JP2002533452A - Protease inhibitor - Google Patents

Abstract

  (57) [Summary] The present invention relates to compounds of formula (I) that inhibit proteases including cathepsin K, pharmaceutically acceptable salts, hydrates and solvates thereof, pharmaceutical compositions of such compounds, novel intermediates of such compounds, And periodontal diseases including osteoporosis, gingivitis and periodontitis, diseases involving excessive bone loss or cartilage and matrix degeneration including arthritis, more particularly osteoarthritis and rheumatoid arthritis, Paget disease, hypercalcemia A method of treating bone disease or malignant and metabolic bone disease, comprising administering to a patient in need of treatment a compound of the present invention to inhibit bone loss or excessive cartilage or matrix degeneration. provide.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates generally to 8-14 membered 1,3-diaminoketone protease inhibitors, particularly to inhibitors of cysteine and serine proteases, and more particularly to Compounds that inhibit cysteine proteases, and even more particularly, compounds that inhibit cysteine proteases of the papain superfamily;
Even more particularly, it relates to compounds that inhibit cathepsin family cysteine proteases, and most particularly to compounds that inhibit cathepsin K. Such compounds are useful for treating diseases involving cysteine proteases, particularly those associated with excessive bone or cartilage loss, such as osteoporosis, periodontitis, and arthritis.

BACKGROUND OF THE INVENTION Cathepsins are enzymes that occupy part of the papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have been described in the literature. Recently, cathepsin K polypeptides and c encoding such polypeptides
DNA was disclosed in US Pat. No. 5,501,969 (referred to therein as Cathepsin O). Cathepsin K has recently been expressed, purified and characterized.
Bossard, MJ, 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 referred to in the literature as cathepsin O or cathepsin O2. The nomenclature cathepsin K is considered more appropriate. Cathepsins function in the normal physiological process of proteolysis in animals, including humans, for example, in the degradation of connective tissue. However, elevated levels of these enzymes in the body can cause physiological conditions that lead to disease. Thus, cathepsins include, but are not limited to, pneumocystis carinii, trypsanoma cruzi (trypsanoma
cruzi), trypsanoma brucei brucei
) And infections with Crithidia fusiculata; and as a causative agent in a variety of disease states, including schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, muscular atrophy, etc. I have. See International Publication No. WO 94/04172 published March 3, 1994 and references cited therein. See also European Patent Application EP 0 603 873 A1 and references cited therein. P. gingivalis (P. g
ingivallis) are involved in the pathogenesis of gingivitis (Potempa, J. et al. (1994) Perspectives in Drug Discovery and Des).
ign, 2, 445-458).

[0003] Cathepsin K is thought to play a causal role in diseases of excessive bone or cartilage loss. Bone consists of a protein matrix into which spindle-shaped or planar crystals of hydroxyapatite are incorporated. Type I collagen contains about 9 of the protein matrix.
The major structural proteins of bone that make up 0% are shown. The remaining 10% of the matrix consists of osteocalcin, proteoglycans, osteopontin, thrombospondin, fibronectin and several non-collagenous proteins including bone sialoprotein. The skeleton undergoes remodeling at discrete locations for a lifetime. These locations, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.

[0004] Bone resorption is performed by osteoclasts, which are multinucleated cells of the hematopoietic lineage. Osteoclasts adhere to the bone surface, forming a tightly sealed zone, and then
That is, the film is rippled over a wide area on the (reabsorption) surface. This results in an encapsulated intracellular compartment on the bone surface that is acidified by the proton pump on the corrugated membrane, into which the osteoclasts secrete proteolytic enzymes. The low pH of the compartment dissolves the hydroxyapatite crystals on the bone surface while the proteolytic enzymes digest the protein matrix. Thus, absorption pits or pits are formed. At the end of the phase of the cycle, the osteoclasts form a new protein matrix,
It then calcifies. In some 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 in each cycle. Ultimately, this can lead to bone weakness and create a large fracture risk with minimal trauma.

[0005] Some published studies show that inhibitors of cysteine proteases are effective in inhibiting osteoclast-mediated bone resorption and have an essential role for cysteine proteases in bone resorption It revealed that. For example, Delais
se et, Biochem. J., 1980, 192 , 365 discloses a series of protease inhibitors in a mouse bone organ culture system, inhibitors of cysteine proteases (e.g., leupeptin, Z-Phe-Ala-CHN 2) is Prevents bone resorption while indicating that the serine protease inhibitor was not effective. Delaisse et al., Biochem., Biophy.
s. Res. Commun., 1984, 125, 441 reported that E-64 and leupeptin also prevented bone resorption in vivo when measuring acute changes in serum calcium in rats on a calcium deficient diet. To be effective. Lern
er et al., J. Bone Min. Res., 1992, 7, 433 disclose that cystatin, an endogenous cysteine protease inhibitor, inhibits PTH-stimulated bone resorption in mouse calvaria. Delaisse et al., Bone, 1987, 8, 305, Hill et al., J. Cell. B
iochem., 1994, 56, 118 and Everts et al., J. Cell.Physiol., 1992, 150, 221.
Other studies have also reported a correlation between inhibition of cysteine protease activity and bone resorption. Tezuka et al., J. Biol. Chem., 1994, 269, 1106, Inaoka.
Biochems Biophys. Res. Commun., 1995, 206, 89 and Shi et al., FEBS Lett.
, 1995, 357, 129 disclose that under normal conditions, cathepsin K, a cysteine protease, is abundantly expressed in osteoclasts and may be the major cysteine protease present in these cells.

[0006] The abundant and selective expression of cathepsin K in osteoclasts strongly suggests that the enzyme is essential for bone resorption. Thus, selective inhibition of cathepsin K is not limited to gingival diseases such as, but not limited to, osteoporosis, gingivitis and periodontitis, Paget's disease, hypercalcemia of malignant tumors and metabolic bone diseases. May provide an effective treatment for severe bone loss diseases. Cathepsin K levels have also been shown to be elevated in cartilage resorbing cells of the osteoarthritis synovium. Therefore, cathepsin K
May also be useful in the treatment of disorders of excessive cartilage or matrix degeneration, including but not limited to osteoarthritis and rheumatoid arthritis.
Metastatic tumor cells typically express high levels of proteolytic enzymes that destroy the surrounding matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.

[0007] Several cysteine protease inhibitors are known. Palmer (1995) J.
Med. Chem. 38, 3193 describes cathepsins B, L, S, O2 and cruzain.
Certain vinyl sulfones that irreversibly inhibit cysteine proteases such as in) are disclosed. Other classes of compounds such as aldehydes, nitriles, α-ketocarbonyl compounds, halomethylketones, diazomethylketones, (acyloxy) methylketones, ketomethylsulfonium salts and epoxysuccinyl compounds have also been reported to inhibit cysteine proteases. . See Palmer (ibid.) And references therein.

[0008] US Pat. No. 4,518,528 discloses peptidyl fluoromethyl ketone as an irreversible inhibitor of cysteine protease. International Patent Application Publication WO9
4/04172 and European patent applications EP 0 525 420 A1, EP 0 603
873 A1 and EP0 611 756 A2 are cysteine proteases,
Alkoxymethyl and mercaptomethyl ketones that inhibit cathepsins B, H and L are described. International patent application PCT / US94 / 08868 and European patent application EP 0 623 592 A1 describe cysteine proteases, alkoxymethyl and mercaptomethyl ketones, which inhibit IL-1b convertase. Alkoxymethyl and mercaptomethylketone have also been described as inhibitors of serine proteases, kininogenases (International Patent Application PCT / GB
91/01479).

Azapeptides designed to deliver azaamino acids to the active site of a serine protease and retain good leaving groups have been described by Elmore et al., Biochem. J., 1968, 107, 103.
Garker et al., Biochem. J., 1974, 139, 555; Gray et al., Tetrahedron, 1977, 33,
837, Gupton et al., J. Biol. Chem., 1984, 259, 4279, Powers et al., J. Biol. Chem.
, 1984, 259, 4288 and are known to inhibit serine proteases. In addition, J. Med. Chem., 1992, 35, 4279 discloses certain azapeptide esters as cysteine protease inhibitors.

[0010] Antipain and leupeptin have been described as reversible inhibitors of cysteine proteases in McConnell et al., J. Med. Chem., 33, 86;
ezawa et al., 45 Meth. Enzymol. 678, disclosed as inhibitors of serine proteases. E64 and its synthetic analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189 and Grinde, Bioche).
m. Biophys. Acta., 701, 328).

[0011] 1,3-Diamino-propanone is disclosed in US Pat. Nos. 4,749,792 and 463.
No. 8010 is described as an analgesic.

Accordingly, structurally diverse cysteine protease inhibitors have been identified. However, these known inhibitors have various disadvantages and are not considered suitable for use as therapeutics in animals, especially humans. These disadvantages include lack of selectivity, cytotoxicity, poor solubility and excessively rapid plasma clearance. Thus, there is a need for a method of treating diseases caused by cysteine proteases including pathological levels of cathepsin, especially cathepsin K, and novel inhibitory compounds useful in such methods. The inventors have now discovered a new class of 8- to 14-membered 1,3-diaminoketone compounds that are protease inhibitors, most particularly inhibitors of cathepsin K.

SUMMARY OF THE INVENTION It is an object of the present invention to provide 8-, 14-membered 1,3-diaminoketone protease inhibitors, especially such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, Even more particularly, compounds that inhibit cysteine proteases of the papain superfamily, even more particularly such compounds that inhibit cysteine proteases of the cathepsin family, most particularly such compounds that inhibit cathepsin K, the activity of such proteases. It is an object of the present invention to provide a compound which is useful for treating a disease which can be therapeutically modified by changing the above.

Thus, in a first aspect, the present invention provides a compound of formula I: In another aspect, the invention provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, diluent or excipient. In yet another aspect, the invention provides intermediates useful in preparing compounds of formula I.

In yet another aspect, the invention relates to proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, and even more particularly of the cathepsin family. Inhibition of cysteine proteases, most particularly cathepsin K, provides a method of treating diseases whose disease pathology can be therapeutically modified.

