NaHC03 an ⁇ ⁇ saturated brine, dried (MgS ⁇ 4), filtered and concentrated. The residue was purified by flash chromatography on 180 g of 230-400 mesh silica gel, eluting with 15% ethyl acetate in hexanes, to provide the title compound as a white solid (3.22 g, 56%).
  • Example l(a)-l(k) Following the procedure of Example l(a)-l(k), except substituting 5-butylpicolinic acid for methyl 6-methylnicotinate in step (a), L-leucine methyl ester for L- ⁇ -rerr- butylalanine methyl ester in step (c), and N-cyclopropyl-N-(2-methylpropyl)amine for N- cyclopropylmethylcyclopropylamine in step (g), the title compound was prepared as a white solid (128 mg, 45%). MS (ESI): 559.3 (M+H) + .
  • Example 1(g)- l(k) Following the procedure of Example 1(g)- l(k), except substituting N-cyclopropyl- N-(2-methylpropyl)amine for N-cyclopropylmethylcyclopropylamine in step (g), and N- te/ ⁇ -butoxycarbonyl-L- ⁇ -rerr-butylalanine for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L- ⁇ -te/r-butylalanine in step (k), the title compound was prepared as a white solid (1.2 g, 76%). MS (ESI): 482.3 (M+H)+.
  • Example 29 Following the procedure of Example l(a)-l(k), except substituting methyl 2- methylnicotinate acid for methyl 6-methylnicotinate in step (a) and N-cyclopropyl-N-(2- methylpropyl)amine for N-cyclopropylmethylcyclopropylamine in step (g), the title compound was prepared as a white solid (125 mg, 89%). MS (ESI): 531.2 (M+H) + .
  • Example 29 Example 29
  • Example 32 Following the procedure of Example 1(c)- l(k), except substituting L-leucine methyl ester hydrochloride for L- ⁇ - / ⁇ -butylalanine methyl ester hydrochloride in step (c), 2- pyridylcarbinol for methyl 6-methyl-3-pyridinylcarbinol in step (d), and cyclohexylamine for cyclopropyolamine and isobutyraldehyde for cyclopropanecarboxaldehyde in step (f), the title compound was prepared as a white solid (95 mg, 62%). MS (ESI): 531.2 (M+H) + .
  • Example 32 Example 32
  • Example 35 Following the procedure of Example 2(e)-2(g), except substituting N- cyclopr ⁇ pylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine in step (e) and 4-(2-pyridinyl)benzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (135 mg, 70%). MS (ESI): 547.3 (M+H) + .
  • Example 35 Example 35
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N- cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine and N- / ⁇ -butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-terr-butoxycarbonyl-L-leucine in step (e) and 5-butylpicolinic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (130 mg, 76%). MS (ESI): 525.3 (M+H) + .
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N- cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine and N- rerr-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-ferr-butoxycarbonyl-L-leucine in step (e) and 4-(2-pyridinyl)benzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (96 mg, 70%). MS (ESI): 545.3 (M+H) + .
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N- cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine and N- rr-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and 6-(l-pyrrolyl)nicotinic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (115 mg, 89%). MS (ESI): 534.3 (M+H)+.
  • Example 45 Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and 6-(l-pyrrolyl)nicotinic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (160 mg, 97%). MS (ESI): 536.3 (M+H) + .
  • Example 45 Example 45
  • Example 48 Following the procedure of Example 1 (k), except substituting N-[2-[N-cyclopropyl- N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N-(L- ⁇ -r£?rr-butylalanyl)hydrazide for N- [2-(N-cyclopropyl-N-cyclopropylmethylamino)thiazol-4-y lcarbonyl]hydrazide and 6-( 1 - pyrrolyl)nicotinic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L- ⁇ -terr-butylalanine, the title compound was prepared as a white solid (90 mg, 76%). MS (ESI): 552.3 (M+H) + .
