Classifications

• • 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
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • 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
  • 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
  • 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
  • C07D409/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

• This invention relates in general to C 3 -Cg 1-amino-l-acyl cycloalkane-substituted
• 4-amino-azepan-3-one 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 0 525 420 Al, EP 0 603 873 Al, and EP 0 611 756 A2 describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine proteases cathepsins B, H and L.
• PCT/US94/08868 and and European Patent Application No. EP 0623 592 Al describe alkoxymethyl and mercaptomethyl ketones which inhibit the cysteine protease IL- l ⁇ convertase. Alkoxymethyl and mercaptomethyl ketones have also been described as inhibitors of the serine protease kininogenase (International Patent Application No. PCT/GB91/01479).
• Azapeptides which are designed to deliver the azaamino acid to the active site of serine proteases, and which possess a good leaving group, are disclosed by Elmore et al., Biochem. J., 1968, 107, 103, Garker et al, Biochem. J., 1974, 139, 555, Gray et al,
• E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189, and Grinde, Biochem. Biophys. Acta, , 701, 328). 1,3-diamido-propanones have been described as analgesic agents in U.S. Patent
• EP 1 008 592 A2 describes cyclic amide derivatives which inhibit cathepsin K.
• protease 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 C3-C6 1-amino-l-acyl cycloalkane- substituted 4-amino-azepan-3-one carbonyl 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 Fonnula 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:
• R 2 is selected from the group consisting of: H, C ⁇ _galkyl, C3_($cycloa ⁇ kyl-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 is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ 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 12 NC(0)-, and R 5 R 12 NC(S)-;
• R ⁇ is selected from the group consisting of: H, Ci.galkyl, C 2 -6 a lk en y > C 2 _ galkynyl, C3_gcycloalkyl-Co_6 a ⁇ ky ' C 2 -6alkanonyl, Ar-Cg-galkyl and Het-Co- ⁇ alkyl;
• R° is selected from the group consisting of: H, C galkyl, Ar-C ⁇ -6alkyl, and Het- Co- ⁇ alkyl;
• R is selected from the group consisting of: H, C ⁇ _galkyl, C3_6cycloalkyl-Co_ galkyl, Ar-C 0 . 6 alkyl, Het-C 0 -6alkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC(O)-, and R 10 R 13 NC(S)-;
• R8 is selected from the group consisting of: H, Ci-6alkyl, C 2 -6alkenyl, C 2 -6 a ky n y > HetCo_galkyl and ArCo_6alkyl;
• R 9 is selected from the group consisting of: Ci.galkyl, C3_6cycloalkyl-Co_6alkyl,
• RIO is selected from the group consisting of: C ⁇ galkyl, C3_gcycloalkyl-Co-6alkyl, Ar-C()-6alkyl and Het-Co- ⁇ alkyl;
• RU is selected from the group consisting of: H, C ⁇ galkyl, Ar-C ⁇ -6 lkyl, and Het- C 0 . 6 alkyl;
• Rl 2 is selected from the group consisting of: H, Ci .galkyl, Ar-C()-6alkyl, and Het- C 0 _ 6 alkyl
• Rl3 is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6 a lkyl, and Het- C 0 _6alkyl;
• R' is selected from the group consisting of: H, C galkyl, Ar-C ⁇ -6 lkyl, and Het-
• H is selected from the group consisting of: H, Cj.galkyl, Ar-C ⁇ -6alkyl, and Het-
• R' is selected from the group consisting of: H, Ci.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-Co-6 a lkyl, and Het-C ⁇ -galkyl;
• Z is selected from the group consisting of: C(O) and CH 2 ; n is an integer from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
• n is preferably 4, to provide 1-amino-l-acyl cyclohexane compounds.
• the cycloalkyl ring may be unsubstituted or substituted with one or more of C ⁇ _6alkyl, C3_gcycloalkyl-Co-6alkyl, C 2 _6alkenyl, C2-6alkynyl, HetCo-galkyl, ArC Q .galkyl, or halogen.
• the cycloalkyl ring is more preferably unsubstituted.
• R4 is selected from the group consisting of: H, C ⁇ _galkyl, C3_gcycloalkyl- C 0 _6alkyl, Ar-C 0 -6alkyl, Het-C 0 -6alkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 13 NC(0)-, and R 1 3 NC(S)-.