In a particular embodiment, the compounds of the invention are used, in particular, for bone loss such as osteoporosis and gingival diseases such as gingivitis and periodontitis, or excess cartilage or matrix such as osteoarthritis and rheumatoid arthritis. It is useful for treating diseases characterized by degeneration.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of formula I:

Embedded image I [In the formula, A is selected from the group consisting of C (O) and CH (OH),; ^{R 1} is

Embedded imageR is selected from the group consisting of:²Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl,
Ar-C_0-6Alkyl, Het-C_0-6Alkyl, R⁹C (O)-, R⁹C
(S)-, R⁹SO₂-, R⁹OC (O)-, R⁹R¹²NC (O)-, R⁹R ¹² NC (S)-, R¹²HNCH (R¹²) C (O)-, R⁹OC (O) NR ¹² CH (R¹²) C (O)-, adamantyl-C (O)-, or

Embedded imageR ″ is H, C_1-6Alkyl, Ar-C_0-6Alkyl, and Het-C _0-6 R "" is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Archi
, Ar-C₀₆Alkyl, and Het-C_0-6Selected from the group consisting of alkyl
Selected; R³And R⁸Are independently H, C_2-6Alkenyl, C_2-6Alkynyl,
Het, Ar, or OR¹³, SR¹³, NR¹³ ₂, R¹³NC (O) O
R⁵, CO₂R¹³, CO₂NR¹³ ₂, N (C = NH) NH₂Or Het
Is C which may be substituted by Ar_1-6R is selected from the group consisting of alkyl;⁴Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl,
Ar-C_0-6Alkyl, Het-C_0-6Alkyl, R⁵C (O)-, R⁵C
(S)-, R⁵SO₂-, R⁵OC (O)-, R⁵R¹⁴NC (O)-, R⁵R ¹⁴ NC (S)-, R¹⁴HNCH (R¹⁴) C (O)-, and R⁵OC (O
) NR¹⁴CH (R¹⁴R) selected from the group consisting of C (O)-;⁵, R⁹, And R¹⁰Is independently C_1-6Alkyl, C_3-6Cycloa
Lequil-C_0-6Alkyl, Ar-C_0-6Alkyl and Het-C_0-6A
Selected from the group consisting of⁶Is H, C_1-6Alkyl, Ar-C_0-6Alkyl, and Het-C_{0 -6} R is selected from the group consisting of alkyl;⁷Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl,
Ar-C_0-6Alkyl, Het-C_0-6Alkyl, R¹⁰C (O)-, R^{1 0} C (S)-, R¹⁰SO₂-, R¹⁰OC (O)-, R¹⁰R^FifteenNC (O)
-, R¹⁰R^FifteenNC (S)-, R^FifteenHNCH (R^Fifteen) C (O)-, and
R¹⁰OC (O) NR^FifteenCH (R^Fifteen) Selected from the group consisting of C (O)-
Or; R⁶And R⁷Combine to form a pyrrolidine, piperidine, or morpholine ring
Each R 'is independently H, C_1-6Alkyl, Ar-C_0-6Alkyl, and
Het-C_0-6R is selected from the group consisting of alkyl;¹¹Is Ar; R¹², R¹³, R¹⁴And R^FifteenAre independently H, C_1-6Alkyl, A
r-C_0-6Alkyl, and Het-C_0-6Selected from the group consisting of alkyl
R; R^*Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl,
Ar-C_0-6Alkyl, and Het-C_0-6Select from the group consisting of alkyl
Z is C (O) and CH₂M is HC = CH; H₂C-CH₂; H (OR²) CC (OR²) H; H (O
R²) C-CH₂H (NR²H) CC (NR²H) H; H (OR²) CC
(NR²H) H; and H (NR²H) C-CH₂X is CH₂, S and O; n is 1 to 7] and a pharmaceutically acceptable salt thereof.

In the compounds of formula I, R ¹ is

Embedded imageIf R³Is H, C_2-6Alkenyl, C_2-6Alkynyl, Het, Ar, or
Is OR¹³, SR¹³, NR¹³ ₂, R¹³NC (O) OR⁵, CO₂R¹³,
CO₂NR¹³ ₂, N (C = NH) NH₂, Het or Ar
May be C_1-6Selected from the group consisting of alkyl, preferably C_1-6A
Alkyl, more preferably isobutyl;⁴Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl,
Ar-C_0-6Alkyl, Het-C_0-6Alkyl, R⁵C (O)-, R⁵C
(S)-, R⁵SO₂-, R⁵OC (O)-, R⁵R¹⁴NC (O)-, R⁵R ¹⁴ NC (S)-, R¹⁴HNCH (R¹⁴) C (O)-, and R⁵OC (O
) NR¹⁴CH (R¹⁴) C (O)-, preferably R⁵ OC (O)-and R⁵C (O)-; R⁵Is C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl, Ar
-C_0-6Alkyl and Het-C_0-6Selected from the group consisting of alkyl,
Preferably Ar-C_0-6Alkyl and Het-C_0-6Alkyl
More preferably, phenyl, benzyl, 2-naphthyl, 2-benzofuranyl, 2-
R 'is independently H, C_1-6Alkyl, Ar-C_0-6Alkyl, and H
et-C_0-6It is selected from the group consisting of alkyl, preferably H.

In the compounds of formula I, R ¹ is

Embedded image R ¹¹ is Ar, preferably 3-biphenyl; R ^* is H, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-6 alkyl,
_{Ar-C 0-6} alkyl, and _{Het-C 0-6} selected from the group consisting of alkyl, preferably _{C 1-6} alkyl, most preferably isobutyl.

[0020] In the formula the compounds of I, ^{R 2} is _{H, C 1-6 alkyl, C 3-6} cycloalkyl _{-C 0-6} alkyl, _{Ar-C 0-6} alkyl, _{Het-C 0-6} alkyl,
_{^{R 9 C (O) -,}} R 9 C (S) -, R 9 SO 2 -, R 9 OC (O) -, R 9 R 1 2 NC (O) -, R 9 R 12 NC (S) - , R ¹² HNCH (R ¹² ) C (O)
-, R ⁹ OC (O) NR ¹² CH (R ¹² ) C (O)-, and adamantyl-
C (O)-, and

Embedded image Wherein R ² is R ¹⁰ SO ₂ and

Embedded image In and, ^{R 6} is selected from the group consisting of _{H, C 1-6} alkyl, _{Ar-C 0-6} alkyl or _{Het-C 0 -6} alkyl, preferably be H; ^{R 7} is H, _{C 1 -6} alkyl, _C3-6 cycloalkyl- _C0-6 alkyl,
_{Ar-C 0-6} alkyl, _{Het-C 0-6} ^{alkyl, R 10 C (O) -} , R 1 0 C (S) -, R 10 SO 2 -, R 10 OC (O) -, R 10 R ¹⁵ NC (O)
^{-, R 10 R 15 NC (} S) -, R 15 HNCH (R 15) C (O) -, and ^{R 10 OC (O) NR 15} CH (R 15) C (O) - is selected from the group consisting of Or R ⁶ or R ⁷ combine to form a pyrrolidine, piperidine or morpholine ring; R ⁸ is H, C _2-6 alkenyl, C _2-6 alkynyl, Het, Ar, or OR ¹³ , SR ^{13 _{, NR 13 2, R 13 NC}} (O) OR 5, CO 2 R 13,
_{^{CO 2 NR 13 2, N (}} C = NH) NH 2, optionally substituted by Het or Ar is selected from the group consisting of _{C 1-6} alkyl, preferably _{C 1-6} alkyl, more preferably R ⁹ and R ¹⁰ are independently C _1-6 alkyl, C _3-6 cycloalkyl-
C _0-6 alkyl is selected from the group consisting of _{Ar-C 0-6} alkyl or _{Het-C 0-6} alkyl, preferably _{Ar-C 0-6} alkyl or _{Het-C 0 -6} alkyl, more preferably is phenyl, benzyl, 2-naphthyl, pyridyl; Z is selected from the group consisting of C (O) and CH _2, preferably a C (O).

Preference is given to compounds of the formula I in which A is C (O). M is HC = CH and _H 2 C-
Selected from the group consisting of CH ₂ , wherein R ″ and R ″ ′ are both H;
Alternatively, compounds of formula I wherein n is 1 are also preferred. A is C (O); M is selected from the group consisting of HC = CH and H ₂ C—CH ₂ ; n is 1; Is more preferred.

A is C (O); R ¹ is

Embedded image R ² is R ¹⁰ SO ₂ and

Embedded image R ³ and R ⁸ are C _1-6 alkyl; R ⁴ is selected from the group consisting of R ⁵ OC (O) — and R ⁵ C (O) —; R ⁵ , R ⁹ , and R ¹⁰ are independently Ar-C _0-6 alkyl and Het.
It is selected from the group consisting of -C _0-6 alkyl; ^{R 6} is an H; ^{R 7} is an ^{R 10 OC (O); R} ' is an H; R''is an H; R'''it is H; Z is C be a (O); M is selected from the group consisting of HC = CH and _{H 2} C-CH 2; n is the compound of formula I is even more preferred is 1.

R ³ and R ⁸ are independently isobutyl; or R ⁵ , R ⁹ and R ¹⁰ are independently phenyl, benzyl, 2-naphthyl,
Compounds that are selected from the group consisting of 2-benzofuranyl, 2-benzo [b] thiophenyl, 2-quinolinyl, and pyridyl are particularly preferred.

The following group: N- (N- (benzyloxycarbonyl) -L-leucinyl) -4- (R, S
) -Amino-1,2,3,4,7,8-hexahydro-3-oxo- [2- (N
-(Benzyloxycarbonyl) -L-leucinyl)]-azocine; N- (N- (benzyloxycarbonyl) -L-leucinyl) -4- (R, S
) -Amino-1,2,3,4,7,8-hexahydro-3-oxo- [2- (N
-(Benzyloxycarbonyl) -L-leucinyl)]-azocine; N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino-1,2,3,4,7,8-hexahydro -3-oxo- (2-pyridinylsulfonyl) -azocine; N- (4-methyl-2- (3-biphenyl) valeryl) -4-amino-1,2
N, (3,4,5,6,7,8-octahydro-3-oxo- (2-pyridinylsulfonyl) -azocine; N- (4-methyl-2- (3-biphenyl) valeryl) -4-amino -1,2
, 3,4,7,8-Hexahydro-3-oxo- (2-pyridinylsulfonyl)
-Azocine; N- (N- (2-quinoline-carbonyl) -L-leucinyl) -4-amino-
1,2,3,4,5,6,7,8-octahydro-3-oxo- (2-pyridinylsulfonyl) -azocine; N- (N- (2-quinoline-carbonyl) -L-leucinyl) -4-amino-
1,2,3,4,7,8-hexahydro-3-oxo- (2-pyridinylsulfonyl) -azocine; N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino -1,2,3,4,5,6,7,8-octahydro-3-oxo- (2-pyridinylsulfonyl) -azocine; N- (N- (2-benzothiophene-carbonyl) -L- Leucinyl) -4-
Amino-1,2,3,4,5,6,7,8-octahydro-3-oxo- (2-
Pyridinylsulfonyl) -azocine; and N- (N- (2-benzothiophene-carbonyl) -L-leucinyl) -4-
Amino-1,2,3,4,7,8-hexahydro-3-oxo- (2-pyridinylsulfonyl) -azocine. Certain exemplary compounds of the present invention are described in Examples 1-10.

Definitions The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of the present invention. A prodrug is any covalently bonded compound that releases the active parent drug of Formula I in vivo. When another form of a chiral or isomer center is present in the compounds of the invention, all forms of such isomers or isomers, including enantiomers and diastereomers, may be encompassed herein. Intended. Invention compounds containing chiral centers can be used as racemic mixtures, enantiomeric enriched mixtures, or racemic mixtures can be separated using well-known techniques, and the individual enantiomers can be used alone. Where a compound has an unsaturated carbon-carbon bond, both the cis (Z) and trans (E) isomers are within the scope of the invention. Where the compounds exist in tautomeric forms, such as keto-enol tautomers, each tautomer is included in the present invention and exists as an equilibrium or one form of the predominant state.

In formula I or any of its complements, the meaning of any substituent at any one event is, unless otherwise specified, at any other event, at its meaning or any other occurrence. Is independent of the meaning of the substituent. Abbreviations and symbols commonly used in the field of peptides and chemistry are used herein to describe the compounds of the present invention. In general, the abbreviations for amino acids are described in the IUPA-IUB Joint Commission on B described in Eur. Biochem., 158, 9 (1984).
According to iochemical Nomenclature.

“Proteases” are enzymes that catalyze the cleavage of amide bonds in peptides and proteins by nucleophilic displacement of the amide bond, and ultimately hydrolyze. Such proteases include cysteine proteases, serine proteases, aspartic proteases, and metalloproteases. The compounds of the present invention are those that can bind more strongly to the enzyme than the substrate and are not cleaved after enzyme-catalyzed attack by a nucleophile. Therefore, they competitively prevent proteases from recognizing and hydrolyzing the native substrate, thereby acting as inhibitors.

