JP2002539160A - Protease inhibitor - Google Patents

Abstract

  (57) [Summary] The present invention provides 7-membered 1,3-dioxepin-5-one protease inhibitors, particularly cysteine and serine protease inhibitors, and methods of treating diseases that can be therapeutically modified by altering the activity of such proteases. provide.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates generally to 7-membered 1,3-dioxepin-5-one protease inhibitors, especially inhibitors of cysteine and serine proteases, more particularly compounds that inhibit cysteine proteases, More particularly, it relates to compounds that inhibit cysteine proteases of the papain superfamily, more particularly compounds that inhibit cysteine proteases of the cathepsin family, and most particularly to compounds that inhibit cathepsin K. Such compounds are useful in the treatment of cysteine protease related disorders, especially disorders of excessive bone or cartilage loss such as osteoporosis, periodontal disease and arthritis.

BACKGROUND OF THE INVENTION Cathepsins are a group of enzymes that 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 polypeptides and cDNAs encoding such polypeptides were disclosed in US Pat. No. 5,501,969, which is referred to as cathepsin O. Cathepsin K has recently been expressed, purified and characterized. B
ossard, 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 is variously represented in the literature as cathepsin O or cathepsin O2. The cathepsin K symbol is considered a more appropriate indication. Cathepsins are a normal physiological process of proteolysis in animals, including humans, for example,
It functions in the breakdown of connective tissue. However, elevated levels of these enzymes in the body can lead to pathological conditions leading to disease. Thus, cathepsins include, but are not limited to, pneumocystis carinii, trypsanoma, as well as schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like.・ Kuruji (Trypsan
oma cruzi), trypsanoma brucei and Crithidia fusiculata, and are involved in the pathogenesis of various medical conditions, including infections. International publication WO published on March 3, 1994
See 94/04172 and the references cited therein. European patent application EP
See 0 603 873 A1 and the references cited therein. Pii Gingivalis (P.gi
ngivallis), two bacterial cysteine proteases termed gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives
See Drug Discovery and Design, 2, 445-458. Cathepsin K is believed to play a causative role in diseases of excessive bone or cartilage loss. Bone is composed of a protein matrix into which spindle-shaped or plate-shaped crystals of hydroxyapatite are incorporated. Type I collagen is the main structural protein of bone, which makes up about 90% of the protein matrix. The remaining 10% of the matrix is osteocalcin,
It is composed of a number of non-collagenous proteins, including proteoglycine, osteopontin, osteonectin, thrombospondin, fibronectin and bone sialoprotein. Skeletal bone undergoes alterations at individual lesions throughout life. The lesions or remodeling units undergo a cycle consisting of a bone replacement phase followed by a bone resorption phase.

