EP1140897A1 - Inhibiteurs de proteases - Google Patents

Inhibiteurs de proteases

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Publication number
EP1140897A1
EP1140897A1 EP99968936A EP99968936A EP1140897A1 EP 1140897 A1 EP1140897 A1 EP 1140897A1 EP 99968936 A EP99968936 A EP 99968936A EP 99968936 A EP99968936 A EP 99968936A EP 1140897 A1 EP1140897 A1 EP 1140897A1
Authority
EP
European Patent Office
Prior art keywords
group
amino
azocine
het
pyridinylsulfonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99968936A
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German (de)
English (en)
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EP1140897A4 (fr
Inventor
Robert Wells Marquis, Jr.
Daniel Frank Veber
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP1140897A1 publication Critical patent/EP1140897A1/fr
Publication of EP1140897A4 publication Critical patent/EP1140897A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings

Definitions

  • This invention relates in general to 8-14 membered ring 1 ,3-diaminoketone 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) 7. 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, 1 18, and Everts, et al, J. Cell. PhysioL, 1992, 750, 221 , also report a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka, et al, J. Biol. Chem., 1994, 269, 1 106, 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 0 525 420 Al, EP 0 603 873 Al, and EP 0 61 1 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L.
  • 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,
  • 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.
  • cysteine proteases particularly cysteine proteases, more particularly cathepsins, most particularly cathepsin K
  • novel inhibitor compounds useful in such methods We have now discovered a novel class of 8-14 membered ring 1 ,3-diaminoketone compounds which are protease inhibitors, most particularly of cathepsin K.
  • An object of the present invention is to provide 8-14 membered ring 1,3- diaminoketone 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.
  • 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 matrix degradation, such as osteoarthritis and rheumatoid arthritis.
  • the present invention provides compounds of Formula I:
  • A is selected from the group consisting of: C(O) and CH(OH);
  • R * is selected from the group consisting of: 0
  • R 2 is selected from the group consisting of: H, C j.galkyl, C3_6 ycloalkyl-Co_ galkyl, Ar-C 0 . 6 alkyl, Het-C 0 . 6 alkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R ' 2 NC(0)-, R 9 R ] 2 NC(S)-, R ] 2 HNCH(R ] 2 )C(0)-, R 9 OC(0)NR ] 2 CH(R ] 2 )C(0)- ,adamantyl-C(0)-, or
  • R" is selected from the group consisting of: H, Cj. ⁇ alkyl, Ar-C()-6 a lkyl, and Het-
  • R'" is selected from the group consisting of: H, Cj.galkyl, C3_ cycloalkyl-C )- galkyl, Ar-Co_6 a lkyl, and Het-Co-6 a lkyl;
  • R 4 is selected from the group consisting of: H, C]_5alkyl, C3_6cycloalkyl-C()- galkyl, Ar-C 0 . 6 alkyl, Het-C 0 . 6 alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 14 NC(0)-, R 5 R 14 NC(S)-, R 14 HNCH(R 14 )C(0)-, and R 5 OC(0)NR 14 CH(R 14 )C(0)-; R- ⁇ R 9 , and R' ⁇ are independently selected from the group consisting of: C j _
  • R ⁇ is selected from the group consisting of: H, Cj.galkyl, Ar-C ⁇ -6 a lkyl, an d Het- C 0 . 6 alkyl;
  • R ⁇ is selected from the group consisting of: H, C j .galkyl, C ⁇ .gcycloalkyl-C ⁇ - 6 alkyl, Ar-C 0 _ 6 alkyl, Het-C 0 . 6 alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 15 NC(O )- 5 R10 R 15 NC(S; R15 HNCH(R 15) C( O)-, and
  • R° and R ' are connected to form a pyrrolidine, a piperidine, or a morpholine ring; each R' is independently selected from the group consisting of: H. C j .galkyl, Ar- C ⁇ -6 a 'kyl, and Uet-C Q .(,a ⁇ ky ⁇ ;
  • R 1 1 is Ar
  • R 12 ; R 13 t 14 anc j 1 are independently selected from the group consisting of:H, Cj.galkyl, Ar-C ⁇ -6 a ⁇ kyl, and Het-Co_6 a lkyl;
  • R* is selected from the group consisting of: H, Ci . ⁇ alkyl, C3_6cycloalkyl-Co_ galkyl, Ar-Co-galkyl, and Het-Co_6alkyl;
  • Z is selected from the group consisting of: C(O) and CH2;
  • X is selected from the group consisting of: CH2, S and O n is 1-7; and pharmaceutically acceptable salts thereof.
  • R 4 is selected from the group consisting of: H, C]_6alkyl, C3_5cycloalkyl-Co_ galkyl, Ar-C 0 _ 6 alkyl, Het-C 0 _6alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 14 NC(0)-, R 5 R 14 NC(S)-, R 14 HNCH(R 14 )C(0)-, and R 5 OC(0)NR 14 CH(R 14
  • Ar-Co-6 a lkyl and Het-Cg.galkyl; preferably Ar-Cg-galkyl and Het-C .galkyl; more preferably phenyl, benzyl, 2-naphthyl, 2-benzofuranyl, 2-benzothiophenyl, and 2- quinolinyl; and
