EP1003846A1 - Inhibiteurs de proteases - Google Patents

Inhibiteurs de proteases

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Publication number
EP1003846A1
EP1003846A1 EP98923299A EP98923299A EP1003846A1 EP 1003846 A1 EP1003846 A1 EP 1003846A1 EP 98923299 A EP98923299 A EP 98923299A EP 98923299 A EP98923299 A EP 98923299A EP 1003846 A1 EP1003846 A1 EP 1003846A1
Authority
EP
European Patent Office
Prior art keywords
amino
leucine
galkyl
tetrahydrofuran
ylcarbonyl
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Withdrawn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
EP98923299A
Other languages
German (de)
English (en)
Other versions
EP1003846A4 (fr
Inventor
Andrew D. Gribble
Ashley Edward Fenwick
Robert W. Marquis
Daniel F. Veber
Jason Witherington
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1003846A1 publication Critical patent/EP1003846A1/fr
Publication of EP1003846A4 publication Critical patent/EP1003846A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/99—Enzyme inactivation by chemical treatment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/22—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel protease inhibitors, particularly inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases.
  • the compounds of this invention even more particularly relate to those compounds which inhibit cysteine proteases of the papain superfamily, and particularly cysteine proteases of the cathepsin family.
  • this invention relates to 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.
  • Cathepsin K is a member of the 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, 1251 1-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132.
  • Cathepsin K has been variously denoted as cathepsin O, cathepsin X or cathepsin 02 in the literature.
  • the designation cathepsin K is considered to be the more appropriate one (name assigned by Nomenclature Committee of the International Union of Biochemistry and Molecular Biology).
  • Cathepsins of the papain superfamily of cysteine proteases function in the normal physiological process of protein degradation in animals, including humans, e.g., in the degradation of connective tissue.
  • elevated levels of these enzymes in the body can result in pathological conditions leading to disease.
  • cathepsins have been implicated 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 structural protein. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
  • Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
  • Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage.
  • the osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
  • the low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed.
  • osteoblasts lay down a new protein matrix that is subsequently mineralized.
  • disease states such as osteoporosis and Paget's disease
  • the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle.
  • this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
  • the abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption.
  • 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.
  • cathepsin K may also be useful for treating certain neoplastic diseases.
  • protease inhibitors most particularly inhibitors of cathepsin K, and these compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis and periodontal disease.
  • An object of the present invention is to provide protease inhibitors, such as inhibitors of cysteine and serine proteases.
  • the present invention relates to compounds which inhibit cysteine proteases, and particularly cysteine proteases of the papain superfamily.
  • this invention relates to compounds which inhibit cysteine proteases of the cathepsin family and particularly, compounds which inhibit cathepsin K.
  • the compounds of the present invention 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.
  • this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, such as cysteine and serine proteases.
  • the method includes treating diseases by inhibiting cysteine proteases, and particularly cysteine proteases of the papain superfamily. More particularly, the inhibition of cysteine proteases of the cathepsin family, such as cathepsin K is described.
  • 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.
  • 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):
  • R 1 is R", R"C(0), R"C(S), R"S0 2 , R"OC(0), R"R NC(0), or R"OC(0)NR CH(R 6 )C(0);
  • R ⁇ is H, Cj.galkyl, C2_6alkenyl, Ar-C ⁇ -6alkyl, or Het-Co- ⁇ alkyl; R ⁇ is H, C ⁇ _6alkyl, C2-6alkenyl, C2-6 a lkynyl, C3_6cycloalkyl-Co_6 a l yl,
  • R 4 is H, C ⁇ _6alkyl, C2_6alkenyl, Ar-C ⁇ -6alkyl, or Het-C 0 -6alkyl; each R ⁇ independently is H, C j . ⁇ alkyl, C2-6alkenyl, Ar-C ⁇ -6alkyl, or Het-Co-6alkyl; R 6 is H, C ⁇ _6alkyl, C 2 -6alkenyl, C3_6cycloalkyl-Co-6-alkyl, Ar-Co_6alkyl,
  • R is H, Cj.galkyl, C2_6 a l enyl, Ar-C ⁇ -6 a lkyl, or Het-C ⁇ -6 a lkyl;
  • R is Ci . ⁇ alkyl, Ar-C ⁇ -6 a lkyl, Het-Co-6 lkyl, Ar-C2_6alkenyl or Het-C2_6alkenyl;
  • X is O or S; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
  • 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.