[0003] Bone resorption is caused by osteoclasts, multinuclear cells of the hematopoietic lineage. Osteoclasts attach to the bone surface, forming a firm sealing zone, followed by extensive cell membrane ruffling at the tip (eg, resorption) surface. This forms a surrounded compartment of extracellular fluid on the bone surface acidified by the proton pump in the ruffled cell membrane, in which the osteoclasts secrete proteolytic enzymes. The low pH compartment
Hydroxyapatite crystals are broken down on the bone surface, and this protease digests the protein matrix. In this way, resorbing voids or pits are formed. At the end of this phase of the cycle, osteoclasts constitute a new protein matrix,
This is then petrified. In some conditions, such as osteoporosis and Paget's disease, the normal balance between bone resorption and production is disrupted, resulting in a net loss of bone in each cycle. Ultimately, this weakens the bone and may result in an increased risk of fracture with minimal trauma. Several published studies have demonstrated that cysteine protease inhibitors are effective in inhibiting osteoclast-mediated bone resorption, indicating an essential role for cysteine protease in bone resorption. For example, Delaisse et al., Biochem. J., 1980, 192.
, 365, discloses a series of protein inhibitors in mouse bone organ culture systems, where cysteine protease inhibitors (eg, leupeptin, Z-Pha-Ala-CHN ₂ ) prevent bone resorption, while serine protease inhibitors Suggests no effect. De
Laisse et al., in Biochem. Biophy. Res. Commum., 1984, 125, 441, show that E-64 and leupeptin are also measured in vivo by abrupt changes in serum calcium in rats on a calcium deficient diet. It discloses that it is effective in preventing absorption. Lerner et al. In J. Bone Min. Res., 1992, 7, 433 disclose that cysteine, an endogenous cysteine protease inhibitor, inhibits PTH-promoted bone resorption in the parietal bone of mice. Also, Delaisse et al., Bone, 1987, 8, 305; Hill et al., J. C.
ell. Biochem., 1994, 56, 118 and Everts et al., J. Cell. Physiol., 1992, 150.
221 have reported an association between cysteine protease activity inhibition and bone resorption. Tezuka et al., J. Biol. Chem., 1994, 269, 1106; Inaoka et al., Biochem. Biophys. Res. Commun., 1995, 206, 89; and Shi et al., FEBS Lett.,
1995, 357, 129 discloses that under normal conditions, cathepsin K, a cysteine protease, may be the major cysteine protease that is abundantly expressed in osteoclast details and present intracellularly. Abundant and selective expression of cathepsin K in osteoclasts strongly suggests that this 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 periodontal disease, Paget's disease, hypercalcemia of malignancy, and metabolic bone diseases. An effective treatment for bone loss disease can be provided. Cathepsin K levels have also been shown to be increased in cartilage resorbing cells of the synovial synovium. Thus, also selective inhibition of cathepsin K is 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. Thus, selective inhibition of cathepsin K is also useful for treating certain tumor diseases. Several cysteine protease inhibitors are known. Palmer (1995)
J. Med. Chem., 38, 3193 discloses certain vinyl sulfones that irreversibly inhibit cysteine proteases such as cathepsins B, L, S, O2, and curzain. Aldehyde, nitrile, α-ketocarbonyl compound, halomethylketone,
Other compounds such as diazomethylketone, (acyloxy) methylketone, ketomethylsulfonium salts and epoxysuccinyl compounds have also been reported to inhibit cysteine proteases. See Palmer Id. And the references cited therein. US Patent No. 4,518,528 discloses peptidyl fluoromethyl ketone as an irreversible inhibitor of cysteine protease. International Publication WO 94/04172 and European Patent Applications EP 0 525 420 A1, EP 0 603 873 A1 and EP 0 611 756 A
No. 2 discloses alkoxymethyl and mercaptomethyl ketones that inhibit the cysteine proteases cathepsins B, H and L. International patent application PCT / US94 / 088
68 and European Patent Application EP 0 623 592 A1 describe the cysteine protease IL-
Disclosed are alkoxymethyl and mercaptomethyl ketones that inhibit 1β convertase. Alkoxymethyl and mercaptomethylketone have also been disclosed as inhibitors of the serine protease kininogenase (International Patent Application
PCT / GB91 / 01479). Azapeptides designed to direct azaamino acids to the serine protease active site and with good leaving groups have been described by Elmore et al., Biochem. J., 1968, 107, 103, Gar.
ker 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., 198.
No. 4,259,4288 and is known to inhibit serine proteases. In addition, J. Med. Chem., 1992, 35, 4279 discloses certain azapeptide esters as cysteine protease inhibitors. Antipain and leupeptin were disclosed as reversible activators of cysteine proteases in McConnell et al., J. Med. Chem., 33, 86;
5 Meth. Enzymol. 678 disclosed as a serine protease inhibitor. E64 and its analogs are also well-known cysteine protease inhibitors (Barrett, Biochem. J., 201, 189 and Grinde, Biochem. Biophys, Acta.,
701, 328). Accordingly, various structurally different cysteine protease inhibitors have been identified. However, these known inhibitors have various drawbacks and are not considered suitable for use as therapeutics for animals, especially humans. These disadvantages include lack of selectivity, cytotoxicity, poor solubility and excessively rapid plasma clearance. Thus, there is a need for methods of treating diseases caused by pathological levels of cysteine proteases, including cathepsins, particularly cathepsin K, and new inhibitor compounds useful in such methods. The present inventors have now discovered a new group of 7-membered 1,3-dioxepin-5-one compounds which are inhibitors of proteases, most particularly cathepsin K.

SUMMARY OF THE INVENTION It is an object of the present invention to provide 7-membered 1,3-dioxepin-5-one protease inhibitors, specifically inhibitors of cysteine and serine proteases, more particularly compounds that inhibit cysteine proteases, and even more. Specifically, it is to provide compounds that inhibit cysteine proteases of the papain superfamily, more particularly compounds that inhibit cysteine proteases of the cathepsin family, and most particularly compounds that inhibit cathepsin K. It is useful for the treatment of diseases that can be modified therapeutically by altering the activity of s. Thus, as 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 present invention provides intermediates useful for 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, even more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K To provide a method for treating a disease whose etiology can be therapeutically modified by inhibiting the disease. In a specific embodiment, the compounds of the present invention may be administered by bone loss such as osteoporosis and gingivitis such as gingivitis and periodontal disease, or excessive cartilage and matrix such as osteoarthritis and rheumatoid arthritis. It is particularly useful for treating diseases characterized by the degradation of