• R4 is preferably selected from the group consisting of: R ⁇ OC(O)-, R->C(0)- and R 5 S0 2 -.
• R 4 is most preferably R 5 C(0)-. In some embodiments, R 4 is preferably methanesulfonyl.
• R is selected from the group consisting of: H, Ci. ⁇ alkyl, C2_galkenyl, C2. galkynyl, C3_6cycloalkyl-C ⁇ _galkyl, C2-6alkanonyl, Ar-C0_galkyl or Het-Co-6 a lkyl.
• R is selected from the group consisting of: Cj.galkyl, C2-6alkenyl, C2- ⁇ alkynyl, C3_6cycloal yl-C ⁇ _6alkyl, C2-6alkanonyl, Ar-Co_galkyl and Het-Co-galkyl.
• R ⁇ is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially Ci.galkoxy and aryloxy substituted methyl, more especially phenoxy-methyl , 4-fluoro- phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl- methyl ; ethyl, especially piperidin-1-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; pentanonyl, especially 4-pentanonyl; phenyl, especially phenyl substituted with one or more halogens, more
• 1,8 naphthyridinyl especially 1,8 naphthyridin-2-yl; indolyl, especially indol-2-yl, indol-6-yl, indol-5-yl, especially C j .galkyl substituted indolyl, more especially N-methyl-indol-2-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially C j .galkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yland l-oxy-pyridin-3-yl; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, C j .galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,
• R-* is preferably pyridin-2-yl or l-oxo-pyridin-2-yl.
• R' is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het-
• R' is selected from the group consisting of: H and naphthalen-2-yl- methyl.
• R' is H.
• R" is selected from the group consisting of: H, C j .galkyl, Ar-Co-6alkyl, and Het- C 0 .galkyl. Most preferably R" is H.
• R' is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl- Co-6alky , and Het-Co-galkyl.
• R'" is preferably selected from the group consisting of: H and C j .galkyl.
• R'" is more preferably selected from the group consisting of: H and methyl.
• R'" is methyl
• R 2 is selected from the group consisting of:
• R 2 is selected from the group consisting of: Ar-C ⁇ -6 a lkyl,
• R 7 ⁇ R 9 C(0)-, R 9 S0 2 , R 9 R n NC(0)-, and R Even more preferably, R 2 is selected from the group consisting of: Ar-C ⁇ -6 a lkyl, R 9 C(0)-, and R S0 2 .
• R 2 is R 9 S0 2 .
• R6 is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, or Het- C ⁇ -galkyl, preferably H.
• R ⁇ is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-C()- galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 14 NC(O)-, and R 10 R 14 NC(S)-.
• R 7 is preferably R 10 OC(O).
• R ⁇ is selected from the group consisting of: H, Cj.galkyl, C2-6 a lkenyl, C2-6 a kynyl, HetC Q .galkyl and ArCo_galkyl; preferably Cj.galkyl, more preferably isobutyl.
• R 9 is selected from the group consisting of: Cj.galkyl, C3_gcycloalkyl-Co_galkyl, Ar-Co-galkyl, -Ar-COOH, and Het-CQ-galkyl.
• R 9 is preferably selected from the group consisting of: Cj.galkyl, Ar-C ⁇ -galkyl, - Ar-COOH, and Het-C 0 .galkyl. More preferably, R 9 is selected from the group consisting of: methyl; ethyl, especially C3_gcycloalkyl-Co_galkyl-substituted ethyl, more especially 2- cyclohexyl-ethy 1 ; propyl; butyl, especially Cj.galkylbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9 OC(0); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl
• R 9 is most preferably selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl.
• R 9 is preferably Ar-C 0 .galkyl, more preferably
• Ar most preferably substituted phenyl such as 2-methyl phenyl, 4-methyl phenyl, 2-chloro phenyl, and 4-fluoro phenyl.
• RU is selected from the group consisting of: H, C j .galkyl, Ar-Co-6alkyl, and Het-C 0 .galkyl.
• R 2 is R 9 S0 2 R ⁇ NC(0)-
• R 11 is preferably H.
• R 9 is preferably selected from the group consisting of C j . galkyl, C3_gcycloalkyl-Co_galkyl, and Het-Co-galkyl, more preferably l-oxy-pyridin-2-yl, cyclohexyl ethyl, and 3-methyl butyl.