  • the S-form at the furan ring junction of formula (I) compounds is preferred.
  • both the cis (Z) and trans (E) isomers are within the scope of this invention.
  • compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • R ⁇ and R 4 are H and R- is Ci . ⁇ alkyl or C2-6 lkenyl.
  • R ⁇ is i-butyl.
  • each R ⁇ is H.
  • R 1 is R"0C(0), R"S0 or R"C(0), in which R" is Ar-C()-6 a lkyl or
  • Het-Cr j . ⁇ alkyl, and, most preferably, R is
  • B is OH, CN, OCF 3 , OC ⁇ _ 6 alkyl, OAr, S0 2 C ⁇ _ 6 alkyl, C ⁇ . 6 alkyl or halo.
  • n is 1 or 2.
  • n is 1.
  • X is O.
  • this invention is a compound of formula (II):
  • the formula (I) compound of this invention is a compound of formula (Ila):
  • formula (I) compound of this invention is a compound of formula (lib):
  • this invention is a compound of formula (lie):
  • this invention provides novel intermediates useful in the preparation of formula (I) compounds represented by formulae (III), (IV) and (V): wherein:
  • R 1 is R", R"C(0), R"C(S), R"S0 2 , R"0C(0), R"R'NC(0), or R"0C(0)NR'CH(R 6 )C(0);
  • R 2 is H, Cj.galkyl, C2_6 a lkenyl, Ar-C ⁇ -6alkyl, or Het-Co_6alkyl;
  • R ⁇ is H, Cj.galkyl, C2-6 a lkenyl, C2-6 a lkynyl, C3_ cycloalkyl-Co_6 a lkyl, Ar-Co_6 a l yl, or Het-Co_6 a lkyl;
  • R 4 is H, Cj.galkyl, C2_6alkenyl, Ar-C ⁇ -6alkyl, or Het-Cr j - ⁇ alkyl; each R ⁇ independently is H, Ci .galkyl, C2_6 a lkenyl, Ar-C ⁇ -6 a lkyl, or Het-C 0 . 6 alkyl;
  • R 6 is H, C ⁇ _ 6 alkyl, C 2 -6alkenyl, C3_6cycloalkyl-C 0 -6-alkyl, Ar-Co_6alkyl, Het-Co-6alkyl;
  • R is H, Ci . ⁇ alkyl, C2_6alkenyl, Ar-Cfj-6 a lkyl, or Het-C()-6 a lkyl;
  • R" is Cj. ⁇ alkyl, Ar-C ⁇ -6 al kyl, Het-Co_6 a 'kyl, Ar-C2_6alkenyl; or Het-C2_6 a lkenyl; and
  • n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof, or
  • R 1 is R", R"C(0), R"C(S), R"S0 2 , R"OC(0), R"R'NC(0), or R"0C(0)NR CH(R 6 )C(0);
  • R 2 is H, CT .galkyl, C2-6 a lkenyl, Ar-C ⁇ -6 a lkyl, or Het-Co_6 a lkyl;
  • R ⁇ is H, Cj.galkyl, C2-6 a l enyl, C2-6 a lkynyl, C3_6cycloalkyl-C ⁇ ..6 a lkyl, Ar-Co_6 a lkyl, or Het-Co_6 a lkyl;
  • R 4 is H, Ci .galkyl, C2-6 a lkenyl, Ar-Cfj-6alkyl, or Het-Co_6alkyl; each R ⁇ independently is H, C j .galkyl, C2_6 a lkenyl, Ar-C ⁇ -6 a lkyl, or Het-Co-6alkyl;
  • R ⁇ is H, Ci .galkyl, C2_6alkenyl, C3_6cycloalkyl-Co_6-alkyl, Ar-C ⁇ -6alkyl, Het-C 0 _6alkyl;
  • R is H, Cj.galkyl, C2_6alkenyl, Ar-C ⁇ -6 a lkyl, or Het-Co-,6 a l yl;
  • R" is Cj. ⁇ alkyl, Ar-C ⁇ -6 a lkyl, Het-Co-6 a lkyl, Ar-C2_6alkenyl; or Het-C2_6alkenyiy and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof, or
  • R 1 is R", R"C(O), R"C(S), R"S0 2 , R"OC(O), R"R'NC(0), or R"OC(0)NR'CH(R 6 )C(0);
  • R ⁇ is H, Ci .galkyl, C2-6 a lkenyl, C2-6 a lkynyl, C3_6cycloalkyl-CQ_ alkyl, Ar-Co_6 a lkyl, or Het-Co- ⁇ alkyl;