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

Embedded image I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹¹ , R ¹⁶ and R ¹⁷ , and R ′ are independently H, C _A group selected from the group consisting of _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl; R ⁹ is C _3-6 alkyl , Ar, Het, CH (R ¹⁰ ) Ar, CH (R ¹⁰ ) OAr, NR ¹⁰ R ¹¹ , and CH (
R ¹⁰ ) a group selected from the group consisting of NR ¹¹ R ¹² ; R ¹⁰ is H, C _2-6 alkenyl, C _2-6 alkynyl, C _3-11 cycloalkyl-C _0-6 -alkyl, Ar- C _0-6 alkyl, Ar-C _2-6 alkenyl, Ar-C _2-6 alkynyl, Het-C _0-6
Alkyl, Het-C _2-6 alkenyl, Het-C _2-6 alkynyl and optionally OR ¹³ ,
SR ¹³ , NR ¹³ R ¹⁴ , N (R ′) CO ₂ R ′, CO ₂ R ′, CONR ¹³ R ¹⁴ or N (C = NH) consisting of C _1-6 alkyl optionally substituted by NH ₂ R ¹² is R ¹⁵ , R ¹⁵ C (O), R ¹⁵ C (S), R ¹⁵ OC (O) and R ¹⁵ OC (O) NR ¹¹ CH (R ¹⁰ ) (CO R ¹³ and R ¹⁴ are independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl or Het-C _0-6 alkyl R ¹⁵ is a group selected from the group consisting of and R ¹⁶ R ¹⁷ NC _2-6 alkyl; R ¹⁵ is C _1-6 alkyl, C _1-6 alkenyl, Ar-C _0-6 alkyl or Het-C _0-6 alkyl Ar is optionally one or more of Ph-C _0-6 alkyl, Het-C _0-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, Ph -C _0-6 alkoxy, Het-C _0-6 alkoxy, OH, NR ¹³ R ¹⁴ , Het-SC _0-6 alkyl, (CH ₂ ) _1-6 OH, (CH ₂ ) _1-6 NR ¹³ R ¹⁴ _{, O (CH 2) 1- 6} NR 13 R 14, (CH 2) 0-6 C O ₂ R ′, O (CH ₂ ) _1-6 CO ₂ R ′, (CH ₂ ) _{1-6 A} group selected from the group consisting of SO ₂ , CF ₃ , OCF ₃ or phenyl and naphthyl substituted by halogen Ph is optionally one or more C _1-6 alkyl, C _1-6 alkoxy, OH,
(CH ₂ ) _1-6 NR ¹³ R ¹⁴ , O (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , CO ₂ R ′, CF ₃ or optionally substituted with halogen; two C _1-6 alkyl or The C _1-6 alkoxy group may be taken together to form a saturated or unsaturated 5- to 7-membered ring fused with the Ar ring; Het is optionally one or more Ph-C _{0- 6} alkyl, C _1-6 alkyl, C _{1 -6} alkoxy, Ph-C _0-6 ^{alkoxy, OH, NR 13 R 14,} (CH 2) 1-6 OH, (CH 2) 1-6 NR 13 R 1 ⁴ , O (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , (CH ₂ ) _0-6 CO ₂ R ', O (CH ₂ ) _1-6 CO ₂ R', (CH ₂ ) _1-6 SO ₂ , CF _3, OC
F ₃ or halogen may be substituted by (including on the nitrogen); Ph may be optionally substituted with one or more C _1-6 alkyl, C _1-6 alkoxy, OH, (CH _{2) 1- 6} NR ¹³ R ¹⁴
, O (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , CO ₂ R ′, CF ₃ or halogen; two C _1-6 alkyl or C _1-6 alkoxy groups may be taken together. Which may form a saturated or unsaturated 5- to 7-membered ring condensed with a Het ring], and a pharmaceutically acceptable salt thereof.