• R 2 is Ar-Co_galkyl
• R 2 is preferably phenyl, especially substituted phenyl, more especially halogen substituted phenyl, even more especially 2-fluorobenzyl.
• R 2 is C j .galkyl
• R 2 is preferably selected from 1-propyl, 1-butyl, and 1- pentyl.
• Het-C ⁇ .galkyl is preferably Het-methyl
• Het in Het-methyl is preferably selected from the group consisting of: pyridinyl, especially pyridin-2-yl, especially C j .galkylpyridinyl, more especially 6- methyl-pyridin-2-yl; thiopheneyl, especially thiophene-2-yl, more especially thiophene-2-yl or benzo[b]thiophene-2-yl; thiazolyl, especially thiazol-4-yl such as l-(2-morpholin-4-yl-thiazol-4-y ⁇ ), and 1- (isothiazol-3-yl); lH-imidazolyl, especially lH-imidazol-2-yl, lH-imidazol-4-yl, especially Cj_ galkyl substituted imidazolyl, more especially l-methyl-lH-imidazol
• R 2 is also preferably: H; toluyl; aryl substituted ethyl, especially 2-phenyl ethyl, 2-[3-(pyridin-2-yl) phenyl] ethyl.
• R 2 is selected from the group consisting of: Ar-C ⁇ -6alkyl, R 9 C(0)-, R 9 S0 2 , R 6 R- Z - R 9 R ⁇ NC(0)-, and R ;
• R 4 is selected from the group consisting of: R 5 OC(0)-, R 5 C(0)- and R 5 S0 2 -;
• R ⁇ is selected from the group consisting of: Cj.galkyl, C 2 _galkenyl, C 2 .galkynyl, C3.gcycloalkyl-Co_galkyl, C 2 _galkanonyl, Ar-C ⁇ _galkyl and Het-Cg-galkyl;
• R 6 is H;
• R 7 is R 10 OC(O);
• R 8 is Cj.galkyl;
• R 9 is selected from the group consisting of: Cj.galkyl, Ar-Cg-galkyl, -Ar-COOH, and Het-Co_galkyl;
• RIO i selected from the group consisting of: Cj.galkyl, Ar-Co-galkyl and Het-Cg. galkyl; R'is H;
• R" is H
• R'" is methyl; and Z is selected from the group consisting of: C(O) and CH .
• R 2 is selected from the group consisting of: Ar-C ⁇ -6 a lkyl, R 9 C(0)-, R 9 S0 2 .
• R 2 is selected from the group consisting of: Ar-C()-6alkyl, R C(0)- and R 9 S02 ⁇ R 4 is R 5 C(0)-;
• R5 is selected from the group consisting of: methyl, especially halogenated methyl, more especially trifluoromethyl , especially C j .galkoxy and aryloxy substituted methyl, more especially phenoxy-methyl , 4-fluoro- phenoxy-methyl , especially heterocycle substituted methyl, more especially 2-thiophenyl- methyl ; ethyl, especially piperidin-1-yl-ethyl; butyl, especially aryl substituted butyl, more especially 4-(4-methoxy)phenyl-butyl; isopentyl; cyclohexyl; butenyl, especially aryl substituted butenyl, more especially 4,4-bis(4- methoxyphenyl)-but-3-enyl; acetyl; pentanonyl, especially 4-pentanonyl; phenyl, especially phenyl substituted with one or more halogens, more especially 3,4-dichlorophenyl and
• 1,8 naphthyridinyl especially 1,8 naphthyridin-2-yl
• indolyl especially indol-2-yl, especially indol-6-yl, indol-5-yl, especially C j .
• a lkyl substituted indolyl more especially N-methyl-indol-2-yl; pyridinyl, especially pyridin-2-yl, pyridin-3-yl, pyridin-5-yl, especially C j .galkyl substituted pyridinyl, more especially 2-methyl-pyridin-5-yl, and oxy-pyridinyl, especially l-oxy-pyridin-2-yland l-oxy-pyridin-3-yl; furo[3,2-b]-pyridinyl, especially furo[3,2-b]-pyridin-2-yl, C j .galkyl substituted furo[3,2-b]-pyridinyl, especially 3-methyl-furo[3,2-b]-pyridin-2-yl; thiopheneyl, especially thiophen-3-yl, also thiophen-2-yl, especially Cj.galkyl substituted thiopheneyl, more especially 5-methyl
• R 9 is selected from the group consisting of: methyl; ethyl, especially C3_gcycloalkyl-Co_galkyl-substituted ethyl, more especially 2- cy clohexy 1-ethy 1 ; propyl; butyl, especially C j .gbutyl, more especially 3-methylbutyl; tert-butyl, particularly when R 2 is R 9 OC(0); isopentyl; phenyl, especially halogen substituted phenyl, more especially 3,4-dichlorophenyl , 4-bromophenyl, 2-fluorophenyl, 3-fluoro ⁇ henyl, 4-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, especially C j .galkoxy phenyl, more especially 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, especially cyanophenyl
• R' is H
• R" is H; and R'" is methyl.