  • R' is independently selected from the group consisting of:H, C j .galkyl, Ar-C ⁇ - 6 a lkyl, and Het-Co_6 a lkyl; preferably H.
  • RU is Ar, preferably 3-biphenyl
  • R* is selected from the group consisting of: H, C j. ⁇ alkyl, C3_6cycloalkyl-Co_ galkyl, Ar-C()-6 a lkyl, a nd Het-Co. ⁇ alkyl, preferably Cj.galkyl, most preferably isobutyl.
  • R- is selected from the group consisting of: H, Cj. 6 alkyl, C 3 _6cycloalkyl-Co-6 a lkyl, Ar-C 0 _6 a lkyl, Het-C 0 _6alkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-, R 9 R 12 NC(0)-, R 9 R 12 NC(S)-, R 12 HNCH(R 12 )C(0)-, R 9 OC(0)NR 12 CH(R 12 )C(0)-, and adamantyl-C(O)-, and
  • R" is selected from the group consisting of: H, C j . ⁇ alkyl, Ar-C ⁇ -6 a lkyl, or Het- Co_6 a lkyl, preferably H;
  • R7 is selected from the group consisting of: H, Cj. ⁇ alkyl, C3_ cycloalkyl-C().
  • R 9 and R ⁇ are independently selected from the group consisting of: C ⁇ _6alkyl, C3_6cycloalkyl-C ⁇ -6alkyl, Ar-Co-galkyl or Het-Co_6 a lkyl; preferably Ar-C ⁇ .galkyl and Het-Co-6 a lkyl; more preferably phenyl, benzyl, 2-naphthyl, pyridinyl, and
  • Z is selected from the group consisting of: C(O) and CH2, preferably C(O).
  • Compounds of Formula I wherein A is C(O) are preferred.
  • compounds of Formula I wherein M is selected from the group consisting of: HC CH and H C-CH2, R" and R'" are both H, or n is 1. More preferred are compounds of Formula I wherein:
  • A is C(O);
  • R" and R"' are both H
  • RI is selected from the group consisting of:
  • R 3 and R 8 are C]-6alkyl
  • R 4 is selected from the group consisting of: R ⁇ OC(O)- and R ⁇ C(O)-;
  • R ⁇ >, R 9 , and R ⁇ ⁇ are independently selected from the group consisting of: A ⁇ -CQ_ galkyl and Het-C()-6 a lkyl; R 6 is H;
  • R 7 is R 10 OC(O);
  • R' is H
  • R" is H
  • R"' is H; and Z is C(O);
  • R 3 and R 8 are independently isobutyl: or
  • R- ⁇ R 9 , and R ' ⁇ are independently selected from the group consisting of: phenyl, benzyl, 2-naphthyl, 2-benzofuranyl, 2-benzo[b]thiophenyl, 2-quinolinyl, and pyridinyl.
  • 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).
  • proteases are enzymes that catalyze the cleavage of amide bonds of peptides and proteins by nucleophilic substitution at the amide bond, ultimately resulting in hydrolysis.
  • proteases include: cysteine proteases, serine proteases, aspartic proteases, and metalloproteases.
  • the compounds of the present invention are capable of binding more strongly to the enzyme than the substrate and in general are not subject to cleavage after enzyme catalyzed attack by the nucleophile. They therefore competitively prevent proteases from recognizing and hydrolyzing natural substrates and thereby act as inhibitors.
  • amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • C ⁇ _6alkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • Any C]_6alkyl group may be optionally substituted independently by one to five halogens, SR', OR', N(R')2, O)N(R')2, carbamyl or C]-4alkyl, where R' is C i-6alkyl.
  • Cgalkyl means that no alkyl group is present in the moiety.
  • Ar-C ⁇ alkyl is equivalent to Ar.
  • C3_6cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane. cyclopentane and cyclohexane.
  • C2-6 alkenyl as applied herein means an alkyl group of 2 to 6 carbons wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • C2-6 a 'kenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C2-6 a lkynyl means an alkyl group of 2 to 6 carbons wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond.
  • C2-6 alkynyl includes acetylene, 1- propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • Halogen means F, Cl, Br, and I.
  • Ar or aryl means phenyl or naphthyl, optionally substituted by one or more of
  • Het represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 1 1- 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 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 CQ. 6 AT, Cj- ⁇ alkyl, OR 1 8 , N(R 1 8 ) 2 , SR 1 8 , CF 3 , N0 2 , CN, C0 2 R 18 , CON(R 18 ), F, Cl, Br and I, where R 1 8 is phenyl, naphthyl, or Ci-6alkyl.
  • heterocycles examples include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl.
  • quinuclidinyl indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazoly, as well as triazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl which are available by routine chemical synthesis and are stable.
  • heteroatom as applied herein refers to oxygen, nitrogen and sulfur.
  • C ⁇ denotes the absence of the substituent group immediately following; for instance, in the moiety ArC ⁇ . fj alkyl, when C is 0, the substituent is Ar, e.g., phenyl. Conversely, when the moiety ArCrj-galkyl is identified as a specific aromatic group, e.g., phenyl, it is understood that the value of C is 0.
  • t-Bu refers to the tertiary butyl radical