As used herein, the term “amino acid” refers to alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, Refers to the D or L isomer of serine, threonine, tryptophan, tyrosine and valine.

As used herein, “C_1-6The term "alkyl" is substituted or unsubstituted
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and
t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl
It is meant to include syl as well as its simple aliphatic isomers. Any C _1-6 Alkyl groups have 1 to 5 halogens, SR¹⁶, OR¹⁶, N (R¹⁶)_Two, C
(O) N (R¹⁶)_Two, Carbamyl or C_1-4Alkyl (where R¹⁶Is C_1-6A
Which is independently alkyl. C₀The alkyl is
It means that there is no alkyl group in the moiety. Therefore, Ar-C₀Archi
Is equal to Ar.

As used herein, the term “C _3-6 cycloalkyl” is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, cyclohexane. As used herein, the term " _C2-6 alkenyl" refers to an alkyl group of 2 to 6 carbons in which a carbon-carbon single bond is replaced by a carbon-carbon double bond. . _C2-6 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and some isomers pentene and hexene. Both cis and trans isomers are included. The term “C _2-6 alkynyl” refers to a group consisting of 2 to 6 carbons in which a 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.

The term “halogen” refers to F, Cl, Br and I.

“Ar” or “aryl” refers to one or more Ph—C _0-6 alkyl, Het—
C _0-6 alkyl, C _1-6 alkoxy, Ph-C _0-6 alkoxy, Het-C _{0-6 alkoxy, OH, (CH 2) 1-6} NR 16 R 17, O (CH 2) 1-6 NR ¹⁶ R ^{1 7,} _{C 1-6 ^{alkyl, OR 18, N (R 18}} ) 2, SR 18, CF 3, NO 2
, CN, CO ₂ R ¹⁸ , CON (R ¹⁸ ), phenyl or naphthyl optionally substituted by F, Cl, Br or I; wherein R ¹⁶ and R ¹⁷ are H, C _1-6 alkyl, _{Ph-C 0-6} alkyl, naphthyl _{-C 0-6} alkyl or _{Het-C 0-6} ^{alkyl; R 18} is phenyl, naphthyl, or _{C 1-6} alkyl.

As used herein, the term “Het” or “heterocyclic” refers to saturated or
Is either unsaturated and is selected from the group consisting of carbon atoms and N, O and S
Consisting of one to three selected heteroatoms, where nitrogen and sulfur heteroatoms
A stable 5 atom which may be oxidized and the nitrogen heteroatom may be quaternized.
To 7-membered monocyclic, stable 7 to 10-membered bicyclic, or stable 11 to
Indicate an 18 membered tricyclic heterocycle, wherein any of the above heterocycles is a benzene ring
And any bicyclic group fused to. Heterocycles are certain stable structures.
Attached at any heteroatom or carbon atom to produce
And may be substituted with one or two groups selected from the following groups:
C_0-6Ar, C_1-6Alkyl, OR¹⁸, N (R¹⁸)₂, SR¹⁸, CF ₃ , NO₂, CN, CO₂R¹⁸, CON (R¹⁸), F, Cl, Br and I
, Where R¹⁸Is phenyl, naphthyl, or C_1-6Alkyl. Such heterocycle
Examples are piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiazinyl
Peridinyl, 2-oxopyrrolidine, 2-oxoazepinyl, azepinyl,
Loryl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imi
Dazolyl, pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxo
Sazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thi
Azolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzo
Imidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tet
Lahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thia
Morpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl
And triazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl
, Isothiozolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazini
And tetrazinyl, which are obtained by conventional chemical synthesis and are stable
Things. The term "heteroatom" herein refers to oxygen, nitrogen and sulfur.

Throughout this application, the term C ₀ indicates that the immediately following substituent is absent; for example, in a partial ArC _0-6 alkyl, when C is 0, the substituent is A
r, for example, phenyl. Conversely, if the partial ArC _0-6 alkyl is identified as a particular aromatic group, eg, phenyl, C is understood to be 0.

Certain groups are abbreviated herein. t-Bu represents a tertiary butyl group;
oc represents a t-butyloxycarbonyl group, Fmoc represents a fluorenylmethoxycarbonyl group, Ph represents a phenyl group, and Cbz represents a benzyloxycarbonyl group.

Certain reagents are abbreviated herein. CSA refers to camphor sulfonic acid, EDC refers to N-ethyl-N '(dimethylaminopropyl) -carbodiimide, DMF refers to dimethylformamide, DMSO refers to dimethylsulfoxide, FMOC refers to 9-fluorenylmethyl. Oxycarbonyl, NMM is N
-Refers to methylmorpholine, TFA refers to trifluoroacetic acid, THF refers to tetrahydrofuran.

Preparation Methods The compounds of general formula I are prepared in an analogous manner to the methods of Schemes 1, 2 and 3.
Boc- (D, L) -allylglycine (1) was converted to allylamine 2 via the formation of diazomethylketone using iso-butyl chloroformate and diazomethane. Diazomethyl ketone was converted to bromomethyl ketone by treatment with HBr. Bromomethyl ketone was reduced using sodium borohydride and then treated with an arylamine. Protection of the amine as an FMOC derivative and protection of the hydroxyl and carbamate nitrogens as acetonide afforded precursor 3 to be ring-closing metathesized. The desired aza-cyclooctene skeleton 4 was obtained by treatment with Grubb's catalyst. Deprotection of the FMOC protecting group with 20% piperidine followed by C
Azocin 5 was obtained by acylation with bz-leucine and EDC. Deprotection of the Boc and acetonide protecting groups may be performed under acidic conditions, such as TFA, to give amino alcohol 6. Compound 6 may be acylated with a carboxylic acid, such as Cbz-L-leucine, in the presence of a coupling reagent conventional in the art, such as EDCI, to give alcohol 7. The desired aza-cyclooctenone may be obtained by oxidizing alcohol 7 using an oxidizing agent such as a pyridine sulfur trioxide complex.

Embedded image Scheme 1 a: ClCO ₂ iBu; NMM; CH ₂ N ₂ ; HBr, AcOH; b) NaBH ₄ ; c) allylamine; d) 2,2-
Dimethoxypropane, CSA; e: N- (9-fluorenylmethoxycarbonyloxy) succinimide, NaHCO ₃ ; f: bis (tricyclohexylphosphine) benzylidineruthenium (IV) dichloride; g: 20% piperidine, DMF; h: Cbz-LeuOH, EDC; i:
TFA, CH ₂ Cl ₂ ; j: TFA, THF, H ₂ O; k: Cbz-LeuOH, EDC; l: DMSO, (COCl) ₂ , TEA
.

In a similar manner, Boc-L-allylglycine (9) may be converted to diazomethylketone from the mixed anhydride and diazomethane, and then converted to bromide using HBr (not shown). The ketone was reduced using a reducing agent such as sodium borohydride to give 10. Amino alcohol was obtained by a nucleophilic substitution reaction of bromide 10 using allylamine. Protection of the amine as an FMOC derivative and protection of the hydroxyl and carbamate nitrogens as acetonides afford the precursor 12 to be ring-closing metathesized. Grubb's catalyst (J. Am. Chem. Soc.
, 1995, 117, 2108-2109) to give the desired aza-cyclooctene skeleton 13. Deprotection of the 13 FMOC protecting groups may be performed using 20% piperidine. The resulting amine (not shown) may be sulfonylated using 2-pyridylsulfonyl chloride to give 14. Deprotection of the Boc and acetonide protecting groups may be performed using HCl to give amino alcohol 15. Amino alcohol 15 may be acylated with an acid such as Boc-L-leucine in the presence of a coupling reagent such as EDCI to give alcohol 16. Deprotection of the 16 Boc groups using an acid such as HCl, followed by coupling of the resulting amine salt with an acid such as 2-benzofuran carboxylic acid in the presence of a coupling reagent such as EDCI. Finally, an oxidizing agent such as Dess-Martin periodinane or pyridine-sulfur trioxide complex is used for final oxidization to obtain aza-cyclooctenone 17.

Embedded image Scheme 2 a: ClCO ₂ iBu; NMM; CH ₂ N ₂ ; HBr, AcOH; b) NaBH ₄ ; c) allylamine; d) 2,2-
Dimethoxypropane, CSA; e: N- (9-fluorenylmethoxycarbonyloxy) succinimide, NaHCO ₃ ; f: bis (tricyclohexylphosphine) benzylidineruthenium (IV) dichloride; g: 20% piperidine, DMF; h: 2-pyridylsulfonyl chloride, Hunig's base; i: 4M HCl, CH ₂ Cl ₂ ; j: 4M HCl, H ₂ O, THF; k: Boc
-LeuOH, EDC; l: 4M HCl, CH ₂ Cl ₂ ; m: 2-benzofurancarboxylic acid, EDC; n: De
ss-Martin periodinan

Reduction of an intermediate such as 18 with hydrogen in the presence of a catalyst such as palladium gives a fully saturated azocine ring system, and an oxidizing agent such as a Dess-Martin reagent or a pyridine sulfur trioxide complex. Oxidation using to give aza-cyclooctaneone 19. 1-Aza-3-hydroxy-4-amino-cyclooct-6-ene 15 (see Scheme 2) is converted to 4-methyl-2 in the presence of a coupling reagent such as EDC.
Acylation with-(3-biphenyl) -valeric acid (see J. Am. Chem. Soc. 1998, 120, 9114-9115) followed by hydrogenation with hydrogen / Pd / C in EtOH; And / or direct oxidation with Dess-Martin periodinane to give the desired products 20 and 21.

Embedded image Scheme 3 a: 10% Pd / C, H ₂ , EtOH; b: Dess-Martin periodinane; c: 4-methyl-2- (3
-Biphenyl) -valeric acid, EDC;

When referring to the methods of preparing compounds of formula I described in Schemes 1-3 above, those skilled in the art will understand that the present invention encompasses all novel intermediates required for preparing compounds of formula I. Will do. In particular, the present invention includes all compounds of formula II.

Embedded image II wherein R is

Embedded image Selected from the group consisting of:

More specifically, the present invention provides the following novel intermediates:

Embedded image 4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (2-pyridinylsulfonyl)-
Azocin

Embedded image N- (L-leucinyl) -4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine

Embedded image 4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (N- (benzyloxycarbonyl) -L-leucinyl)]-azocine

The starting materials used herein are commercially available amino acids, or are prepared by conventional methods well known to those of ordinary skill in the art, and
It can be found in standard reference books such as ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-Interscience).

The coupling methods for forming amide bonds herein are generally well-known in the art. Bodansky et al., THE PRACTICE OF PEPTIDE SYNTHESIS, Springe
r-Verlag, Berlin, 1984; E. Gross and J. Meienhofer, THE PEPTIDES, Vol.
1, 1-284 (1979); and JM Stewart and JD Young, SOLID PHASE PEPTI
The method of peptide synthesis set forth by DE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Ill., 1984, is generally exemplary of the technology and is hereby incorporated by reference.

Synthetic methods for preparing compounds of the present invention often employ protective groups to mask reactive functionality or to minimize unnecessary side reactions. Such protecting groups are generally described in Green, TW, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & So
ns, New York (1981). The term "amino protecting group" is generally
Refers to Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known in the art. Methods of protection and deprotection, and replacement of an amino protecting group with another group are well known.