• Most preferred are compounds of Formula I wherein:
• R 2 is R 9 S0 2 ;
• R 4 is R 5 C(0); R-> is selected from the group consisting of: benzofuran-2-yl, 3-methyl-benzofuran-
• R 9 is selected from the group consisting of: pyridin-2-yl and l-oxy-pyridin-2-yl, preferably pyridin-2-yl.
• R' is H
• R'" is methyl
• Example 1-8 Specific representative compounds of the present invention are set forth in Example 1-8.
• the 7 membered ring compounds of the present invention are configurationally more stable at the carbon center alpha to the ketone.
• the present invention includes deuterated analogs of the inventive compounds.
• a representative synthesis of deuterated analogs is shown in Scheme 8.
• the deuterated compounds of the present invention should exhibit superior chiral stability compared to the protonated isomer.
• the present invention includes quaternary salts of the inventive compounds.
• 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.
• 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.
• a representation of an element is understood to include all isotopes of that element.
• H includes all isotopes of hydrogen, including deuterium.
• Cj-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.
• 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 lkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
• C2-6 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.
• C 2 _galkanonyl includes, for example, acetyl, 1- and 2-propanonyl, 1-, 2-, and 3-butanonyl, 1-, 2-, 3- and 4-pentanonyl and 1-, 2-, 3-, 4- and 5- hexanonyl.
• Halogen means F, CI, Br, and I.
• Ar or aryl means phenyl or naphthyl, optionally substituted by one or more of
• Het or "heterocychc” represents a stable 5- to 7-membered monocyclic, a stable 7- to 10-membered bicyclic, or a stable 11- to 18-membered tricyclic heterocychc 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 heterocychc rings is fused to a benzene ring.
• the heterocychc ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from C 0 .gAr, Cj.galkyl, OR 17 , N(R 17 ) 2 , SR 17 , CF 3 , N0 2 , CN, C0 2 R 17 , C0N(R 17 ), F, CI, Br and I, where R 17 is phenyl, naphthyl, or C j.galkyl.
• heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, 1-oxo-pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, quinoxalinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furanyl, benzoimid
• heteroatom refers to oxygen, nitrogen and sulfur.
• CQ denotes the absence of the substituent group immediately following; for instance, in the moiety ArCo-galkyl, when C is 0, the substituent is Ar, e.g., phenyl.
• ArCo-galkyl when C is 0, the substituent is Ar, e.g., phenyl.
• ArCo-galkyl is identified as a specific aromatic group, e.g., phenyl, it is understood that the value of C is 0.
• Certain radical groups are abbreviated herein.
• t-Bu refers to the tertiary butyl radical
• Boc refers to the t-butyloxycarbonyl radical
• Fmoc refers to the fluorenylmethoxycarbonyl radical
• Ph refers to the phenyl radical
• Cbz refers to the benzyloxycarbonyl radical.
• m-CPBA refers to 3-chloroperoxybenzoic acid
• EDC refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide
• DMF refers to dimethyl formamide
• DMSO refers to dimethyl sulfoxide
• HBTU refers to O-Benzotriazol- l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate
• TEA refers to triethylamine
• NMM refers to N-methylmorpholine
• TFA refers to trifluoroacetic acid
• THF refers to tetrahydrofuran.
• Epoxidation of 3 with standard oxidizing agents common to the art such as w-CPBA provide the epoxide 4.
• ⁇ ucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 5 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with hydrogen gas in the presence of a catalyst such as palladium on carbon.
• Acylation of 5 with an acid such as Cbz-amino-cyclohexanecarboxylic acid in the presence of a coupling agent such as EDC followed by removal of the BOC protecting group under acidic conditions provides the amine salt 6.