[0006] Preference is given to compounds of the formula I in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. A particularly preferred embodiment of the invention is a compound of formula I selected from the following group: (6-RS) -6- [N- (N-benzofuran-2-oil-L-leucinyl) amino] -1 , 3-Dioxepin-5-one; (6-RS) -6- [N- [N- (5,6-dimethoxybenzofuran-2-oil) -L-leucinyl] amino
] -1,3-dioxepin-5-one; (6-RS) -6- [N- (N-benzothiophen-2-oil-L-leucinyl) amino] -1,3-dioxepin-5-one; (6-S) -6- [N- [N- (5,6-dimethoxybenzofuran-2-oil) -L-leucinyl] amino]
-1,3-dioxepin-5-one; (6-R) -6- [N- [N- (5,6-dimethoxybenzofuran-2-oil) -L-leucinyl] amino]
-1,3-dioxepin-5-one; (6-RS) -6- [N- [N- (5,6-methylenedioxybenzothiophen-2-oyl) -L-leucinyl] amino] -1, 3-dioxepin-5-one; (6-RS) -6- [N- [N- (5,6-mimethoxybenzothiophen-2-oyl) -L-leucinyl] amino] -1,3-dioxepin- 5-one; and (6-RS) -6- [N- (N-naphtho [1,2-b] thiophen-2-oil-L-leucinyl) amino] -1,3
-Dioxepin-5-on. Specific representative compounds of the present invention are shown in Examples 1 to 8 below.

Definitions The present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of the present invention. Prodrugs are all covalent compounds that release the active parent drug of the formula I in vivo. When asymmetric centers or other forms of isomer centers are present in the compounds of the invention, all isomers, including isomers or enantiomers and diastereomers, are within the scope of the invention. Compounds of the invention containing a chiral center can be utilized as a racemic mixture, enantiomerically enriched mixtures or racemates can be separated using well known techniques, and the individual enantiomers can be used alone. Is also good. When the compound has an unsaturated carbon-carbon double bond, cis (Z) and trans (E)
Both isomers are within the scope of the present invention. Where the compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is either within equilibrium or one form predominant within the scope of the present invention. belongs to. The meaning of any substituent in any one of formula I or any one of its sub formulas is independent of the meaning of the substituent in any other, unless otherwise specified. Abbreviations and symbols used in the peptide and chemical arts are utilized herein to describe the compounds of the invention. In general, the abbreviations for amino acids are Eu
Follow the Joint Commission on Biochemical Nomenclature described in r. J. Biochem., 158, 9 (1984). The term "protease" refers to an enzyme that catalyzes the cleavage of amide bonds in peptides and proteins by nucleophilic substitution at the amide bond, and eventually hydrolyzes. Such proteases include cysteine protease, serine protease,
Includes aspartic proteases and metalloproteases. The compounds of the present invention can bind to enzymes more strongly than substrates and generally do not undergo cleavage after enzyme-catalyzed attack by nucleophiles. Thus, they competitively interfere with the protease from its recognition and hydrolysis of the natural substrate, thereby acting as an inhibitor. 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, serine, threonine, tryptophan, tyrosine. And the D- or L-isomer of valine.