  • R 4 is H, Cj.galkyl, C2_6alkenyl, Ar-C ⁇ -6alkyl, or Het-Co-6 al kyl; each R ⁇ independently is H, Cj.galkyl, C2_6 'kenyl, Ar-C ⁇ -6 a lkyl, or Het-C 0 . 6 alkyl;
  • R ⁇ is H, Cj.galkyl, C2_6alkenyl, C3_6cycloalkyl-C ⁇ -6- a lkyl, Ar-C ⁇ -6 lkyl, Het-Co_6 lkyl;
  • R is H, Ci .galkyl, C2_6 a lkenyl, Ar-C ⁇ -6 a lkyl, or Het-Co-6 a lkyl;
  • R ' is Ci.galkyl, Ar-C ⁇ -6 a lkyl, Het-C Q -galkyl, Ar-C2_6 a l enyl; or Het-C 2 _6 a lkenyl;
  • X is O or S; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
  • Representative intermediates of this invention are: tr ⁇ ns-4-(R,S)-Arnino-N-[(benzyloxycarbonyl)-S-leucine]-3- hydroxytetrahydrofuran; tran.?-4-(R,S)-Amino-N-[(t -butoxycarbonyl)-S-leucine]-3- hy droxy tetrahy drofuran ; tran5-4- ?,S)-Amino-N-(S-leucine)-3-hydroxytetrahydrofuran; tra/w-4-(/.,5 -Amino-N-[(3,4-methylenedioxybenzoyl)-5-leucine]-3- hy droxy tetrahy drofuran ; rr ⁇ n5-4-(R,S)-Amino-N-[(3,4-dichlorobenzoyl)-S-leu
  • Prodrugs of compounds of the present invention may be a prodrug of the ketone functionality of formula (I) compounds, specifically ketals or hemiketals, of the formula (VI):
  • R 1 is R", R"C(0), R"C(S), R"S0 2 , R"0C(0), R"R'NC(0), or R"OC(0)NR CH(R 6 )C(0);
  • R 2 is H, Ci .galkyl, C2_6alkenyl, Ar-C ⁇ -6 a lkyl, or Het-C ⁇ -6 a lkyl;
  • R3 is H, Ci .galkyl, C2-6 a lkenyl, C2-6 a lkynyl, C3_6cycloalkyl-C _6alkyl, Ar-Co-6 a lkyl, or Het-C ⁇ _ alkyl
  • R 4 is H, Cj-galkyl, C2_6 a ' enyl, Ar-C ⁇ -6 a lkyl, or Het-C ⁇ . alkyl; each R ⁇ independently is H, C ] _6alkyl, C2_6 a l enyl, Ar-C ⁇ -6alkyl, or Het-Co-6 a l yl; ⁇
  • R ⁇ is H, Ci .galkyl, C2_6 a lkenyl, C3_6cycloalkyl-C()-6- a l yl, Ar-C ⁇ -6 a lkyl, Het-Co-6 alky 1 ;
  • R' is H, Cj.galkyl, C2_6 a lkenyl, Ar-C ⁇ -6 a 'kyl, or Het-C()-6 a lkyl;
  • R" is Ci .galkyl, Ar-C ⁇ -6 a lkyl, Het-Co_6 a lkyl, Ar-C2_6 a lkenyl; or Het-C2_6 a lkenyl;
  • R a and R a independently are H or Cj ⁇ alkyl, with the proviso that when one of R a or R a is H, the other is Cj ⁇ alkyl; or together are (CH2)2-3 forming a 5- or 6-membered ring; or a pharmaceutically acceptable salt thereof.
  • Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).
  • amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • C ⁇ _6 alkyl 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 or two halogens, SR', OR',
  • C 0 alkyl means that no alkyl group is present in the moiety.
  • Ar-C ⁇ alkyl is equivalent to Ar.
  • C3-6 cycloalkyl as applied herein is meant to include substituted (i.e., alkyl, OR, SR or halogen) and unsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • C2-6 a lkenyl 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.
  • C2-6 alkynyl 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 1 ' or halo means F, Cl/Br, and I.