• Coupling of 6 with Cbz-amino- cyclohexanecarboxylic acid may be effected with a coupling agent such as EDC to provide the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7.
• a coupling agent such as EDC to provide the intermediate alcohol (not shown) which was oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 7.
• Nucleophilic epoxide ring opening may be effected with a reagent such as sodium azide to provide the azido alcohol (not shown) which may be reduced to the amino alcohol 12 with a reducing agent such as propanedithiol in the presence of triethylamine.
• a reducing agent such as propanedithiol in the presence of triethylamine.
• Acylation of 12 with N-Boc- amino-cyclohexanecarboxylic acid and a coupling agent such as EDC followed by removal of the Cbz protecting group under hydrogenolysis conditions provides the amine 13.
• Coupling of 13 with a carboxylic acid was effected with a coupling agent such as EDC followed by removal of the acid labile N-Boc protecting group with an acid such as HCl or TFA provides intermediate 14.
• Acylation of 14 may be effected with a carboxylic acid in the presence of a coupling agent common to the art such as EDC to give the intermediate alcohol (not shown) which is oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 15.
• a coupling agent common to the art such as EDC to give the intermediate alcohol (not shown) which is oxidized with an oxidant such as pyridine sulfur trioxide complex in DMSO and triethylamine to provide the ketone 15.
• Reagents and conditions a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride catalyst, CH j Cl.,; c.) m-CPBA,
• amine 13 treatment of amine 13 with an isocyanate followed by deprotection of the N-Boc group provides the amine salt 18.
• Acylation and oxidation provides the ketone 19.
• Further derivatization of amine 13 may be effected by treatment with a sulphonyl chloride followed by deprotection of the N-Boc group to provide the amine salt 20.
• Acylation and oxidation provides the ketone 21.
• Reagents and conditions a.) R,CHO, NaBH(OAc) 3 ; b.) HCl; c.) R,C0 2 H, EDC, CH,C1 2 ; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) R,NCO, base; f.) R 1 S0 2 C1, TEA, CH 2 C1 2 .
• the intermediate azido alcohol may be reduced to the amino alcohol 26 under conditions common to the art such as 1,3-propanedithiol and triethylamine in methanol or with triphenylphosphine in tetrahydrofuran and water.
• Acylation of 26 may be effected with an acid such as N-Boc-amino-cyclohexanecarboxylic acid in the presence of a coupling agent such as EDC.
• EDC a coupling agent
• Removal of the benzyloxycarbonyl protecting group with hydrogen gas in the presence of 10% Pd/C provides the amine 27.
• Reagents and Conditions a.) NaH, 5-bromo-l-pentene, DMF; b.) bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride, CH 2 C1 2 ; c.) /7J-CPBA, CH 2 C1 2 ; d.) NaN 3 , CH 3 OH, H,0, NH 4 C1; e.) 1,3-propanedithiol, TEA, methanol; f.) N-Boc-amino- cyclohexanecarboxylic acid, EDC, CH 2 C1 2 ; g.) 10% Pd/C, H 2 ; h.) 2-pyridinesulphonyl chloride, TEA, CH 2 C1 2 ; i.) 4 N HCl dioxane, methanol; j.) benzofuran-2-carboxylic acid, EDC, CH 2 C1 2 ;
• the quatemized, 4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 5.
• the skilled artisan will understand from Scheme 5 how to make any of the quatemized, 4-amino-azepan-3-one compounds of the present invention.
• Reductive animation of 13 may be effected by treatment with an aldehyde followed by a reducing agent such as sodium triacetoxyborohydride. Subsequent deprotection of the N-Boc group under acidic conditions provides the amine salt 16.
• Reagents and conditions a.) R ⁇ HO, NaBH(OAc) 3 ; b.) HCl; c.) R 2 C0 2 H, EDC, CH 2 C1 2 ; d.) pyridine sulfur trioxide complex, DMSO, TEA; e.) iodomethane
• the 6-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 6.
• 2-Methyl-pent-4-enoic acid ethyl ester is converted to a N-2-pyridinesulfonyl-azapine by reduction to the aldehyde, reductive amination with allylamine, sulfonylation with 2-pyridyl sulfonyl chloride, and olefin metathesis with Grubbs' catalyst.
• Epoxidation with mCPBA affords a mixture of epoxides that are separable by column chromatography.
• the syn epoxide is converted into an amino alcohol by opening with sodium azide followed by reduction with triphenylphosphine.