  • Boc refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz refers to the benzyloxycarbonyl radical.
  • CSA camphorsulphonic acid
  • EDC N-ethyl-N'(dimethylaminopropyl)-carbodiimide
  • DMF dimethyl formamide
  • DMSO dimethyl sulfoxide
  • FMOC 9- flourenylmethyloxycarbonyl
  • NMM N-methylmorpholine
  • TEA TFA refers to trifluoroacetic acid
  • THF tetrahydrofuran
  • Deprotection of the FMOC protecting group with 20% piperidine, followed by acylation with Cbz-leucine and EDC provides the azocine 5.
  • Deprotection of the Boc and acetonide protecting groups may be effected under acidic conditions such as TFA provides the amino alcohol 6.
  • Compound 6 may be acylated with a carboxylic acid such as Cbz-L-leucine in the presence of a coupling agent common to the art such as EDCI to provide the alcohol 7.
  • Alcohol 7 may be oxidised with an oxidising agent such as pyridine sulfur trioxide complex to provide the desired aza-cycloocteneone 8.
  • Boc-L-allyl glycine (9) may be converted to a diazomethyl ketone from the mixed anhydride and diazomethane, which may then converted to the bromide (not shown) with HBr.
  • the ketone could be reduced with a reducing agent such as sodium borohydride to provide 10.
  • Nucleophilic displacement of the bromide 10 with allyl amine provided the amino alcohol 11.
  • Protection of the amine as an FMOC derivative, and further protection of the hydroxyl and carbamate nitrogen as an acetonide provides the precursor to ring-closing metathesis 12.
  • Treatment of the diene 12 with Grubb's catalyst (cf.
  • Deprotection of the Boc group of 16 with an acid such as HC1 followed by coupling of the resulting amine salt with an acid such as 2-benzofuran carboxylic acid in the presence of a coupling reagent such as EDCI and final oxidation with an oxidant such as Dess-Martin periodinane or pyridine sulfurtrioxide complex provide the aza-cycloocteneone 17.
  • the present invention includes all novel intermediates required to make the compounds of Formula I. Specifically, the present invention includes all compounds of Formula II.
  • R is selected from the group consisting of:
  • Coupling methods to form amide bonds herein are generally well known to the art.
  • the methods of peptide synthesis generally set forth by Bodansky et al, THE PRACTICE OF PEPTIDE SYNTHESIS, Springer- Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1 , 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally illustrative of the technique and are incorporated herein by reference.
  • 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 "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.
  • This invention also provides a pharmaceutical composition which comprises a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament.
  • compositions of the compounds of Formula I prepared as hereinbefore described may be formulated as solutions or lyophihzed powders for parenteral administration Powders ma ⁇ be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use
  • the liquid formulation may be a buffered, isotonic, aqueous solution
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation It may be desirable to add excipients such as polyvinylpyrrohdone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, man tol, 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 earners 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 When a liquid
  • 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 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 fusiculat
  • 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 resorption, such as bisphosphonates (1 e , allendronate), hormone replacement therapy, anti-estrogens, or calcitonin
  • a compound of this invention and an anabolic agent such as bone morphogemc protein, lproflavone, 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
  • 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 resorption or to achieve any other therapeutic indication as disclosed herein
  • a pharmaceutical composition containing the compound is administered at an oral dose of between about 0 1 to about 50 mg/kg in a manner consistent with the condition of the patient
  • the oral dose would be about 0 5 to about 20 mg/kg 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 Determination of cathepsin K proteolytic catalytic activity
  • v is the velocity of the reaction with maximal velocity V m
  • A is the concentration of substrate with Michaelis constant of K a
  • / is the concentration of inhibitor
  • [AMC] v ss t + (vo - v ss ) [1 - exp (-k 0 b s t)] / k ⁇ b s (2)
  • [AMC] is the concentration of product formed over time t
  • VQ is the initial reaction velocity
  • v ss is the final steady state rate.