  • Ar or aryl means unsubstituted phenyl or naphthyl; or phenyl or naphthyl substituted by one or more of Ph-C Q _6alkyl, Het-C()-6alkyl, Cj.galkoxy,
  • Het represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above- defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from Cnalkyl, OR', N(R') 2 , SR', CF 3 , N0 2 , CN, C0 2 R', CON(R') 2 , F, Cl, Br and I, where R' is as defined herein before.
  • heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, thienyl, pyrrolyl, 4-piperidonyl, pyrrclidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, isothiazolyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzopyranyl, benzoxazolyl, benzofuranyl
  • t-Bu refers to the tertiary butyl radical
  • Boc or BOC refers to the t-butyloxycarbonyl radical
  • Fmoc refers to the fluorenylmethoxycarbonyl radical
  • Ph refers to the phenyl radical
  • Cbz or CBZ refers to the benzyloxycarbonyl radical.
  • DCC refers to dicyclohexylcarbodiimide
  • EDC or EDCI refers to N-ethyl-N'(dimethylaminopropyl)- carbodiimide.
  • HOBT or HOBt refers to 1-hydroxybenzotriazole
  • PMF refers to dimethyl formamide
  • DIEA refers to di-isopropylethylamine
  • Lawesson's reagent is 2,4- bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide
  • TFA refers to trifluoroacetic acid
  • THF refers to tetrahydrofuran.
  • R ⁇ R 2 , R-', R 4 , R J and n are as defined in formula (I), with any reactive functional groups protected, with an oxidizing agent; or
  • R l , R 2 , R- > , R 4 , R-> and n are as defined in formula (I), with any reactive functional groups protected; or
  • the amine salt 3-Scheme-l may be coupled with a carboxylic acid by methods that are known in the art, such as acylation with an acid chloride or coupling with an acid in the presence of EDC and HOBT, to provide the amide 4-Scheme-l .
  • the tert-butoxycarbonyl group may be removed by treatment with a strong acid, such as TFA, in an aprotic solvent, such as dichloromethane, to provide 5-Scheme-l .
  • the salt 5-Scheme-l may be acylated with an acid chloride in 1 ,4-dioxane in the presence of an aqueous base, such as saturated sodium hydrogen carbonate, to yield 6-Scheme-l.
  • the alcohol 6-Scheme-l may be oxidized by methods known in the art, such as by treatment with Dess-Martin periodinane, in an aprotic solvent, such as dichloromethane.
  • ester group is hydrolysed, for example, with potassium trimethylsilanoate in THF, and the liberated acid group is coupled with 3,3- dimethoxy-4-amino-tetrahydofuran using, for example, EDC in NMP, to give rise to 4; Scheme-2.
  • the blocking group is then removed by known cleaving methods, such as by the addition of 7:2: 1 TFA/CH 2 C1 2 /H 2 0, to give rise to the desired compound, 5-Scheme-2.
  • Scheme 4 shows the preparation of certain formula (I) compounds which are S-diastereomers at the furan ring junction.
  • the R-diastereomer is prepared in an identical way from the opposite 3-azido-4- hydroxytetrahydrofuran enantiomer:
  • a nitrogen-protecting group is added by reacting 3-hydroxy-4-aminotetrahydofuran with benzylchloroformate in dioxane containing aqueous sodium carbonate. Thereafter, the alcohol group is oxidized by known methods, such as by the addition of bleach containing sodium bicarbonate in the presence of sodium bromide and TEMPO in EtOAc, toluene, and water, to give rise to the ketone. The ketone is converted to the dimethylketal by the addition of trimethyl-orthoformate in the presence of paratoluenesulphonic acid in methanol.
  • the protecting group is removed by hydrogenation using, for example, palladium on charcoal in the presence of ethanol under an atmosphere of hydrogen.
  • 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 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 resorption, 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 resorption, 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 morphogenic protein, iproflavone may be used to prevent bone loss or to increase bone mass.
  • an effective amount of the compounds of formula (I) is administered to inhibit the protease implicated with a particular condition or disease.
  • this dosage amount will further be modified according to the type of administration of the compound.
  • "effective amount" for acute therapy parenteral administration of a compound of formula (I) is preferred.
  • An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful.
  • 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.
  • Prodrugs of compounds of the present invention may be prepared by any suitable method. For those compounds in which the prodrug moiety is a ketone functionality, specifically ketals and/or hemiacetals, the conversion may be effected in accordance with conventional methods.
  • 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 a compound which is required to have a given pharmacological effect.