The acid addition salt of a compound of Formula I is prepared in a suitable solvent with the parent compound and an excess of an acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid. , Maleic acid, succinic acid or methanesulfonic acid in a standard manner. Certain compounds form acceptable internal salts or zwitterions. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent containing a suitable cation, such as a hydroxide, carbonate or alkoxide; or by treating with a suitable organic amine. Li ⁺ , Na ⁺ ,
Cations such as K ⁺ , Ca ⁺⁺ , Mg ⁺⁺ and NH ₄ ⁺ are particular examples of cations present in pharmaceutically acceptable salts. The halides, sulfates, phosphates, alkanates (eg, acetate and trifluoroacetate), benzoates, and sulfonates (eg, mesylate) are anions present in pharmaceutically acceptable salts This is an example.

The present invention also provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Thus, the compounds of formula I can be used for the manufacture of a medicament. Pharmaceutical compositions of the compound of formula I prepared herein above may be formulated as solutions for parenteral administration or as lyophilized powders. The powder is
Prior to use, they may be reconstituted by the addition of a suitable diluent or other pharmaceutically acceptable carrier. The liquid formulation may be a buffered isotonic aqueous solution. Examples of suitable diluents are normal isotonic saline solutions, standard 5% dextrose water or buffered sodium or ammonium acetate solutions. Such formulations are particularly suitable for parenteral administration, but may also be used for oral administration, or may be included in an inhaler or nebulizer with a dosimeter for inhalation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, gum arabic, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

[0047] Alternatively, 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 extend 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,
Includes talc, pectin, gum arabic, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier is
Also, a sustained release material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be included. The amount of solid carrier varies,
Preferably, from about 20 mg to about 1 g per dosage unit. Pharmaceutical preparations are prepared according to conventional pharmaceutical techniques, including, when necessary, in the form of tablets, grinding, mixing, granulating and compressing; or in the case of hard gelatin capsules, grinding, mixing and filling. If a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or aqueous or non-aqueous suspension. Such liquid formulations may be administered orally directly or may be filled into soft soft gelatin capsules.

For rectal administration, the compounds of the present invention may be mixed with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycol and formed into suppositories.

Utility of the Invention The compounds of formula I are useful as protease inhibitors, in particular as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, and even more particularly of the papain superfamily. And more particularly as an inhibitor of the cysteine protease of the cathepsin family, most particularly as an inhibitor of cathepsin K.
The present invention also provides useful compositions and formulations of the compounds, including pharmaceutical compositions and formulations of the compounds.

The compounds of the present invention may be used as pneumocystis carini, Trypanosoma cruzi,
Infection with Trypanosoma brucei and Chrysizia fusicata; and cysteine protease-related diseases including schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, muscular atrophy; and, in particular, cathepsin K Diseases, most particularly gingival diseases including osteoporosis, gingivitis and periodontitis, arthritis, more particularly osteoarthritis and rheumatoid arthritis, Page
t disease; useful for treating hypercalcemia of malignancy, and diseases of excessive bone or cartilage loss, including metabolic bone disease.

Also, metastatic neoplastic cells typically express high levels of proteolytic enzymes that disrupt the surrounding matrix, and certain tumor and metastatic neoplastic tissue formation may occur with compounds of the present invention. It can be treated effectively.

The invention also relates to proteases at the pathological level, in particular cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, even more particularly the cathepsin family. A method of treating a disease caused by a cysteine protease of the present invention, said method comprising administering a compound of the invention to an animal in need of treatment, particularly a mammal, most particularly a human. I do. The present invention relates to a method for treating diseases caused by cathepsin K, particularly at a pathological level,
The method of treatment provides a method comprising administering to an animal in need of treatment, particularly a mammal, most particularly a human, an inhibitor of cathepsin K, including a compound of the present invention. The present invention specifically relates to infections by Pneumocystis carini, Trypsanoma cruzi, Trypsanoma bursei and Criticia fusiculata; and schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, muscular atrophy. Diseases involving cysteine proteases, and particularly those involving cathepsin K, most particularly gingival diseases including osteoporosis, gingivitis and periodontitis, arthritis, more particularly osteoarthritis and rheumatoid arthritis, Methods for treating disorders of excessive bone or cartilage loss, including Paget's disease, malignant hypercalcemia, and metabolic bone disease.

The present invention is further directed to a method of treating osteoporosis or inhibiting bone loss, comprising administering an effective amount of a compound of formula I alone or with another inhibitor of bone resorption, such as a bisphosphonate (ie, alendronate). ), Hormone replacement therapy, in vivo administration to a patient in combination with an antiestrogen or calcitonin. In addition, treatment with compounds of the present invention and anabolic substances, such as bone morphogenetic protein, iproflavone, may be used to prevent bone loss or increase bone mass.

For acute treatment, parenteral administration of the compounds of the formula I is preferred. Intravenous infusion of a similar formulation with 5% dextrose water or a compound in a normal saline or similar excipient is most effective, but intramuscular mass injection is also effective. Typically,
Parenteral administration can be accomplished in a manner that maintains the drug concentration in plasma at a concentration sufficient to inhibit cathepsin K, from about 0.01 to about 100 mg / kg; preferably from 0.1 to 2 mg / kg.
0 mg / kg. Compounds are administered 1 to 4 times daily, for a total daily dose of about 0.4
It is administered at a level to reach about 400 mg / kg / day. The exact amount of a compound of the invention that is therapeutically effective and the route by which the compound is best administered is determined by comparing the blood level of the drug to the concentration required to have a therapeutic effect.
It is easily determined by one of ordinary skill in the art.

The compounds of the invention may also be sufficient that the drug concentration is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein. In such a method, it may be administered orally to the patient. Typically, a pharmaceutical composition containing the compound will provide from about 0.1 to about 50 m in a manner consistent with the condition of the patient.
It is administered at an oral dose of g / kg. Preferably, the oral dose will be from about 0.5 to about 20 mg / kg.

When a compound of the present invention is administered in accordance with the present invention, no unacceptable toxicological effects are expected.

Biological Assays Compounds of the invention may be tested in one of several biological assays to determine the concentration of a compound required to have a given pharmacological effect.

Measurement of Cathepsin K Proteolytic Catalytic Activity All assays for cathepsin K were performed using human recombinant enzymes. Standard assay conditions for the determination of rate constants are fluorogenic peptide substrates, typically Cbz-Ph
Using e-Arg-AMC, measurements were taken in 100 mM Na acetate at pH 5.5 containing 20 mM cysteine and 5 mM EDTA. The stock substrate solution is either 10 or 20 mM in DMSO with a final substrate concentration of 20 μM in the assay.
It was prepared at a concentration. All assays contained 10% DMSO. Independent experiments revealed that the level of DMSO had no effect on enzyme activity or rate constants. All assays were performed at ambient temperature. Product fluorescence (360
nM excitation light; 460 nM emission) was monitored on a Perceptive Biosystems Cytofluor II fluorescence plate reader. The product transition curve shows that after the formation of the AMC product, 20
Over 30 minutes.

Study on Inhibition Potential inhibitors were evaluated using the transition curve method. Assays were performed in the presence of various concentrations of test compound. The reaction was started by adding the enzyme to a buffer solution of inhibitor and substrate. 2 depending on the appearance of the progression curve in the presence of the inhibitor
Data analysis was performed by one of two methods. For compounds whose progress curves are linear, the apparent inhibition constant (K _i , app) was calculated according to Equation 1 (Brandt et al., Biochemistry, 1989, 28, 140).

V = V_mA / [K_a(1 + I / K_i, App) + A] (1) where v is the reaction rate, the maximum rate is Vm, and A is the Michaelis constant K _a And I is the concentration of the inhibitor.

For compounds whose transition curves showed a downward curve characterized by time-dependent inhibition, the data from the individual sets was analyzed to determine k _obs according to Equation 2. [AMC] = v _ss t + (v 0 −v _ss ) [1-exp (−k _obs t)] / k _obs (2) where [AMC] is the concentration of product formed over time t , V0
Is the initial reaction rate and _vss is the steady state rate. The value of k _obs is then analyzed as a linear function of inhibitor concentration to yield an apparent second order rate constant (k _obs / inhibitor concentration or k _obs / [I]) that represents time-dependent inhibition. Was. A complete discussion of this kinetic process is well documented (Morrison et al., Adv. Enzymol.
Relat. Areas Mol. Biol., 1998, 61, 201).

Human Osteoclast Resorption Assay An aliquot of the cell suspension from osteoclastoma was removed from liquid nitrogen storage and
℃ quickly, centrifugation (1000 rpm, 5 minutes, 4 ℃) RPMI-
Washed once in 1640 medium. The medium is aspirated and in RPMI-1640 medium 1:
Replaced with 3 diluted murine anti-HLA-DR antibodies and incubated on ice for 30 minutes. The cell suspension was mixed frequently.

The cells were centrifuged (1000 rpm, 5 minutes, 4 ° C.) with cold RPMI-164
Washed twice at 0 and then transferred to a 15 mL centrifuge tube. Neub with improved mononuclear cell count
Counted in the auer counting chamber. Sufficient magnetic beads (5 per mononuclear cell) coated with goat anti-mouse IgG were removed from the stock bottle and placed in 5 mL of fresh medium (which removes toxic azide preservatives). The medium was removed by fixing the beads on a magnet and replaced with fresh medium.

The beads were mixed with the cells and the suspension was incubated on ice for 30 minutes. The suspension was mixed frequently. The cells coated with beads are fixed on a magnet, and the remaining cells (
The osteoclast-rich fraction) was decanted into a sterile 50 mL centrifuge tube. Fresh media was added to the cells coated with beads to remove any captured osteoclasts. This washing process was repeated 10 times. Cells coated with beads were discarded.

Samples were filled into the counting chamber using a large caliber disposable plastic Pasteur pipette and osteoclasts were counted in the counting chamber. The cells were pelleted by centrifugation and the density of the osteoclasts was adjusted to 1.5 × in EMEM medium supplemented with 10% fetal calf serum and 1.7 g / L sodium bicarbonate.
Adjusted to 10 ⁴ / mL. 3 mL aliquots of cell suspension (per treatment)
Was decanted into a 15 mL centrifuge tube. These cells were pelleted by centrifugation. To each tube was added 3 mL of the appropriate treatment (50 μM in EMEM medium).
M). Also, a suitable vehicle control, positive control (87 MEM1 diluted to 100 μg / mL) and isotype control (IgG2 diluted to 100 μg / mL)
a) is also included. The tubes were incubated at 37 ° C. for 30 minutes.

A 0.5 mL aliquot of cells was plated on sterile dentin slices in a 48 well plate and incubated at 37 ° C. for 2 hours. Each treatment was screened in quadruplicate. The slices were washed with 6 changes of warm PBS (10 mL / well in a 6-well plate), then placed in a fresh treatment or control and incubated at 37 ° C. for 48 hours. The slices are then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2 M sodium cacodylate) for 5 minutes, after which
They were washed with water and incubated for 5 minutes at 37 ° C in buffer.
The slices were then washed in cold water and incubated in cold acetate buffer / Fast Red Garnet at 4 ° C. for 5 minutes. Aspirate excess buffer,
After washing with water, the slices were air-dried.

The TRAP-positive osteoclasts were counted by bright-field microscopy and then removed from the dentin surface by sonication. Fossa volume was measured using a Nikon / Lasertec ILM21W confocal microscope.