  • Example 48 Following the procedure of Example 1 (k), except substituting N-[N-cyclopropyl- N-(2-methylpropyl)amino]thiazol-4-ylcarbony
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclopentylamine for cyclopropylamine in step (d), N-r -butoxycarbonyl-L- ⁇ - cyclopropylalanine for N-f rr-butoxycarbonyl-L-leucine in step (e) and 3,4-difluorobenzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (118 mg, 89%). MS (ESI): 534.3 (M+H)+.
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclopentylamine for cyclopropylamine in step (d), N-r ⁇ ?rr-butoxycarbonyl-L- ⁇ - cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and 3,4- dimethoxybenzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (86 mg, 64%). MS (ESI): 558.3 (M+H) + .
  • Example 51 Following the procedure of Example 2(d)-2(g), except substituting cyclopentylamine for cyclopropylamine in step (d), N-rerr-butoxycarbonyl-L- ⁇ - cyclopropylalanine for N-terr-butoxycarbonyl-L-leucine in step (e) and 4-methylimidazole- 5-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (100 mg, 71%). MS (ESI): 502.3 ( +H)+.
  • Example 51 Example 51
  • Example 1(c)- l(k) Following the procedure of Example 1(c)- l(k), except substituting L-leucine methyl ester hydrochloride for L- ⁇ -rerr-butylalanine methyl ester hydrochloride in step (c), 2- pyridylcarbinol for 6-methyl-3-pyridylcarbinol in step (d), and cyclobutylamine for cyclopropylamine and isobutyraldehyde for cyclopropanecarboxaldehyde in step (f), the title compound was prepared as a white solid (0.192 g, 83%). MS (ESI): 517.3 (M+H) + .
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d) and 4-methylimidazole-5-carboxylic acid for 6- phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.092 g,
  • Example 59 Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d), N-r ⁇ /t-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-tert- butoxycarbonyl-L-leucine in step (e) and 3,4-difluorobenzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.095g, 63%). MS (ESI): 520.3 (M+H) + .
  • Example 59 Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d), N-r ⁇ /t-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-tert- butoxycarbonyl-L-leucine in step (e) and 3,4-difluorobenzoic acid for 6-phenylnicot
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d), N-rerr-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-tert- butoxycarbonyl-L-leucine in step (e) and 3,4-dimethoxybenzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.100 g, 64%). MS (ESI): 544.3 (M+H) + .
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d), N-rerr-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-tert- butoxycarbonyl-L-leucine in step (e) and 4-methylimidazole-5-carboxylic acid for 6- phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.076 g,
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d), N-rerr-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-tert- butoxycarbonyl-L-leucine in step (e) and 5-methyl-2-phenyloxazole-4-acetic acid for 6- phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.115 g,
  • Example 65 Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-ferr-butoxycarbonyl-L-leucine in step (e) and benzothiophene-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (50 mg, 32%). MS (ESI): 526.3 (M+H) + .
  • Example 65 Example 65
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d), N- rr-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-tert- butoxycarbonyl-L-leucine in step (e) and 4-hydroxymethylbenzoic acid for 6- phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.098 g, 66%). MS (ESI): 514.4 (M+H) + .
  • Example 68 Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and 4-hydroxymethylbenzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (90 mg, 86%). MS (ESI): 500.3 (M+H)+.
  • Example 68 Example 68
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclopentylamine for cyclopropylamine in step (d), N-rerr-butoxycarbonyl-L- ⁇ - cyclopropylalanine for N-r -butoxycarbonyl-L-leucine in step (e) and benzothiazole-6- carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (90 mg, 82%). MS (ESI): 552.2 (M+H)+.
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N- cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine and N- fej-f-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and 2,3-dihydrobenzofuran-5-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (98 mg, 85%). MS (ESI): 510.3 (M+H) + .
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclopentylamine for cyclopropylamine in step (d), N-rerf-butoxycarbonyl-L- ⁇ - cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and 4- trifluoromethoxybenzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (70 mg, 56%). MS (ESI): 582.4(M+H)+.