  • [AMC] v ss t + (vo - v ss ) [1 - exp (-kobsOJ / kobs (2)
  • the compounds used in the method of the present invention have a Kj value of less than 1 micromolar. Most preferably, said compounds have a Kj value of less than 100 nanomolar.
  • 4-(R,S)- Amino-N-[(8-quinolinesulfonyl)-S-leucine]-3-tetrahydrofuran-3-one, a compound of formula (I), has a K j value that is greater than 10 micromolar.
  • the cells were washed x2 with cold RPMI-1640 by centrifugation (1000 rpm, 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 minutes 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 1.7g/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 tube 3 mL of the appropriate treatment was added (diluted to 50 ⁇ M in the EMEM medium).
  • a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL).
  • The, tubes were incubated at 37°C for 30 minutes.
  • 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 hours. 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 hours.
  • the slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 minutes, following which they were washed in water and incubated in buffer for 5 minutes at 37°C.
  • the slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 minutes 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.
  • Trimethylacetyl chloride (3.5 ml, 29 mmol) was added to a stirred solution of N-Boc-L- leucine (7.3 g, 31 mmol) and diisopropylethylamine (9 ml, 52 mmol) in dichloromethane (200 ml). After 1 h, tran5-4-amino-3-hydroxytetrahydrofuran. HCl (4 g, 28 mmol) was added and the mixture was allowed to stir overnight. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were washed with 0.5N HCl, saturated sodium hydrogen carbonate, brine and dried.
  • Trimethylorthoformate 29ml was added dropwise to a refluxing solution of 4- benzyloxycarbonylamino-tetrahydrofuran-3-one (18g, 78mmol) and PTSA(500mg) in MeOH (100ml). After 3 hours, the reaction mixture was filtered and concentrated to afford, after column chromatography, the title compound as a yellow oil, 16.2g, 76%.
  • ⁇ NMR ⁇ (CDCl,) 7.35 (s, 5H), 5.30 (s, IH), 5.1 1 (s, 2H), 4.70 (app t, IH, J 8.9Hz), 4.36-4.17 (m, 2H), 3.96-3.76 (2H).
  • NMP was added to a mixture of the above resin, carboxylic acid (10 equiv) and EDC (10 equiv). The mixture was then shaken for 3 hours then washed with DMF (x3), CH 2 C1 2 (x3), MeOH (x2) and ether (x2). The resin was then resubjected to the above reaction conditions and again washed after 3 hours.
  • Step C Potassium trimethylsilanoate (10 equiv) was added to a shaken mixture of the above resin in THF. After 18 hours, the resin was washed with 5% citric acid in THF (x2), THF (x2), THF-H 2 0 (x2), H 2 0 (x2), THF-H 2 0 (x2) and finally THF (x2).
  • Step D 3,3-Dimethoxy-4-amino-tetrahydrofuran (3 equiv) was added to a mixture of the above resin and EDC (3 equiv) in NMP. After 3 hours, the resin was washed with DMF (x7), CH C1 2 (x7) and ether (x2). The resin was then resubjected to the reaction conditions for a further 3 h, then again washed as above.
  • Step E Cleavage.
  • Example 1 By analogous procedures to those described in either Example 1 or Example 15, using the appropriate amino acid and acid or acid chloride reagents consistent with the final products, the compounds of Table 1 were prepared. H NMR spectra and/or mass spectra were consistent with the structures in Table 1.
  • Benzothiophene-2-carbonyl chloride (442 mg, 2.25 mmol) was added to a solution of fr ⁇ n5-4-(R,S)-amino-N-(S-leucine)-3-hydroxytetrahydropyran (133 mg, 0.5 mmol) in dioxan (7ml) and saturated sodium hydrogen carbonate (7 ml). After 30 min, the reaction mixture was diluted with ethyl acetate, the organic layer washed with saturated sodium hydrogen carbonate, dried and evaporated under reduced pressure to give a white solid.
  • Trimethylacetyl chloride (5.4 ml, 44 mmol) was added to a stirred solution of N-Cbz-L-leucine (12.7 g, 48 mmol) and triethylamine ( 14 ml, 52 mmol) in THF (200 ml). After 1 h, .ran.s-4-S-amino-3-R-hydroxytetrahydrofuran.HCl (5.58 g, 40 mmol) was added and the mixture was allowed to stir at reflux for 16 h. The reaction mixture was filtered and evaporated under reduced pressure. Flash column chromatography (80% ethyl acetate-hexane) afforded the title compound as a white foam, 10.6 g, 76% yield.