General Nuclear magnetic resonance spectra were recorded on either a Bruker AM 250 or Bruker AC 400 spectrometer at 250 or 400 MHz, respectively. CDCl ₃ is deuteriochloroform, DMSO-d ₆ is hexadeuteriodimethylsulfoxide, and CD ₃ OD is tetradeuteriomethanol. Chemical shifts represent the downfield from the internal standard tetramethylsilane in parts per million (d
). Abbreviations of NMR data are as follows. s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
dd = doublet of doublet, dt = doublet of triplet, app = apparent, br = wide. J indicates the NMR coupling constant measured in Hertz.
Continuous wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra are recorded in transmission mode, and band positions are recorded at the reciprocal wave number (cm ^-1 ). Mass spectra can be obtained using the fast atom bombardment (FAB) or electrospray (ES) ionization techniques
Performed on either 70 FE, PE Syx API III or VG ZAB HF equipment. Elemental analysis was obtained using a Perkin-Elmer 240C elemental analyzer. Melting point is Thomas-Hoov
Measured in er melting point apparatus, no correction. All temperatures are recorded in degrees Celsius.

Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin plate were used in thin layer chromatography. Both flash and gravity chromatography were performed on E. Merck Kieselgel 60 (230-400 mesh) silica gel. When indicated, certain substances may be found in Aldrich, Milwaukee, Wisconsin.
Chemical Co., Chemical Dyn, South Plainfield, NJ
Purchased from amics Corp. and Advanced Chemtech, Louisville, KY.

EXAMPLES In the following synthesis examples, temperatures are in degrees Celsius (° C.). Unless otherwise noted, all starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art using the above description can utilize the present invention to its fullest extent. These examples are provided to illustrate the present invention and are not intended to limit its scope. What is reserved for the inventors is referred to in the claims.

Examples 1 and 2 N- (N- (benzyloxycarbonyl) -L-leucinyl) -4- (R, S)
-Amino-1,2,3,4,7,8-hexahydro-3-oxo- [2- (N-
Preparation of (benzyloxycarbonyl) -L-leucinyl)]-azocine a) 3- (R, S) -N-Boc-3-amino-2-hydroxy-hex-5-
Enyl-1N-allyl-amine N-methylmorpholine (5.82 ml, 5 in THF (20 ml) at -40 ° C)
N-Boc-D, L-allyl-glycine (9.5 g, 44.
1 mmol) in a solution of isobutyl chloroformate (7.24 ml, 35.9 mmol).
) Was added. The reaction mixture was stirred for 15 minutes before filtering to remove salts. The filtrate was treated with a solution of diazomethane (179 mmol) in Et ₂ O (260 ml) (1-methyl-3-nitro-1-nitrosoguanidine (26.3 g, 179 mmol), 4
0% KOH (80 ml) and Et ₂ O (260 ml))
The reaction mixture was stored in a refrigerator at 0 ° C. overnight. AcOH (20 m
1) 30% HBr in was added dropwise. Complete consumption of starting material observed (by TLC)
The reaction mixture was stirred at this temperature until complete. The reaction mixture was then washed with water, Na
Washed with saturated aqueous HCO ₃ then brine, dried (over magnesium sulfate), filtered, concentrated in vacuo and used in the next reaction without further purification. The product was then dissolved in MeOH (100 ml) and sodium borohydride was added in small portions. The reaction was stirred until TLC analysis showed consumption of material. The reaction mixture was concentrated, diluted with ether and extracted with water, 1N HCl, and then brine. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid (5.3 g). This material was dissolved in methanol (20ml) and allylamine (9.3ml) and stirred at room temperature overnight. The next morning, the reaction mixture was concentrated under reduced pressure to give the title compound as an oil. MS ES: 271.3 (M + H)
.

B) (3-R, S) -N-Boc-3-amino-2-hydroxy-hex-5-
Nyl-1N-allyl, 1N- (9-fluorenylmethoxycarbonyl) -amine N- (9-fluorenylmethoxycarbonyloxy) succinimide (0.6
8g, 2.03mmol) in (3S) -N-Boc in acetone (10ml).
-3-Amino-2-hydroxy-hex-5-enyl-1N-allyl-amine (
0.5 g, 1.85 mmol), and the reaction mixture was stirred for 10 min. The reaction mixture is then concentrated, the residue is washed with ethyl acetate, 1N HCl, N
Washed with aHCO ₃ saturated solution, brine, dried organic layer over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.99 g).

C) 1,1-Dimethylethyl-2,2-dimethyl-4- (methyl-N- (9-fluorenylmethoxycarbonyl), N-allyl-amino) -5-allyl-oxazolinecarboxylate CH ₂ Cl ₂ (20 ml) solution of (3S) -N-Boc-3- amino-2-hydroxy - hex-5-enyl -1N- allyl -1N- (9-fluorenyl methoxy carbonyl) - amine (0. 91 g, 1.85 mml) with 2,2-dimethoxy-propane (2.2 ml) and camphor sulfonic acid (88 mg, 0.4 ml).
mol). The reaction mixture was stirred at 55 ° C. overnight, then the reaction mixture was concentrated under reduced pressure and chromatographed (silica gel, 25% EtOAc / hexane).
To give the title compound as a white foam (0.74 g): MA ES: 5
33.2 (M + H).

D) 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,
2-dimethyl-5- (9-fluorenylmethoxy-carbonyl) oxazolo [5
. 4-c] Azocin-1 (2H) -carboxylate (3S) -N-Boc-3-amino-2-hydroxy-hex-5-enyl-
1N-allyl-, 1N- (9-fluorenylmethoxy-carbonyl) -amine-
Acetonide (0.66 g, 1.23 mmol) was dissolved in toluene (62 ml) and then argon was bubbled through the solution for 5 minutes. Grubb's catalyst (0.44 g, 0
. 53 mmol) was added and the reaction mixture was stirred at 80 ° C. for 1.5 hours, then
Further, Grubb's catalyst (0.1 g) was added. The reaction mixture was stirred at 80 ° C. overnight, then cooled to room temperature, concentrated under reduced pressure, and chromatographed (silica gel, 8
: 1 hexane: EtOAc) to give the title compound as a white foam: M
S ES: 505.2 (M + H ⁺ ).

E) 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,
2-dimethyl-5-oxazolo [5,4-c] azocin-1 (2H) -carboxylate 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,2
-Dimethyl-5- (9-fluorenylmethoxy-carbonyl) oxazolo [5.
4-c] azocin-1 (2H) -carboxylate (0.45 g, 0.91 mm
ol) was dissolved in 20% piperidine / DMF (5 ml) and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with brine (3 times), dried (over MgSO ₄ ), filtered and concentrated. The residue was chromatographed (silica gel, 19: 1 CH ₂ Cl ₂ : MeOH) to give the title compound (0.2 g): MS ES: 283.3 (M + H ⁺ ).

F) 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,
2-dimethyl-5-[(N- (benzyloxycarbonyl) -L-leucinyl)
]-[5,4-c] azocin-1 (2H) -carboxylate CH₂Cl₂1,1-dimethylethyl 3a, 4,5,6,9, (5 ml)
9a-Hexahydro-2,2-dimethyl-5-oxazolo [5,4-c] azosi
In a solution of -1 (2H) -carboxylate (0.2 g, 0.71 mmol),
Cbz-leucine (0.18 g, 0.71 mmol) and EDC (0.15 g
, 0.8 mmol) was added. Continue until TLC analysis confirms the completion of the reaction.
The reaction mixture was stirred at room temperature. Concentrate the reaction mixture, dissolve the residue in EtOAc,
1N HCl, NaHCO₃Wash with saturated solution, brine, dry (MgSO 4)
₄), Filtered and concentrated. The residue was chromatographed (2: 1 EtOAc:
Hexane) to give the title compound (324 mg): MS ES: 530.4
(M + H).

G) 4-Amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (
N- (benzyloxycarbonyl) -L-leucinyl)]-azocine 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,2
-Dimethyl-5-[(N- (benzyloxycarbonyl) -L-leucinyl)]
-[5,4-c] azocin-1 (2H) -carboxylate (0.32 g, 0.
6 mmol) in CH₂Cl₂(5 ml) and TFA (3.0 ml),
The reaction mixture was stirred at room temperature for 18 hours, then the reaction mixture was concentrated and the residue was
Dissolved in OAc and K₂CO₃Wash with saturated solution, brine, dry (K₂CO ₃ ), Filtered and concentrated. The residue was then washed with 1: 1 THF: H₂O (4 ml)
And TFA (2 ml) was added. Stir the reaction mixture overnight, then concentrate
And then diluted with EtOAc and K₂CO₃Extract with saturated solution, brine and dry
Let dry (K₂CO₃), Filtered and concentrated to give the title compound (250mg)
This was used for the next reaction without further purification: MS ES: 390.4 (M + H
⁺).

H) N- (N-Cbz-L-leucinyl) -4-amino-1,2,3,4,7,
8-Hexahydro-3-hydroxy- (N- (benzyloxycarbonyl) -L
- leucinyl)] - azocin CH ₂ Cl ₂ (5ml) solution of 4-amino -1,2,3,4,7,8- hexahydro-3-hydroxy - (N-(benzyloxycarbonyl) -L- leucinyl) To a solution of] -azocin (249 mg) was added Cbz-leucine (187 mg) and EDC (131 mg). The reaction mixture was stirred at room temperature for 50 minutes, then concentrated, the residue was dissolved in EtOAc, 1N HCl, saturated K ₂ CO ₃ solution,
Washed with brine, dried (over K ₂ CO ₃ ), filtered and concentrated. The residue was chromatographed (1: 1 hexane: EtOAc) to give 107 mg of the fast eluting diastereomer and 115 mg of the late eluting diastereomer. MS ES: 637.4 (M + H).

I) N- (N-Cbz-L-leucinyl) -4-amino-1,2,3,4,7,
8-Hexahydro-3-oxo- (N- (benzyloxycarbonyl) -L-leucinyl)]-azocine DMSO (0.023 ml) was added to a solution of oxalyl chloride (0.014 ml) at -78 ° C.
ml) was added and the reaction mixture was stirred for 10 minutes before CH ₂ Cl ₂ (2 × 2
ml) N- (N-Cbz-L-leucinyl) -4-amino-1,2,3,4
, 7,8-Hexahydro-3-hydroxy- (N- (benzyloxycarbonyl) -L-leucinyl)]-azocine (50 mg of the fast-eluting diastereomer)
Was added. The reaction mixture was stirred for 10 minutes before TEA (0.076
ml) was added. The reaction mixture was warmed to room temperature, diluted with EtOAc and NaHC
Saturated O ₃ solution, washed with brine, dried (over MgSO ₄ ), filtered and concentrated. The residue was subjected to column chromatography (2: 1 hexane: EtOAc) to give the title compound (39 mg). MS ES: 635.6 (M + H). In a similar manner, the late-eluting diastereomer obtained in Example 1 (I) is treated to give a second
The diastereomer of was obtained. MS ES: 635 (M + H).