  • Values for k Q bs were then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (k 0 bs / inhibitor concentration or k OD s / [I]) describing the time-dependent inhibition.
  • 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 1.5xl ⁇ 4/mL in EMEM medium, supplemented with 10% fetal calf serum and 1 Jg/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 (87MEM 1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/ L).
  • 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.
  • reaction mixture was filtered, then a solution of diazomethane (179 mmol) in Et 2 0 (260 ml) generated from l-methyl-3-nitro-l- nitrosoguanidine (26.3 g, 179 mmol), 40% KOH (80 ml) and Et 2 0 (260 ml) was added and the reaction mixture was stored overnight in a refrigerator at 0°C. 30% HBr in AcOH (25 ml, 93 mmol) was added dropwise, then the reaction mixture was stirred an additional 7 minutes. The reaction mixture was then diluted with 15% aq. citric acid (100 ml), and the organics were repeatedly extracted (3x) with aq. sat.
  • N-(9-Fluorenylmethoxycarbonyloxy)succinimide ( 12.7 g, 37.7 mmol) was added to a solution of (3S)-N-Boc-3-amino-2-hydroxy-hex-5-enyl- lN-allyl-amine (6.6 g, 25 mmol) in acetone (40 ml)/ H,0 (40 ml), and the reaction mixture was stirred for 15 minutes. The reaction mixture was then concentrated and the residue was diluted with water (30 ml), and was repeatedly extracted (2x) with EtOAc (50 ml). The combined organics were then extracted with IN aq. HCl (20 ml), H 0 (20 ml), sat.
  • HBTU ( 1.25 g, 3.3 mmol) was added to a solution 4-amino- 1 ,2, 3,4,7, 8-hexahydro- 3-hydroxy-(2-pyridinylsulfonyl)-azocine ( 1.0 g, 2.8 mmol), Boc-L-leucine (0.7 g, 2.8 mmol) in N-methyl morpholine ( 1.4 ml, 12.6 mmol) in DMF ( 12 ml) and was stirred for 3h at RT.
  • HBTU 250 mg, 0.66 mmol
  • 2-benzofurancarboxylic acid 105 mg, 0.65 mmol
  • N-(L-leucinyl)-4-amino- 1,2,3,4,7, 8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine (0.305 g, 0.65 mmol) in N-methylmorpholine (0.3 ml) and DMF (4 ml) and was stirred at RT for 4h.
  • the reaction mixture was then diluted with EtOAc (40 ml) and was extracted with H 2 0, then brine.
  • Dess-Martin periodinane 130 mg, 0.3 mmol was added to a solution of N-(N-(2- benofuran-carbonyl)-L-leucinyl)-4-amino- 1,2,3,4,7, 8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine (110 mg, 0.20 mmol) in CH 2 C1 2 (3 ml) and was stirred for 1 h at RT. Then additional Dess-Martin periodinane (65 mg, 0.15 mmol) was added and the reaction was stirred an additional hour at RT. The reaction mixture was then diluted with CH 2 C1 (50 ml), extracted with 10% aq.
  • HBTU (0.34 g, 0.88 mmol) was added to a solution 4-amino- 1 ,2,3,4,7,8- hexahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine (0.28 g, 0.8 mmol), 4-methyl-2-(3- biphenyl-valeric acid (0.215g, 0.8 mmol), N-methyl morpholine (0.44 ml, 12.6 mmol) in DMF (12 ml) and was stirred for 3h at RT.
  • Dess-Martin periodinane 60 mg, 0.14 mmol was added to a solution N-(4-methyl- 2-(3-biphenyl)valeryl)-4-amino- 1 ,2, 3,4,5, 6,7, 8-octahydro-3-hydroxy-(2-pyridinylsulfonyl)- azocine (50 mg, 0.09 mmol) in CH,C1, (2 ml) and was stirred for 1 h at RT. Then additional Dess-Martin periodinane (30 mg, 0.07 mmol) was added and the reaction was stirred an additional h at RT. The reaction mixture was then diluted with CH 2 C1 2 (50 ml), extracted with 10% aq.
  • Example 4b Following the procedure of Example 4b except substituting the compound of Example 6a for N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- 1,2,3,4,7, 8-hexahydro-3- hydroxy-(2-pyridinylsulfonyl)-azocine of Example 4b, the title compound was prepared: MS ES: 554.3 (M+H+).
  • Example 6c Following the procedure of Example 6c except substituting N-(N-(2-quinoline- carbonyl)-L-leucinyl)-4-amino- 1,2, 3,4,7, 8-hexahydro-3-hydroxy-(2-pyridinylsulfonyl)- azocine of Example 6a for N-(N-(2-quinoline-carbonyl)-L-leucinyl)-4-amino- 1 , 2,3,4,5,6,7, 8-octahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine of Example 6c, the title compound was prepared: MS ES: 550.4 (M+H + ).
  • Example 4b Following the procedure of Example 4b except substituting the compound of Example 9a for N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- 1 ,2, 3,4,7, 8-hexahydro-3- hydroxy-(2-pyridinylsulfonyl)-azocine of Example 4b, the title compound was prepared: MS ES: 559 (M+H+).
  • Example 4c Following the procedure of Example 4c except substituting N-(N-(2- benzothiophene-carbonyl)-L-leucinyl)-4-amino- 1 ,2,3,4,7,8-hexahydro-3-hydroxy-(2- pyridinylsulfonyl)-azocine of Example 9a for N-(4-methyl-2-(3-biphenyl)valeryl)-4-amino- l,2,3,4,5,6,7,8-octahydro-3-hydroxy-(2-pyridinylsulfonyl)-azocine of Example 4c, the title compound was prepared: MS ES: 555.3 (M+H + ).