  • N,N-Diisopropylethylamine (0.4 ml, 2.0 mmol) was added to a stirred solution of trani.-4-S-amino-N-(S-leucine)-3-R-hydroxytetrahydrofuran.HCl salt (380 mg, 1.1 mmol) in dichloromethane (10 ml). After 5 minutes benzo[b]thiophene-2-carbonyl chloride (196 mg, 1.0 mmol) was added and the mixture was allowed to stir for 1 h then evaporated under reduced pressure. Flash column chromatography (40% acetone- hexane) afforded the title compound as a white foam, 271 mg, 75% yield.
  • Benzo[b]thiophene-2-carbonyl chloride (4.9 g, 25 mmol) was added to a stirred solution of L-leucine methyl ester (4.5 g, 25 mmol) and diisopropylethylamine (9 ml, 51 mmol) in DCM (200 ml). After stirring for 2 hours at room temperature, the mixture was poured into water and washed with brine and dried (MgS0 4 ). Evaporation under reduced pressure afforded the title compound as a white solid, 7.6 g, 100% yield.
  • Lithium hydroxide (1.41 g, 59 mmol) was added in one portion to a stirred solution of /V-benzo[b]thiophene-2-ylcarbonyl-L-leucine methyl ester (8.99 g, 29.4 mmol) in THF/H 2 0 (1/1, 300 ml). After stirring for 12 hours at room temperature, the mixture was poured into water and acidifed to pH 1 with cHCl and extracted with Et,0 (x2). Evaporation under reduced pressure afforded the title compound as a yellow solid, 6.1 g, 71 % yield.
  • Methyl bromoacetate (0.6 ml, 6.3 mmol) was added and the mixture was left for a further 0.5 hours before being poured into water and extracted with EtOAc(x3). The combined organic layers were washed with brine, dried (MgS0 4 ) and evaporated under reduced pressure. Flash column chromatography (40% hexane-Et 2 0) afforded the title compound as a white solid, 1.6g, 70 %.

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Abstract

Cette invention se rapporte à des composés de leucine à substitution 3-hydroxy-cyclohétéro et 3-céto-cyclohétéro, qui constituent des inhibiteurs des cystéine-protéases, en particulier la cathépsine K, et qui sont utiles dans le traitement des maladies pour lesquelles l'inhibition de la déperdition osseuse constitue un facteur. La fraction 3-hydroxy ou 3-céto est liée à un cycle tétrahydrothiophène, tétrahydrothiopyranne, tétrahydrofuranne ou tétrahydropyranne.
EP98923299A 1997-05-06 1998-05-06 Inhibiteurs de proteases Withdrawn EP1003846A4 (fr)

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EP1232155A4 (fr) * 1999-11-10 2002-11-20 Smithkline Beecham Corp Inhibiteurs de protease
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PT1362052E (pt) 2001-01-17 2007-04-30 Amura Therapeutics Ltd Inibidores de cruzipaína e de outras proteases de cisteína
US7132449B2 (en) 2001-01-17 2006-11-07 Amura Therapeutics Limited Inhibitors of cruzipain and other cysteine proteases
CA2435117A1 (fr) * 2001-01-17 2002-07-25 Amura Therapeutics Limited 2-carbonylaminocetones cycliques, inhibiteurs de la cruzipain et autres cysteine proteases
JP2004520365A (ja) 2001-01-17 2004-07-08 アミュラ テラピューティクス リミテッド クルジパインおよび他のシステインプロテアーゼの阻害剤
US6841571B2 (en) * 2001-10-29 2005-01-11 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
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KR100962972B1 (ko) 2002-07-26 2010-06-09 주식회사유한양행 1-페닐피페리딘-3-온 유도체 및 그의 제조방법
WO2005041684A2 (fr) 2003-08-06 2005-05-12 Senomyx Inc. Saveurs, modificateurs de saveur, agents gustatifs, rehausseurs de gout, agents gustatifs et/ou rehausseurs umami ou sucres, et utilisation correspondante
AU2016206281B2 (en) * 2003-08-06 2017-11-30 Senomyx, Inc. Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof
BRPI0506719A (pt) * 2004-01-08 2007-05-02 Medivir Ab composto, composição farmacêutica, e, uso de um composto
EP1931657B1 (fr) * 2005-08-17 2013-12-25 Merck Sharp & Dohme Corp. Nouveaux ligands de kinases a base de quinoline a affinite elevee
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