Example 3 N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino-1,2,3,4,7,8-hexahydro-3-oxo (2-pyridylsulfonyl) A) (3S) -N-Boc-3-amino-2-hydroxy-hex-5-enyl-bromide Isobutyl chloroformate (7.24 ml, 35.9 mmol) at -40 ° C
To N-methylmorpholine in THF (6.13 ml, 55.9 mmol)
-Boc-L-allyl-glycine (10 g, 46.5 mmol) was added to the solution and then stirred for 15 minutes. The reaction mixture was filtered and 1-methyl-3-nitro-1
-Nitrosoguanidine (26.3 g, 179 mmol), 40% KOH (80
ml) and Et _{2 Et} obtained from the O 2 O (260 ml) solution of diazomethane (17
9 mmol) was added and the reaction mixture was stored in a refrigerator at 0 ° C. overnight. Ac
30% HBr in OH (25 ml, 93 mmol) was added dropwise and the reaction mixture was stirred for a further 7 minutes. The reaction mixture was then treated with a 15% aqueous citric acid solution (100 ml).
And the organic phase was extracted three times with a saturated aqueous solution of NaHCO ₃ , then with brine, dried over magnesium sulfate, filtered, concentrated in vacuo, and used for the next reaction without further purification. The product was then dissolved in MeOH (150 ml) and
, Sodium borohydride (3 g, 80 mmol) was added dropwise and the reaction mixture was stirred at room temperature for another 15 minutes. The reaction mixture was concentrated to two thirds by rotary evaporation, diluted with EtOAc (100 ml), extracted with water and then brine. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (7.47 g, 63%). 1H NMR (
CDCl ₃ , 360 MHz): δ 5.85-5.70 (m, 1H), 5.14 (d, 1H), 5.12 (s, 1H), 4.60
(bs, 1H), 3.80 (bs, 1H), 3.78-3.70 (m, 1H), 3.60-3.40 (m, 2H), 2.95 (bs
, 1H), 2.45-2.25 (m, 2H), 1.42 (s, 9H)

B) (3S) -N-Boc-3-amino-2-hydroxy-hex-5-enyl-1N-allyl-amine At room temperature allylamine (25 ml, 343 mmol) was treated with MeOH (50 m
1) to a solution of (3S) -N-Boc-3-amino-2-hydroxy-hex-5-enyl-bromide (7.3 g, 25 mmol) in 1) and stirred overnight. The reaction mixture was concentrated under reduced pressure and concentrated repeatedly three times from toluene (50 ml) to remove excess allylamine to give the title compound as a yellow oil (6.6 g, 9).
9%). MS ES: 271.2M + H ⁺

C) (3S) -N-Boc-3-amino-2-hydroxy-hex-5-enyl-1N-allyl-, 1N- (9-fluorenylmethoxycarbonyl) -amine N- (9- Fluorenylmethoxycarbonyloxy) succinimide (12.
7 g, 37.7 mmol) in acetone (40 ml) / H ₂ O (40 ml).
3S) -N-Boc-3-amino-2-hydroxy-hex-5-enyl-1N
-Allyl-amine (6.6 g, 25 mmol) was added and the reaction mixture was treated with 1
Stir for 5 minutes. Then the reaction mixture was concentrated, the residue was diluted with water (30 ml),
Extracted twice with EtOAc (50 ml). Combine the organic phases with 1 Naq
. HCl (20 ml), H ₂ O (20 ml), NaHCO ₃ saturated aqueous solution (20 m
l), extract with brine (20 ml), dry over magnesium sulfate, filter,
Concentration under reduced pressure gave the title compound as a white solid (8.2 g, 67%): MS E
S: 493.2M + H ⁺

D) 1,1-dimethylethyl-2,2-dimethyl-4- (methyl-N- (9-fluorenylmethoxy-carbonyl), N-allyl-amino) -5-allyl-oxazoline carboxylate (3S) -N-Boc-3-amino-2-hydroxy-hex-5-enyl-
1N-allyl-, 1N- (9-fluorenylmethoxycarbonyl) -amine (8
. (1 g, 16.46 mmol) was dissolved in 2.2-dimethoxy-propane (65 ml), then camphor sulfonic acid (88 mg, 0.4 mmol) was added and the reaction mixture was stirred at 55 ° C. overnight. The reaction mixture was concentrated under reduced pressure.
Redissolve in propane (65 ml) and add camphor sulfonic acid (50 mg, 0
. 2 mmol) was added and the reaction mixture was stirred at 55 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and subjected to chromatography (silica gel, 10% EtOAc / hexane) to give the title compound as a white foam (5.5 g, 71%). As Elemental Analysis _{C 32 H 40 N 2 O 5} : Calculated: C, 72.15; H, 7.57 ; N, 5.26; Found: C,
72.30; H, 7.67; N, 5.25; MS ES 533.3 (M + H ⁺ )

E) 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,
2-dimethyl-5- (9-fluorenylmethoxy-carbonyl) oxazolo [5
, 4-c] Azocin-1 (2H) -carboxylate (3S) -N-Boc-3-amino-2-hydroxy-hex-5-enyl-
1N-allyl-, 1N- (9-fluorenylmethoxycarbonyl) -amine-acetonide (2.2 g, 4.14 mmol) was dissolved in toluene (120 ml),
The solution was then flushed with argon for 5 minutes. Grubb's catalyst (0.44 g, 0.
53 mmol) was added and argon was bubbled through the solution for 1 minute. The reaction mixture was then stirred at 85 ° C. for 3 hours. Grubb's catalyst (0.22g, 0.27m
mol, J. Am. Chem. Soc., 1995, 117, 2108-2109) was added and the reaction mixture was stirred at 85 ° C. for a further 2 hours. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure and subjected to chromatography (silica gel, 10% EtOAc / hexane) to give the title compound as a white foam (1.35 g, 60%): MS E
S: 505.4 (M + H ⁺ )

F) 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,
2-dimethyl-5-oxazolo [5,4-c] azocin-1 (2H) -carboxylate 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,2
-Dimethyl-5- (9-fluorenylmethoxy-carbonyl) oxazolo [5
4-c] azocin-1 (2H) -carboxylate (2.5 g, 4.96 mmol)
l) was dissolved in 20% piperidine / DMF (32 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and chromatographed (silica gel, 5-7.5%
MeOH / CH ₂ Cl ₂ ) to give the title compound as a light brown solid (1.
2g, 86%). MS ES: 283.2 (M + H ^< + ^> )

G) 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,
2-Dimethylamino-5- (2-pyridinylmethoxy sulfonyl) oxazolo [5,4-c] azocine -1 (2H) - carboxylate CH ₂ Cl ₂ (15 ml) and Hunig base (2 ml, 11.47 mmol
1,1) -dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2
2-pyridylsulfonyl chloride (2 g, 10.64 mol) was added to a solution of 2,2-dimethyl-5-oxazolo [5,4-c] azocin-1 (2H) -carboxylate (1.2 g, 4.26 mmol). Then, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo, redissolved in _{EtOAc (50ml), H 2 O} (30ml), then extracted with brine (30 ml). The combined organic phases are dried over magnesium sulfate, filtered, concentrated under reduced pressure and chromatographed (silica gel, 0.7% Me
To give the title compound as a white foam was subjected to OH / _{CH 2} Cl 2). As Elemental Analysis _{C 20 H 29 N 3 O 5} S: Calculated: C, 56.72; H, 6.90 ; N, 9.92; S, 7.57; Found: C, 56.47; H, 6.80 ; N, 9.82; S, 7.83 ; MS ES 424.2 (M + H ⁺ )

H) 4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (
2-pyridinylsulfonyl) -azocine 1,1-dimethylethyl 3a, 4,5,6,9,9a-hexahydro-2,2
-Dimethyl-5- (2-pyridinylsulfonyl) oxazolo [5,4-c] azocin-1 (2H) -carboxylate (1.5 g, 3.55 mmol) was treated with dioxane (15 ml) and CH ₂ Cl ₂ ( (15 ml) in 4M HCl and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and then dioxane (20 ml
), THF (20 _ml), redissolved in H 2 O (20ml) Medium 4M HCl, and stirred overnight at room temperature and used in the next reaction without further purification. MS ES 284.3 (
M + H ⁺ )

I) N- (N-Boc-L-leucinyl) -4-amino-1,2,3,4,7,
8-Hexahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine N-methylmorpholine (1.4 ml, 12.6 mmol) in DMF (12 ml)
4-)-1,2,3,4,7,8-hexahydro-3-hydroxy-
(2-pyridinylsulfonyl) -azocine (1.0 g, 2.8 mmol), Bo
HBTU (1.25 g) was added to a solution of cL-leucine (0.7 g, 2.8 mmol).
, 3.3 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and then chromatographed (silica gel, 3: 2 EtOAc: hexane) to give the title compound as a white foam (1.33 g, quantitative): ESM
S: 497.3 (M + H ⁺ )

J) N- (L-leucinyl) -4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine N- (N- Boc-L-leucinyl) -4-amino-1,2,3,4,7,8
-Hexahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine (
1.3 g, 2.62 mmol) in dioxane (10 ml) and CH ₂ Cl ₂ (
(10 ml), stirred at room temperature for 3 h, then concentrated and used for the next reaction without further purification (1.23 g, quantitative). MS ES 397
. 3 (M + H ⁺ )

K) N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (2-pyridini Rusulfonyl) -azocine 2-benzofurancarboxylic acid (105 mg, 0.65 mmol) in N-methylmorpholine (0.3 ml) and DMF (4 ml), N- (L-leucinyl)
-4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (2
HBTU (250 mg, 0.66 mmol) was added to a solution of -pyridylsulfonyl) -azocine (0.305 g, 0.65 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then diluted with _{EtOAc (40ml), H 2 O} , then extracted with brine. The combined organic phases are dried over magnesium sulfate, filtered,
After concentration under reduced pressure, chromatography (silica gel, 2% MeOH / CH ₂ Cl ₂₎
) To give the title compound as a white foam (0.27 g, 77%). MS
ES: 541.4 (M + H ⁺ )

1) N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino-1,2,3,4,7,8-hexahydro-3-oxo- (2-pyridini Rusuruhoniru) - azocine CH ₂ Cl ₂ (3ml) solution of N- (N- (2- benzofuran - carbonyl) -
(L-leucinyl) -4-amino-1,2,3,4,7,8-hexahydro-3-
Hydroxy- (2-pyridinylsulfonyl) -azocine (110 mg, 0.20
mmol) in a solution of Dess-Martin periodinane (13 mg, 0.3 mmol).
) Was added and stirred at room temperature for 1 hour. Then more Dess-Martin periodinane (65 mg, 0.15 mmol) was added and the reaction mixture was stirred for another hour. Afterwards, the reaction mixture was diluted with CH ₂ Cl ₂ (50 ml) and 10% NaH
Extract with aqueous CO ₃ (30 ml), 10% aqueous Na ₂ S ₂ O ₃ (30 ml), dry over magnesium sulfate, filter, concentrate under reduced pressure, and chromatograph (
Silica gel, 1.5% MeOH / CH ₂ Cl ₂ ) gave the title compound as a white foam (83 mg, 75%). MS ES: 539.1 (M + H ⁺ ), 561.3 (M + Na ⁺ ), 584.3 (M + 2Na ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.70 (d, 1H), 7.94-7.92
(m, 2H), 7.60 (d, 1H), 7.55-7.50 (m, 3H), 7.45-7.40 (m, 1H), 7.11 (t, 2H
), 5.90-5.80 (m, 1H), 5.55-5.48 (m, 1H), 5.15-5.00 (m, 1H), 4.78-4.70 (m
, 1H), 4.45 (d, 2H), 3.85 (d, 1H), 3.70 (dd, 1H), 3.60-3.50 (m, 1H), 2.5
5-2.48 (m, 1H), 1.78-1.70 (m, 3H), 0.98 (2d, 6H)