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclopentylamine for cyclopropylamine in step (d), N-terr-butoxycarbonyl-L- ⁇ - cyclopropylalanine for N- /T-butoxycarbonyl-L-leucine in step (e) and 4-propyloxybenzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (95 mg, 67%). MS (ESI): 556.4(M+H)+.
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d), N- rr-butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-tert- butoxycarbonyl-L-leucine in step (e) and 3-(2-pyridinyl)benzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.019 g, 12%). MS (ESI): 561.4 (M+H)+.
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d), N-r -butoxycarbonyl-L- ⁇ -cyclopropylalanine for N- / ⁇ - butoxycarbonyl-L-leucine in step (e) and 5-methyl-2-phenyloxazole-4-carboxylic acid for 6- phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.150 g,
  • Example 2(d)-2(g) Following the procedure of Example 2(d)-2(g), except substituting cyclobutylamine for cyclopropylamine in step (d) and l-methylindole-2-carboxylic acid for 6- phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.122 g,
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and indole-4-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.091 g, 60%). MS (ESI): 509.3 (M+H)+.
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and indole-5-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.105 g, 69%). MS (ESI): 509.3 (M+H) + .
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting ⁇ N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-terr-butoxycarbonyl-L-leucine in step (e) and 5-fluoroindole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.117 g, 74%). MS (ESI): 527.3 (M+H)+.
  • Example 97 Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N- rr-butoxycarbonyl-L-leucine in step (e) and 5-methyl-2-phenylthiazole-4-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.113 g, 68%). MS (ESI): 551.3 (M+H) + .
  • Example 97 Example 97
  • Example 100 Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and 5-chloroindole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.073 g, 45%). MS (ESI): 543.2 (M+H) + .
  • Example 100 Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and 5-chloroindole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.073 g, 45%). MS (ESI): 543.2
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N- rf-butoxycarbonyl-L-leucine in step (e) and 4-fluorobenzimidazole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.101 g, 64%). MS (ESI): 528.2 (M+H) + .
  • Example 103 Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-rerr-butoxycarbonyl-L-leucine in step (e) and quinoline-3-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.111 g, 71%). MS (ESI): 521.3 (M+H) + .
  • Example 103 Example 103
  • Example 106 Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-r -butoxycarbonyl-L-leucine in step (e) and 5-chlorobenzofuran-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.105 g, 64%). MS (ESI): 544.2 (M+H) + .
  • Example 106 Example 106
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N-rerr- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-r_? ⁇ -butoxycarbonyl-L-leucine in step (e) and indole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.110 g, 72%). MS (ESI): 509.3 (M+H) + .
  • Example 136 Following the procedure of Example l(k), except substituting N-[2-[N-cyclopropyl- N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-[2-(N- cyclopropyl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 3- methylthiophene-2-carboxylic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L- ⁇ - ⁇ err- butylalanine, the title compound was prepared as a white solid (110 mg, 89%). MS (ESI): 492.3 (M+H)+.
  • Example 136 Following the procedure of Example l(k), except substituting N-[N-cyclopropyl- N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[
  • Example 139 Following the procedure of Example 2(e)-2(g), except substituting N-terr- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-re/ -butoxycarbonyl-L-leucine in step (e) and 2-(2-mercaptopyridinylmethyl)furan-5-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.129 g, 74%). MS (ESI): 583.3 (M+H) + .
  • Example 139 Example 139
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting ⁇ -tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-tert-butoxycarbonyl-L-leucine in step (e) and 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.111 g, 61%). MS (ESI): 605.3 (M+H)+.
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N- rr-butoxycarbonyl-L-leucine in step (e) and S-benzodioxane-2-carboxlyic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.080 g, 50%). MS (ESI): 528.2 (M+H) + .
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N-tert- butoxycarbonyl-L- ⁇ -cyclopropylalanine for N-r -butoxycarbonyl-L-leucine in step (e) and 5-trifluoromethoxyindole-2-carboxylic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (0.096 g, 54%). MS (ESI): 593.2 (M+H) + .