• Acylation of the free amine with Boc-amino-cyclohexanecarboxylic acid and a coupling reagent such as HBTU or EDC, followed by deprotection of the Boc group with HCl, and acylation with a variety of aromatic carboxylic acids and coupling reagents such as HBTU or EDC gives the intermediate alcohols.
• Final oxidation with Dess-Martin periodinane and HPLC affords the desired ketones.
• the 7-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 7.
• Carbobenyzloxy-D-alaninol (Cbz-D- alaninol)is first converted to an iodide, then is reacted with allyl Grignard with a copper (I) catalyst or a similar allyl organometallic reagent.
• the amine is then alkylated with allyl iodide.
• Grubbs' catalyst is then used to form the azapine ring by ring closing metathesis.
• Epoxidation of the alkene followed by separation of the diastereomers followed by opening of the epoxide of the minor component with sodium azide provides the intermediate azido alcohol.
• the 2,2-4-trideutero-4-amino-aze ⁇ an-3-one compounds of the present invention may be conveniently prepared according to Scheme 8.
• Deuterated inhibitors can be prepared from the parent inhibitors such as benzofuran-2-carboxylic acid ⁇ (S)-3-methyl-l- [(4S,7R)-7-methyl-3-oxo-l-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl ⁇ -amide by treating with a base such as triethyl amine and stirring for several days in a deteurated protic solvent such as CD 3 OD: D 2 0.
• Scheme 8
• the 7-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 9.
• Intermediate (S)-3-Cyclohexyl-N- ((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-yl)-2-methyl-propionamide, as described in Scheme 3, is reductively aminated with an aldehyde or a ketone such as propionaldehyde, then treated with a reducing agent such as sodium borohydride.
• the 7-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 10.
• Intermediate 1-Methyl- cyclohexanecarboxylic acid ((3S,4S,7R)-3-hydroxy-7-methyl-azepan-4-yl)-arnide, as described in Scheme 3, is acylated with an isocyanate such as (S)-(-)-2-isocyanato-4- methyl valeric acid methyl ester.
• Boc group followed by acylation with an acylating agent such as benzofuran-2-carboxylic acid, HBTU, NMM, and final oxidation of the secondary alcohol to the ketone with an oxidant such as Dess-Martin periodinane or sulfur trioxide-pyridine provides the desired products.
• an acylating agent such as benzofuran-2-carboxylic acid, HBTU, NMM
• an oxidant such as Dess-Martin periodinane or sulfur trioxide-pyridine
• the 5-methyl-4-amino-azepan-3-one compounds of the present invention may be conveniently prepared according to Scheme 11.
• the synthesis of the C-5 methyl azepinone, 4,5 (R,S)-benzofuran-2-carboxylic acid ⁇ (S)-3-methyl-l-[5-methyl-3-oxo-l- (pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl ⁇ amide, (Example 61) is outlined below in Scheme 7.
• Coupling methods to form amide bonds herein are generally well known to the art.
• the methods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springer- Veriag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol. 1, 1-284 (1979); and J.M. Stewart and J.D. Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, 111., 1984. are generally illustrative of the technique and are incorporated herein by reference.
• Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions.
• amino protecting groups generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art. Methods for protection and deprotection, and replacement of an amino protecting group with another moiety are well known.
• Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
• Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
• Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH4+ are specific examples of cations present in pharmaceutically acceptable salts.
• Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
• Quaternary ammonium salts are prepared by treating a parent amine compound with an excess of alkyl halide, such as methyl iodide.
• 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.