Example 4 N- (4-methyl-2- (3-biphenyl) valeryl) -4-amino-1,2,2
3,4,7,8-Hexahydro-3-oxo- (2-pyridinylsulfonyl)-
Preparation of Azocine a) N- (4-Methyl-2- (3-biphenyl) valeryl) -4-amino-1,
2,3,4,7,8-Hexahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine 4-amino-1,2,3,4,7,8-hexahydro- in DMF (12 ml) 3-hydroxy- (2-pyridinylsulfonyl) -azocine (0.28 g,
0.8 mmol), 4-methyl-2- (3-biphenyl-valeric acid (0.215 g
, 0.8 mmol), N-methylmorpholine (0.44 ml, 12.6 mmol)
HBTU (0.34 g, 0.88 mmol) was added to the solution of (1), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and then chromatographed (silica gel, 1: 1 EtOAc: hexane) to give the title compound as a white foam (0.33 g, 78%). ES MS: 534.1 (M + H ^< + ^> )

B) N- (4-methyl-2- (3-biphenyl) valeryl) -4-amino-1,
2,3,4,5,6,7,8-octahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine N- (4-methyl-2- (3-biphenyl) valeryl) -4-amino -1,2
, 3,4,7,8-Hexahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine (80 mg, 0.15 mmol) in 1: 4 EtOAc: EtO
H (10 ml). Then, 10% Pd / C (10 mg) was added and the reaction mixture was stirred under a balloon of hydrogen gas for another 2 hours. The reaction mixture was filtered through diatomaceous earth, concentrated under reduced pressure and used for the next reaction without further purification (60 mg,
75%). MS ES 536.3 (M + H ^< + ^> )

C) N- (4-methyl-2- (3-biphenyl) valeryl) -4-amino-1,
N- (4-methyl-2- (3) in 2,3,4,5,6,7,8-octahydro-3-oxo- (2-pyridinylsulfonyl) -azocine CH ₂ Cl ₂ (2 ml) -Biphenyl) valeryl) -4-amino-1,2,3,4,5,6,7,8-octahydro-3-hydroxy- (2-pyridylsulfonyl) -azocine (50 mg, 0.09 mmol)
Dess-Martin periodinane (60 mg, 0.14 mmol) was added to the solution of 1), and the mixture was stirred at room temperature for 1 hour. Next, Dess-Martin periodinan (3
0 mg, 0.07 mmol) was added and the reaction mixture was stirred at room temperature for another hour. The reaction mixture was then diluted with CH ₂ Cl ₂ (50 ml) and 10% NaHC
O ₃ aqueous solution (30 ml), extracted with 10% Na ₂ S ₂ O ₃ aqueous solution (30 ml),
Dry over magnesium sulfate, filter, concentrate under reduced pressure, and chromatograph (silica gel, 1% MeOH / CH ₂ Cl ₂ ) to give the title compound as a white foam (22 mg, 44%). MS ES: 534.4 (M + H ⁺ ), 579.4 (M + 2Na ⁺ ); ( ¹ H NMR, CDCl ₃ , 400 MHz, diastereomeric mixture): δ 8.70-8.62 (m, 1H), 8
.12-7.88 (m, 2H), 7.55-7.52 9m, 2H), 7.55-7.27 (m, 8H), 6.20-6.15 (m, 1H
), 5.10-5.02 (m, 1H), 4.70-4.60 (dd, 1H), 3.80-3.70 (m, 1H), 3.12-2.92
(dd, 1H), 2.20-2.10 (m, 1H), 2.10-1.95 (m, 2H), 1.90-1.70 (m, 5H), 1.55-
1.35 (m, 2H), 1.30-1.15 (m, 1H), 0.95-0.90 (m, 6H)

Example 5 N- (4-Methyl-2- (3-biphenyl) valeryl) -4-amino -1,2,3,4,7,8-hexahydro-3-oxo- (2-pyridini Rusuruhoniru) - azocine preparation CH ₂ Cl ₂ (5 ml) solution of N-(4-methyl-2- (3-biphenyl) valeryl) -4-amino -1,2,3,4,7,8- hexahydro To a solution of -3-hydroxy- (2-pyridinylsulfonyl) -azocine (44 mg, 0.08 mmol) was added Dess-Martin periodinane (64 mg, 0.15 mmol),
Stirred at room temperature for 1 hour. The reaction mixture was then diluted with CH ₂ Cl ₂ (50 ml) and 10% aqueous NaHCO ₃ (30 ml), 10% aqueous Na ₂ S ₂ O ₃ (3 ml).
0 ml), dried over magnesium sulfate, filtered, concentrated under reduced pressure, and chromatographed (silica gel, 0.5% MeOH / CH ₂ Cl ₂ ) to give the title compound as a white foam ( 30 mg, 68%). MS ES: 539.1 (M + H ⁺ ),
579.4 (M + 2Na ⁺ ); ¹ H NMR (CDCl ₃ , 400 MHz, diastereomeric mixture): δ 8.68
(d, 1 H), 8.62 (d, 1H), 8.0-7.85 (m, 4H), 7.62 (7.30 (m, 20H), 6.75 (d,
1H), 6.62 (d, 1H), 5.90-5.80 (m, 1H), 5.75-5.60 (m, 1H), 5.50-5.40 (m,
2H), 5.10-5.00 (m, 2H), 4.36 (d, 2H), 4.28 (d, 2H), 3.83 (d, 2H), 3.73
(d, 2H), 3.60-3.37 (m, 4H), 2.55-2.50 (m, 1H), 2.48-2.38 (m, 1H), 2.10-2
.00 (m, 2H), 1.80-1.70 (m, 2H), 1.55-1.45 (m, 2H), 0.96-0.90 (m, 12H)

Example 6 N- (N- (2-quinoline-carbonyl) -L-leucinyl) -4-amino-1,2,3,4,5,6,7,8- octahydro-3-oxo- (2-pyridinyl sulfonyl) - preparation of azocine a) N-(N-(2-quinoline - carbonyl) -L- leucinyl) -4-amino -1,2,3,4,7,8- hexahydro-3- Hydroxy- (2-pyridinylsulfonyl) -azocine The title compound was prepared according to the method of Example 3k except that 2-quinolinecarboxylic acid was used instead of 2-benzofurancarboxylic acid: MS ES: 552.
4 (M + H ⁺ )

B) N- (N- (2-quinoline-carbonyl) -L-leucinyl) -4-amino-1,2,3,4,5,6,7,8-octahydro-3-hydroxy- ( 2-Pyridinylsulfonyl) -azocine N- (4-methyl-2- (3-biphenyl) valeryl) -4-amino-1,2,3,4,7,8-hexahydro-3- of Example 4b The title compound was prepared according to the method of Example 4b except that the compound of Example 6a was used instead of hydroxy- (2-pyridinylsulfonyloxy) -azocine: MS ES: 554.
3 (M + H ⁺ )

C) N- (N- (2-quinoline-carbonyl) -L-leucinyl) -4-amino-1,2,3,4,5,6,7,8-octahydro-3-oxo- ( 2-Pyridinylsulfonyl) -azocine To a solution of the compound of Example 6b (100 mg, 0.18 mmol) in DMSO was added TEA (0.3 ml) and pyridine sulfur trioxide complex (920 mg). The reaction mixture was stirred at room temperature until TLC indicated the reaction was complete, then diluted with ethyl acetate and washed with brine. The organic layer was dried, filtered, and concentrated. The residue was subjected to column chromatography (2% methanol: dichloromethane) to obtain 50 mg of the product. MS ES 552.3 (M + H ^< + ^> )

Example 7 N- (N- (2-quinoline-carbonyl) -L-leucinyl) -4-amino- 1,2,3,4,7,8-octahydro-3-oxo- (2-pyr Jinirusuruhoni Le) - azocine Preparative example 6c of N- (N- (2- quinoline - carbonyl) -L- leucinyl) -
Instead of 4-amino-1,2,3,4,5,6,7,8-octahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine, the N- (N-
(2-quinoline-carbonyl) -L-leucinyl) -4-amino-1,2,3,
4,7,8-Hexahydro-3-hydroxy- (2-pyridinylsulfonyl)-
The title compound was prepared according to the method of Example 6c except that azocine was used.
MS ES: 550.4 (M + H ^< + ^> )

Example 8 N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino- 1,2,3,4,5,6,7,8-octahydro-3-oxo- (2-pyrid Nirusuruhoniru) - preparation a) N- of azocine (N-(2-benzofuran - carbonyl) -L- leucinyl) -4-amino -1,2,3,4,5,6,7,8 -Octahydro-3-hydroxy- (2
-Pyridinylsulfonyl) -azocine N- (N- (2-quinoline-carbonyl) -L-leucinyl)-of Example 6b
4-amino-1,2,3,4,7,8-octahydro-3-hydroxy- (2-
Example 3k N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino-1,2,3,4 in place of pyridinylsulfonyl) -azocine
The title compound was prepared according to the method of Example 6b except that 7,8-hexahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine was used. MS E
S: 543.4 (M + H +)

B) N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino-1,2,3,4,5,6,7,8-octahydro-3-oxo- ( 2-Pyridinylsulfonyl) -azocine N- (4-Methyl-2- (3-biphenyl) valeryl) -4-amino-1,2,3,4,5,6,7,8- of Example 4c N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino-1,2,3 of Example 9b instead of octahydro-3-oxo- (2-pyridinylsulfonyl) -azocine , 4,5
, 6,7,8-Octahydro-3-hydroxy (2-pyridinylsulfonyl)-
The title compound was prepared according to the method of Example 4c but using azocine: MS
ES: 541.3 (M + H ⁺ )

[0102] Example 9 N- (N- (2- benzothiophene - carbonyl) -L- leucinyl) -4-amino-1,2,3,4,5,6,7,8-octahydro-3- oxo - (2-Hoon lysine sulfonyl sulfonyl) - preparation of azocine a) N-(N-(2-benzothiophene - carbonyl) -L- leucinyl) -4
-Amino-1,2,3,4,7,8-Hexahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine Except for using 2-benzothiophene carboxylic acid instead of 2-benzofuran carboxylic acid. The title compound was prepared according to the method of Example 3k: MS ES: 55
7.3 (M + H ⁺ )

B) N- (N- (2-benzothiophene-carbonyl) -L-leucinyl) -4
-Amino-1,2,3,4,5,6,7,8-octahydro-3-hydroxy-
(2-pyridinylsulfonyl) -azocine N- (4-Methyl-2- (3-biphenyl) valeryl) -4-amino-1,2,3,4,7,8-hexahydro-3 of Example 4b The title compound was prepared according to the method of Example 4b except that the compound of Example 9a was used instead of -hydroxy- (2-pyridinylsulfonyl) -azocine: MS ES: 559 (M + H ⁺ )

C) N- (N- (2-benzothiophene-carbonyl) -L-leucinyl) -4
-Amino-1,2,3,4,5,6,7,8-octahydro-3-oxo- (2
-Pyridinylsulfonyl) -azocine N- (4-Methyl-2- (3-biphenyl) valeryl) -4-amino-1,2,3,4,5,6,7,8-octahydro of Example 4c -3-Hydroxy- (2
-Pyridinylsulfonyl) -azocine was prepared according to the method of Example 4c except for using the compound of Example 9b. MS ES: 557.4
(M + H ⁺ )

[0105] Example 10 N-(N-(2-benzothiophene - carbonyl) -L- leucinyl) -4-amino -1,2,3,4,7,8- octahydro-3-oxo - (2 - pyridinyl sulfonyl) - azocine example 4c of N-(4-methyl-2- (3-biphenyl) valeryl) -4-amino-1,2,3,4,5,6,7,8-octahydro -3 -Hydroxy- (2
-Pyridinylsulfonyl) -azocine instead of the N- (N- (2-
Benzothiophene-carbonyl) -L-leucinyl) -4-amino-1,2,3
, 4,7,8-Hexahydro-3-hydroxy- (2-pyridinylsulfonyl)
-The title compound was prepared according to the method of Example 4c except using -azocin. M
S ES: 555.3 (M + H ⁺ )