  • Example 2(e)-2(g) Following the procedure of Example 2(e)-2(g), except substituting N- cyclopropylmethylcyclopropylamine for N-cyclopropyl-N-(2-methylpropyl)amine and N- r -butoxycarbonyl-L-cyclohexylglycine for N-r -butoxycarbonyl-L-leucine in step (e), and 3,4-dimethoxybenzoic acid for 6-phenylnicotinic acid in step (g), the title compound was prepared as a white solid (90 mg, 53%). MS (ESI): 556.3 (M+H) + .
  • Example 164 Following the procedure of Example l(k), except substituting N-[2-[N-cyclopropyl- N-(2-methylpropyl)amino]thiazol-4-ylcarbonyl]-N'-[L-leucinyl]hydrazide for N-[2-(N- cyclopro ⁇ yl-N-cyclopropylmethylamino)thiazol-4-ylcarbonyl]hydrazide and 4-( 1 ,2,3- thiadiazol-5-yloxy)benzoic acid for N-(6-methyl-3-pyridinylmethoxycarbonyl)-L- ⁇ -terr- butylalanine, the title compound was prepared as a white solid (125 mg, 85%). MS (ESI): 572.2 (M+H) + .
  • Example 164 Following the procedure of Example l(k), except substituting N-[N-cyclopropyl- N-(2-methylpropyl)amino]thiazol-4-yl

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Abstract

L'invention porte sur des composés de diacylhydrazine et leurs sels, hydrates et solvates pharmacocompatibles inhibant les protéases, y compris la cathépsine K, sur des préparations pharmaceutiques contenant ces composés, sur de nouveaux intermédiaires de ces composés, sur des procédés de traitement des pertes osseuses excessives, ou la dégradation des matrices ou cartilages dont l'ostéoporose, les maladies gingivales dont la gingivite et la périodontite, l'arthrite et plus spécialement l'ostéoarthrite et l'arthrite chronique, la maladie de Piaget, l'hypercalcémie maligne, les troubles du métabolisme de l'os, consistant à inhiber lesdites pertes osseuses excessives, ou la dégradation des matrices ou cartilages par administration à un patient le nécessitant un des composés de la présente invention.
PCT/US1999/014561 1998-06-24 1999-06-24 Inhibiteurs de proteases WO1999066925A1 (fr)

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US6534498B1 (en) 1999-11-10 2003-03-18 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
US6933308B2 (en) 2002-12-20 2005-08-23 Bristol-Myers Squibb Company Aminoalkyl thiazole derivatives as KCNQ modulators
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US7176310B1 (en) 2002-04-09 2007-02-13 Ucb Sa Pyrimidinecarboxamide derivatives and their use as anti-inflammatory agents
US7273866B2 (en) 2002-12-20 2007-09-25 Bristol-Myers Squibb Company 2-aryl thiazole derivatives as KCNQ modulators
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
CN102408387A (zh) * 2010-09-26 2012-04-11 韩南银 一种具有抗肿瘤作用的金属络合物
CN103113300A (zh) * 2013-03-06 2013-05-22 广西中医药大学 一种具有抗肿瘤活性的化合物的制备方法和用途
CN103242321A (zh) * 2013-05-21 2013-08-14 苏州科捷生物医药有限公司 苄基哌嗪类化合物及其抗肿瘤用途
WO2014031784A1 (fr) * 2012-08-23 2014-02-27 Alios Biopharma, Inc. Composés pour le traitement d'infections virales par paramyxovirus