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Abstract

L'invention concerne des composés représentés par la formule (I) ainsi que leurs solvates, hydrates et sels pharmaceutiquement acceptables, lesquels inhibent les protéases, y compris la cathepsine K. L'invention concerne également des compositions pharmaceutiques renfermant ces composés, de nouveaux intermédiaires de ces composés et des méthodes de traitement de la déperdition osseuse ou de la détérioration excessive du cartilage ou de la matrice osseuse, l'ostéoporose notamment, de pathologies gingivales, notamment la gingivite et la parodontite, de l'arthrite, plus précisément l'arthrose et la polyarthrite rhumatoïde, de la maladie osseuse de Paget, de l'hypercalcémie de type malin et de la maladie métabolique des os. Ces méthodes consistent à administrer un composé selon l'invention à un sujet, chez lequel il est nécessaire d'inhiber une déperdition osseuse ou une détérioration excessive du cartilage ou de la matrice osseuse.
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US20030144175A1 (en) 1998-12-23 2003-07-31 Smithkline Beecham Corporation Protease inhibitors
WO2001034599A1 (fr) 1999-11-10 2001-05-17 Smithkline Beecham Corporation Inhibiteurs de protease
WO2001034600A1 (fr) 1999-11-10 2001-05-17 Smithkline Beecham Corporation Inhibiteurs de protease
US6534498B1 (en) 1999-11-10 2003-03-18 Smithkline Beecham Corporation Protease inhibitors
AU2001243441B2 (en) 2000-03-21 2004-11-25 Smithkline Beecham Corporation Protease inhibitors
US6982263B2 (en) 2001-06-08 2006-01-03 Boehringer Ingelheim Pharmaceuticals, Inc. Nitriles useful as reversible inhibitors of cysteine proteases
WO2003075853A2 (fr) 2002-03-08 2003-09-18 Bristol-Myers Squibb Company Derives cycliques servant de modulateurs de l'activite du recepteur de la chimiokine
JP2008512461A (ja) * 2004-09-07 2008-04-24 スミスクライン・ビーチャム・コーポレイション 新規化合物
WO2006076575A2 (fr) * 2005-01-13 2006-07-20 Bristol-Myers Squibb Company Composes de biaryle substitue en tant qu'inhibiteurs du facteur xia

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WO1998005336A1 (fr) * 1996-08-08 1998-02-12 Smithkline Beecham Corporation Inhibiteurs de la protease a cysteine
WO1998050534A1 (fr) * 1997-05-08 1998-11-12 Smithkline Beecham Corporation Inhibiteurs de proteases

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Publication number Priority date Publication date Assignee Title
WO1998005336A1 (fr) * 1996-08-08 1998-02-12 Smithkline Beecham Corporation Inhibiteurs de la protease a cysteine
WO1998050534A1 (fr) * 1997-05-08 1998-11-12 Smithkline Beecham Corporation Inhibiteurs de proteases

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Title
See also references of WO0039115A1 *

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