The above specification and examples fully disclose how to make and use the compounds of the present invention. However, the invention is not limited to the specific embodiments described above, but encompasses all modifications falling within the scope of the appended claims. Various references to cited journals, patents, and other publications are inclusive of the state of the art and are hereby incorporated by reference.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 19/04 A61P 19/04 19/08 19/08 19/10 19/10 29/00 29/00 43 / 00 111 43/00 111 C07D 401/12 C07D 401/12 401/14 401/14 405/14 405/14 409/14 409/14 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD) , RU, TJ, TM), AE, AL, AU BA, BB, BG, BR, CA, CN, CZ, EE, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KP, KR, LC, LK, LR, LT, LV , MA, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, SL, TR, TT, UA, US, UZ, VN, YU, ZA (72) Inventor Daniel Frank Baber United States 19002 Ambler, Pennsylvania, Beiterson Road 290 F-term (Reference) 4C034 EA04 4C063 AA01 AA03 BB08 CC20 CC76 CC94 DD12 DD14 EE01 4C086 AA01 AA02 AA03 BC33 GA02 GA04 GA07 GA08 MA17 MA22 MA23 MA55 MA55 MA55 MA55 NA14 ZA96 ZA97 ZB15 ZC41 ZC54

Claims (35)

[Claims] 1. A compound of the formula I: I wherein A is selected from the group consisting of C (O) and CH (OH);¹IsR is selected from the group consisting of:²Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl,
Ar-C_0-6Alkyl, Het-C_0-6Alkyl, R⁹C (O)-, R⁹C
(S)-, R⁹SO₂-, R⁹OC (O)-, R⁹R¹²NC (O)-, R⁹R ¹² NC (S)-, R¹²HNCH (R¹²) C (O)-, R⁹OC (O) NR ¹² CH (R¹²) C (O)-, adamantyl-C (O)-, orR ″ is H, C_1-6Alkyl, Ar-C_0-6Alkyl, and Het-C _0-6 R "" is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Archi
, Ar-C₀₆Alkyl, and Het-C_0-6Selected from the group consisting of alkyl
Selected; R³And R⁸Are independently H, C_2-6Alkenyl, C_2-6Alkynyl,
Het, Ar, or OR¹³, SR¹³, NR¹³ ₂, R¹³NC (O) O
R⁵, CO₂R¹³, CO₂NR¹³ ₂, N (C = NH) NH₂Or Het
Is C which may be substituted by Ar_1-6R is selected from the group consisting of alkyl;⁴Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl,
Ar-C_0-6Alkyl, Het-C_0-6Alkyl, R⁵C (O)-, R⁵C
(S)-, R⁵SO₂-, R⁵OC (O)-, R⁵R¹⁴NC (O)-, R⁵R ¹⁴ NC (S)-, R¹⁴HNCH (R¹⁴) C (O)-, and R⁵OC (O
) NR¹⁴CH (R¹⁴R) selected from the group consisting of C (O)-;⁵, R⁹, And R¹⁰Is independently C_1-6Alkyl, C_3-6Cycloa
Lequil-C_0-6Alkyl, Ar-C_0-6Alkyl and Het-C_0-6A
Selected from the group consisting of⁶Is H, C_1-6Alkyl, Ar-C_0-6Alkyl, and Het-C_{0 -6} R is selected from the group consisting of alkyl;⁷Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl,
Ar-C_0-6Alkyl, Het-C_0-6Alkyl, R¹⁰C (O)-, R^{1 0} C (S)-, R¹⁰SO₂-, R¹⁰OC (O)-, R¹⁰R^FifteenNC (O)
-, R¹⁰R^FifteenNC (S)-, R^FifteenHNCH (R^Fifteen) C (O)-, and
R¹⁰OC (O) NR^FifteenCH (R^Fifteen) Selected from the group consisting of C (O)-
Or; R⁶And R⁷Combine to form a pyrrolidine, piperidine, or morpholine ring
Each R 'is independently H, C_1-6Alkyl, Ar-C_0-6Alkyl, and
Het-C_0-6R is selected from the group consisting of alkyl;¹¹Is Ar; R¹², R¹³, R¹⁴And R^FifteenAre independently H, C_1-6Alkyl, A
r-C_0-6Alkyl, and Het-C_0-6Selected from the group consisting of alkyl
R; R^*Is H, C_1-6Alkyl, C_3-6Cycloalkyl-C_0-6Alkyl,
Ar-C_0-6Alkyl, and Het-C_0-6Select from the group consisting of alkyl
Z is C (O) and CH₂M is HC = CH; H₂C-CH₂; H (OR²) CC (OR²) H; H (O
R²) C-CH₂H (NR²H) CC (NR²H) H; H (OR²) CC
(NR²H) H; and H (NR²H) C-CH₂X is CH₂, S and O; n is 1 to 7] and pharmaceutically acceptable salts, hydrates and solvates thereof. 2. The compound according to claim 1, wherein A is C (O). 3. The compound according to claim 1, wherein R ″ and R ″ ″ are both H. Wherein A is C (O); M is selected from the group consisting of HC = CH and _{H 2} C-CH 2; n is be 1; R '' and R '''is both The compound according to claim 1, wherein H is H. 5. A is C (O); R ¹ is R ² is selected from the group consisting of: R ¹⁰ SO ₂ and R ³ and R ⁸ are C _1-6 alkyl; R ⁴ is selected from the group consisting of R ⁵ OC (O) — and R ⁵ C (O) —; R ⁵ , R ⁹ , and R ¹⁰ are independently Ar-C _0-6 alkyl and Het.
It is selected from the group consisting of -C _0-6 alkyl; ^{R 6} is an H; ^{R 7} is an ^{R 10 OC (O); R} ' is an H; R''is an H; R'''it is H; Z is be a C (O); compound of claim 1 n is 1; M is selected from the group consisting of HC = CH and _{H 2} C-CH 2. 6. R ² is embedded image The compound according to claim 5, which is 7. The compound according to claim 5, wherein R ³ and R ⁸ are independently isobutyl. 8. R ⁵ , R ⁹ and R ¹⁰ are phenyl, benzyl, 2-naphthyl, 2-benzofuranyl, 2-benzo [b] thiophenyl, 2-quinolinyl,
The compound according to claim 5, which is independently selected from the group consisting of and pyridinyl. 9. N- (N- (benzyloxycarbonyl) -L-leucinyl) -4- (R, S) -amino-1,2,3,4,7,8-hexahydro-3-oxo- [ 2- (N- (benzyloxycarbonyl) -L-leucinyl)]-azocine; N- (N- (benzyloxycarbonyl) -L-leucinyl) -4- (R, S
) -Amino-1,2,3,4,7,8-hexahydro-3-oxo- [2- (N
-(Benzyloxycarbonyl) -L-leucinyl)]-azocine; N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino-1,2,3,4,7,8-hexahydro -3-oxo- (2-pyridinylsulfonyl) -azocine; N- (4-methyl-2- (3-biphenyl) valeryl) -4-amino-1,2
N, (3,4,5,6,7,8-octahydro-3-oxo- (2-pyridinylsulfonyl) -azocine; N- (4-methyl-2- (3-biphenyl) valeryl) -4-amino -1,2
, 3,4,7,8-Hexahydro-3-oxo- (2-pyridinylsulfonyl)
-Azocine; N- (N- (2-quinoline-carbonyl) -L-leucinyl) -4-amino-
1,2,3,4,5,6,7,8-octahydro-3-oxo- (2-pyridinylsulfonyl) -azocine; N- (N- (2-quinoline-carbonyl) -L-leucinyl) -4-amino-
1,2,3,4,7,8-hexahydro-3-oxo- (2-pyridinylsulfonyl) -azocine; N- (N- (2-benzofuran-carbonyl) -L-leucinyl) -4-amino -1,2,3,4,5,6,7,8-octahydro-3-oxo- (2-pyridinylsulfonyl) -azocine; N- (N- (2-benzothiophene-carbonyl) -L- Leucinyl) -4-
Amino-1,2,3,4,5,6,7,8-octahydro-3-oxo- (2-
Pyridinylsulfonyl) -azocine; and N- (N- (2-benzothiophene-carbonyl) -L-leucinyl) -4-
The compound according to claim 1, wherein the compound is selected from the group consisting of amino-1,2,3,4,7,8-hexahydro-3-oxo- (2-pyridinylsulfonyl) -azocine. 10. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient. 11. A pharmaceutical composition comprising the compound according to claim 9 and a pharmaceutically acceptable carrier, diluent or excipient. 12. The method of claim 1, wherein said amount is effective for a patient in need of protease inhibition.
A method for inhibiting a protease, which comprises administering the compound described above. 13. The method of claim 12, wherein said protease is selected from the group consisting of cysteine protease and serine protease. 14. The method of claim 9, wherein said amount is effective for a patient in need of protease inhibition.
A method for inhibiting a protease, which comprises administering the compound described above. 15. The method according to claim 14, wherein said protease is selected from the group consisting of cysteine protease and serine protease. 16. The method according to claim 1, wherein the protease is a cysteine protease.
3. The method according to 3. 17. The method of claim 1, wherein said protease is a cysteine protease.
5. The method according to 5. 18. The method according to claim 1, wherein said cysteine protease is cathepsin K.
6. The method according to 6. 19. The method according to claim 1, wherein the cysteine protease is cathepsin K.
7. The method according to 7. 20. Characterized by bone loss, characterized by inhibiting bone loss by administering an effective amount of a compound of claim 1 to a patient in need of treatment for a disease characterized by bone loss. How to treat the disease. 21. The method according to claim 20, wherein said disease is osteoporosis. 22. The method according to claim 20, wherein said disease is periodontitis. 23. The method according to claim 20, wherein said disease is gingivitis. 24. Inhibiting excessive cartilage or matrix degeneration by administering an effective amount of a compound of claim 1 to a patient in need of treatment for a disease characterized by excessive cartilage or matrix degeneration. A method for treating a disease characterized by excessive cartilage or matrix degeneration, characterized in that: 25. The method according to claim 24, wherein said disease is osteoarthritis. 26. The method according to claim 24, wherein said disease is rheumatoid arthritis. 27. A method characterized by bone loss characterized by inhibiting bone loss by administering an effective amount of a compound according to claim 9 to a patient in need of treatment for a disease characterized by bone loss. To treat the disease. 28. The method of claim 27, wherein said disease is osteoporosis. 29. The method of claim 27, wherein said disease is periodontitis. 30. The method according to claim 27, wherein said disease is gingivitis. 31. Suppressing excessive cartilage or matrix degeneration by administering an effective amount of a compound of claim 9 to a patient in need of treatment for a disease characterized by excessive cartilage or matrix degeneration. A method for treating a disease characterized by excessive cartilage or matrix degeneration, characterized in that: 32. The method according to claim 31, wherein said disease is osteoarthritis. 33. The method according to claim 31, wherein the disease is rheumatoid arthritis. 34. A compound of formula II: II wherein R is Selected from the group consisting of: 35. embedded image 4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (2-pyridinylsulfonyl)-
Azocin N- (L-leucinyl) -4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (2-pyridinylsulfonyl) -azocine 35. The method according to claim 34, which is selected from the group consisting of 4-amino-1,2,3,4,7,8-hexahydro-3-hydroxy- (N- (benzyloxycarbonyl) -L-leucinyl)]-azocine. Compound.