CN103880701A (zh) * 2014-03-14 2014-06-25 浙江工业大学 O-肉桂酰-氟苯水杨酰胺类化合物及其在制备抗人宫颈鳞状癌药物中的应用
CN103880703A (zh) * 2014-03-14 2014-06-25 浙江工业大学 O-肉桂酰-氟苯水杨酰胺类化合物及其在制备抗人胎盘绒毛癌药物中的应用
CN103880702A (zh) * 2014-03-14 2014-06-25 浙江工业大学 O-肉桂酰-氟苯水杨酰胺类化合物及其在制备抗白血病药物中的应用
CN104487415A (zh) * 2013-05-08 2015-04-01 杨永亮 一种马来酰胺化合物、其制备方法及其用途
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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US7935698B2 (en) * 2003-11-10 2011-05-03 Synta Pharmaceuticals Corporation Heteroaryl-hydrazone compounds
BRPI0721298A2 (pt) * 2006-12-29 2014-03-25 Abbott Gmbh & Co Kg Composto de carboxamida e seus usos como inibidores de calpaína
TWI453019B (zh) * 2007-12-28 2014-09-21 Abbvie Deutschland 甲醯胺化合物

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7405209B2 (en) 1998-12-23 2008-07-29 Smithkline Beecham Corporation Protease inhibitors
US6534498B1 (en) 1999-11-10 2003-03-18 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
US7071184B2 (en) 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US7563784B2 (en) 2000-03-21 2009-07-21 Smithkline Beecham Corporation Protease inhibitors
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7176310B1 (en) 2002-04-09 2007-02-13 Ucb Sa Pyrimidinecarboxamide derivatives and their use as anti-inflammatory agents
US6933308B2 (en) 2002-12-20 2005-08-23 Bristol-Myers Squibb Company Aminoalkyl thiazole derivatives as KCNQ modulators
US7273866B2 (en) 2002-12-20 2007-09-25 Bristol-Myers Squibb Company 2-aryl thiazole derivatives as KCNQ modulators
CN102408387A (zh) * 2010-09-26 2012-04-11 韩南银 一种具有抗肿瘤作用的金属络合物
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
US11014935B2 (en) 2012-08-23 2021-05-25 Janssen Biopharma, Inc. Compounds for the treatment of paramyxovirus viral infections
CN104736530A (zh) * 2012-08-23 2015-06-24 艾丽奥斯生物制药有限公司 治疗副粘病毒病毒性感染的化合物
AU2013305759C1 (en) * 2012-08-23 2018-01-18 Janssen 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
CN103113300A (zh) * 2013-03-06 2013-05-22 广西中医药大学 一种具有抗肿瘤活性的化合物的制备方法和用途
CN104487415A (zh) * 2013-05-08 2015-04-01 杨永亮 一种马来酰胺化合物、其制备方法及其用途
CN103242321A (zh) * 2013-05-21 2013-08-14 苏州科捷生物医药有限公司 苄基哌嗪类化合物及其抗肿瘤用途
US11021444B2 (en) 2013-08-21 2021-06-01 Janssen Biopharma, Inc. Antiviral compounds
CN103880701A (zh) * 2014-03-14 2014-06-25 浙江工业大学 O-肉桂酰-氟苯水杨酰胺类化合物及其在制备抗人宫颈鳞状癌药物中的应用
CN103880701B (zh) * 2014-03-14 2016-04-13 浙江工业大学 O-肉桂酰-氟苯水杨酰胺类化合物及其在制备抗人宫颈鳞状癌药物中的应用
CN103880703B (zh) * 2014-03-14 2016-04-13 浙江工业大学 O-肉桂酰-氟苯水杨酰胺类化合物及其在制备抗人胎盘绒毛癌药物中的应用
CN103880702B (zh) * 2014-03-14 2016-04-13 浙江工业大学 O-肉桂酰-氟苯水杨酰胺类化合物及其在制备抗白血病药物中的应用
CN103880702A (zh) * 2014-03-14 2014-06-25 浙江工业大学 O-肉桂酰-氟苯水杨酰胺类化合物及其在制备抗白血病药物中的应用
CN103880703A (zh) * 2014-03-14 2014-06-25 浙江工业大学 O-肉桂酰-氟苯水杨酰胺类化合物及其在制备抗人胎盘绒毛癌药物中的应用
US10358453B2 (en) 2015-02-25 2019-07-23 Alios Biopharma, Inc. Antiviral compounds

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