• R 2 is selected from the group consisting of: H, Ci .galkyl, C3_gcycloalkyl-Co_galkyl, Ar- C 0 .galkyl, Het-C 0 .galkyl, R 9 C(0)-, R 9 C(S)-, R 9 S0 2 -, R 9 OC(0)-,
• R4 is selected from the group consisting of: H, Ci .galkyl, C3_gcycloalkyl-C()- galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 5 C(0)-, R 5 C(S)-, R 5 S0 2 -, R 5 OC(0)-, R 5 R 12 NC(0)-, and R 5 R 12 NC(S)-;
• R ⁇ is selected from the group consisting of: H, Ci .galkyl, C 2 .galkenyl, C 2 . galkynyl, C3_gcycloalkyl-Co_galkyl, C 2 _galkanonyl, Ar-CQ.galkyl and Het-Co_galkyl;
• R6 is selected from the group consisting of: H, Ci .galkyl, Ar-C ⁇ -6 a lkyl, or Het-
• R ⁇ is selected from the group consisting of: H, Ci .galkyl, C3_gcycloalkyl-C()- galkyl, Ar-C 0 .galkyl, Het-C 0 .galkyl, R 10 C(O)-, R 10 C(S)-, R 10 SO 2 -, R 10 OC(O)-, R 10 R 13 NC(O)-, and R 10 R 13 NC(S)-;
• R8 is selected from the group consisting of: H, Ci .galkyl, C 2 .galkenyl,
• R 9 is selected from the group consisting of: Cj.galkyl, C3_gcycloalkyl-C()-galkyl, Ar-C 0 .galkyl, Ar-COOH, and Het-C 0 _galkyl;
• RIO is independently selected from the group consisting of: Ci .galkyl, C3_gcycloalkyl-Co-galkyl, Ar-Cr j -galkyl and Het-Co-galkyl;
• RU is selected from the group consisting of: H, Ci .galkyl, Ar-C ⁇ -6 a lkyl > and Het- C 0 .galkyl;
• R* 2 is selected from the group consisting of: H, Cj.galkyl, Ar-C ⁇ -6alkyl, and Het- Co-galkyl;
• R 3 is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6alkyl, and Het- Co-galkyl;
• R' is selected from the group consisting of: H, Cj.galkyl, Ar-C()-6alkyl, and Het-
• R" is selected from the group consisting of: H, C j .galkyl, Ar-C ⁇ -6 a lkyl, or Het-C ⁇ . galkyl;
• R' is selected from the group consisting of: H, Cj.galkyl, C3_gcycloalkyl-Co_ galkyl, Ar-Co_galkyl, and Het-C ⁇ _galkyl;
• Z is selected from the group consisting of: C(O) and CH 2 ; n is an integer of from 1 to 5; and pharmaceutically acceptable salts, hydrates and solvates thereof.
• the present invention provides a process for the synthesis of compounds of Formula (I) comprising the step of oxidizing the appropriate compound of Formula (II) with an oxidant to provide the compound of Formula (I) as a mixture of diastereomers.
• the oxidant is Dess-Martin periodinane or pyridine sulfur trioxide complex in DMSO and triethylamine.
• the present invention also provides a process for the synthesis of deuterated compounds of Formula (I). Specifically, when a deuterated isomer is desired, an additional step, following the oxidation step, of deuterating the protonated isomer with a deuterating agent to provide the deuterated compound of Formula (I) as a mixture of diastereomers is added to the synthesis.
• the deuterating agent is CD 3 OD:D 2 0 (10:1) in triethylamine.
• the process further comprises the step of separating the diasteromers of Formula (I) by separating means, preferably by high presssure liquid chromatography (HPLC).
• separating means preferably by high presssure liquid chromatography (HPLC).
• 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 especially the preferred 1-amino-l-acyl cyclohexane compounds exhibit superior selectivity for cathepsin K versus cathepsins L,S, and B when compared to structurally similar compounds containing a leucine instead of 1-amino-l-acyl cyclohexane.
• the present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cmzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy; and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease; hypercalcemia of malignancy, and metabolic bone disease.
• Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
• the present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, most particularly a human in need thereof 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.
• 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.
• 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.
• 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 ⁇ bs (2)
• This assay measures the affinity of inhibitors to cysteine proteases, in this case, especially cathepsin K, as well as cathepsins L,S, and B.
• inhibitors to cysteine proteases in this case, especially cathepsin K, as well as cathepsins L,S, and B.
• the skilled artisan would consider any compound exhibiting a Kj value of less than 1 micromolar to be a potential lead compound for further research, and an inhibitor exhibiting a Kj of less than 100 nM to be a dmg development dmg candidate assuming an acceptable pathology/toxicology profile and in vivo activity.
• Table I below, provides inhibition assay data for selected compounds of the present invention. These data demonstrate that the inventive compounds efficiently inhibit cathepsin K. These data also show that the present compounds are highly selective for binding with cathepsin K, compared to binding with cathepsins L, S, or B.
• 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 x 10. 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 semm 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 uM 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 incubate at 37°C for 30 min.
• 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.
• Ki 1.4 nM (human Cathepsin K)
• Ki 926 nM (human Cathepsin B)
• Ki >26 nM (human Cathepsin K), sample may not have been completely free of S isomer.
• Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Braker AM 250 or Broker AC 400 spectrometer.
• CDCI3 is deuteriochloroform
• DMSO-dg is hexadeuteriodimethylsulfoxide
• CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane.
• Triphenylphospine (24 g, 91.8 mmol) was added to a solution of imidazole (12.5 g, 184 mmol) in CH 2 C1 2 (231 ml), then was cooled to 0 degrees C. Iodine (23.3 g, 91.8 mmol) was added to the suspension. The reaction mixture turned yellow, then faintly brown. After 5 minutes ((R)-2-hydroxy-l-methyl-ethyl)-carbamic acid benzyl ester (9.59 g, 45.9 mmol) was added and the reaction mixture was warmed to RT then stirred for 3 h.
• Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of (2R,5S,6S)-5- azido-6-hydroxy-2-methyl-azepane-l -carboxylic acid benzyl ester (0.193 g, 0.635 mmol) in THF (10 ml) and H 2 0 (0.04 ml), then was heated to 45 degrees C overnight. The reaction mixture was then diluted with toluene (100 ml x 2) and was azeotroped in vacuo by rotary evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et 2 0 and the resulting salt was collected following filtration and was used in the next reaction without further purification (0.27 g, 90%).
• 4-methylmorpholine (388mg, 0.42 ml, 3.84 mmol) was added to a solution of Boc- 1-amino-cyclohexanecarboxylic acid (255 mg, 1.05 mmol), HBTU(398 mg, 1.05 mmol), and (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-l-carboxylic acid benzyl ester (300 mg, 0.96 mmol) in DMF (5.0 ml).
• Dess-Martin periodinane (137 mg, 0.324mmol) was added to a solution of .
• Benzofuran-2-carboxylic acid ⁇ l-[(3S,4S,7R)-3-hydroxy-7-methyl-l-(pyridine-2-sulfonyl)- azepan-4-ylcarbamoyl]-cyclohexyl ⁇ -amide (90 mg, 0.162 mmol) in CH 2 C1 2 (5 ml) and was stirred at RT for 2 h. The solution was washed with 10% aq. Na 2 S 2 0 3 , then aq. sat. NaHC0 3 , then brine.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Physical Education & Sports Medicine (AREA)
• Rheumatology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Pain & Pain Management (AREA)
• Immunology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Priority Applications (11)

Applications Claiming Priority (2)

Publications (2)

Family

ID=22956303

Family Applications (1)

Country Status (17)

Cited By (5)

Citations (1)

Family Cites Families (2)

• 2001
  • 2001-11-19 JP JP2003554091A patent/JP2005513083A/ja not_active Withdrawn
  • 2001-11-19 KR KR10-2003-7006807A patent/KR20040004445A/ko not_active Application Discontinuation
  • 2001-11-19 MX MXPA03004542A patent/MXPA03004542A/es unknown
  • 2001-11-19 IL IL15599701A patent/IL155997A0/xx unknown
  • 2001-11-19 CA CA002436850A patent/CA2436850A1/en not_active Abandoned
  • 2001-11-19 AU AU2001298052A patent/AU2001298052A1/en not_active Abandoned
  • 2001-11-19 BR BR0115473-7A patent/BR0115473A/pt not_active Application Discontinuation
  • 2001-11-19 CN CNA018220533A patent/CN1635903A/zh active Pending
  • 2001-11-19 CZ CZ20031403A patent/CZ20031403A3/cs unknown
  • 2001-11-19 PL PL01366232A patent/PL366232A1/xx not_active Application Discontinuation
  • 2001-11-19 HU HU0301964A patent/HUP0301964A3/hu unknown
  • 2001-11-19 WO PCT/US2001/051647 patent/WO2003053331A2/en not_active Application Discontinuation
  • 2001-11-19 EP EP01275089A patent/EP1392657A4/en not_active Withdrawn
  • 2001-11-20 AR ARP010105409A patent/AR034278A1/es unknown
  • 2001-11-21 UY UY27032A patent/UY27032A1/es not_active Application Discontinuation
• 2003
  • 2003-05-16 ZA ZA200303848A patent/ZA200303848B/en unknown
  • 2003-05-22 NO NO20032328A patent/NO20032328L/no unknown

Patent Citations (1)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events