“C _1-6 alkyl” as used herein refers to substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl,
Pentyl, n-pentyl, isopentyl, neopentyl and hexyl are meant to include the simple aliphatic isomers. All C _1-6 alkyl groups, optionally one wife was more ^{OR 13, SR 13, NR 13} R 14, N (R ') CO 2 R', CO 2 R ', CONR 13 R 1 4 or N (C = NH) may be substituted independently by NH _{2. C0} alkyl means that there is no alkyl group in the group. Thus, Ar- C ₀ alkyl is
Same as Ar. “C _3-6 cycloalkyl” as used herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane. “C _2-6 alkenyl” as used herein refers to an alkyl group of 2 to 6 carbons in which a single carbon-carbon bond is replaced with a carbon-carbon double bond. _C2-6 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and some isomers of pentene and hexene. Also included are the cis and trans isomers. “C _2-6 alkynyl” means an alkyl group of 2 to 6 carbons in which one carbon-carbon single bond is replaced by a carbon-carbon triple bond. _C2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne. "Halogen" means F, Cl, Br and I. "Ar" or "aryl", if desired, one or more of Ph-C _0-6 alkyl, Het-C _0-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, Ph-C _{0 -6} alkoxy, Het-C _0-6 alkoxy, OH, NR ¹³ R ¹⁴ , Het-SC _0-6 alkyl, (CH ₂ ) _1-6 OH, (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , O ( (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , (CH ₂ ) _0-6 CO ₂ R ', O (CH ₂ ) _1-6 CO ₂ R', (CH ₂ ) _1-6 S
Phenyl or naphthyl optionally substituted by O ₂ , CF ₃ , OCF ₃ or halogen; Ph is optionally one or more C _1-6 alkyl, C _1-6 alkoxy, OH, ^{_{(CH 2) 1-6 NR 13 R}} 14, O (CH 2) 1-6 NR 13 R 14, CO 2 R ', it may be substituted by a CF ₃ or halogen; two C _1-6 alkyl Alternatively, the C _1-6 alkoxy groups may be taken together to form a saturated or unsaturated 5- to 7-membered ring condensed with an Ar ring. As used herein, “Het” or “heterocyclic” refers to a saturated or unsaturated stable 5 carbon atom and 1-3 heteroatoms selected from the group consisting of N, O and S. Represents a 7-7 membered monocyclic, stable 7-10 membered bicyclic or stable 11-18 membered tricyclic heterocycle, wherein nitrogen and sulfur heteroatoms may be optionally oxidized; The heteroatom may be quaternized if desired,
Includes any bicyclic group wherein any of the heterocycles defined above are fused to a benzene ring. The heterocycle may be attached at any heteroatom or carbon atom to create a stable structure, optionally, Ph-C _0-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, Ph-
C _0-6 alkoxy, OH, NR ¹³ R ¹⁴ , (CH ₂ ) _1-6 OH, (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , O (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , (CH ₂ ) _0-6 CO ₂ R ′, O (CH ₂ ) _1-6 CO ₂ R ′, (CH ₂ ) _1-6 One or more groups selected from SO ₂ , CF ₃ , OCF ₃ or halogen Is optionally substituted with one or more C _1-6 alkyl, C _1-6 alkoxy, OH, (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , O (CH ₂ ) _1-6 optionally substituted with NR ¹³ R ¹⁴ , CO ₂ R ′, CF ₃ or halogen;
Two C _1-6 alkyl or C _1-6 alkoxy groups may together form a saturated or unsaturated 5- to 7-membered ring fused on the heterocycle. Examples of such heterocycles include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidine, 2-oxoazepinyl,
Azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridinyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl, quinolinyl Oxazolyl, furyl,
Pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, benzofuranyl, benzothiophenyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazoli, and stable triazolyl, thiadiazolyl, which are available by ordinary chemical synthesis , Oxadiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyridazinyl, pyrimidinyl, triazinyl and tetrazinyl. The term heteroatom as used herein refers to oxygen, nitrogen and sulfur. Throughout the specification and application, the term C ₀ means that there is no immediate substituent; for example, when C is 0 in an ArC _0-6 alkyl group, the substituent is Ar, for example, phenyl. Conversely, C is interpreted as 0 when the ArC _0-6 alkyl group matches a particular aromatic group, for example, phenyl. Certain radical groups are abbreviated herein. t-Bu means tertiary butyl radical, Boc means t-butyloxycarbonyl radical, Fmoc means fluorenylmethoxycarbonyl radical, Ph means phenyl radical,
Cbz means benzyloxycarbonyl radical. Certain reagents are abbreviated herein. m-CPBA means meta-chloroperbenzoic acid, EDC means N-ethyl-N '(dimethylaminopropyl) -carbodiimide, 1-HOBT means 1-hydroxybenzotriazole, DMF means dimethylformamide , DMSO means dimethylsulfoxide, TEA means triethylamine, TFA means trifluoroacetic acid, and THF means tetrahydrofuran.

Methods of Preparation Compounds of formula I wherein R ^{1 to} R ⁸ are hydrogen are prepared by methods similar to those described in Scheme 1. Scheme 1

Embedded image g) Treatment of Dess-Martin periodinane 4,7-dihydrodioxepin ( 1-Scheme 1 ) with m-CPBA in methylene chloride to give 2-Scheme 1 , which is sodium azide in aqueous methanol and Treatment with ammonium chloride provided 3-Scheme 1 . 3-Scheme 1 is treated with propanedithiol and triethylamine in methanol to give 4 ski beam 1, which, aprotic solvent (such as DMF) Medium carboxylic acid (N-tert
-Butoxycarbonyl-L-leucine) and peptide binding reagents (EDC.
HCl / 1-HOBT) to give 5-Scheme 1 . Alternatively, 3-scheme 1, by treatment with platinum under an atmosphere of hydrogen in methanol catalytic amount (II) oxide can be converted to 4-Scheme 1. 5- Treatment with trifluoroacetic acid in dichloromethane in Scheme 1 gives 6-Scheme 1 which is conjugated with a carboxylic acid (benzofuran-2-carboxylic acid, 5,6-dimethoxybenzofuran) in an aprotic solvent (such as DMF). 7-Scheme treated with 2-carboxylic acid or benzothiophene-2-carboxylic acid) and a peptide binding reagent (such as EDC.HCl / 1-HOBT)
1 was obtained. Treatment of 7-Scheme 1 with Dess-Martin periodinane in methylene chloride provided 8-Scheme 1 .

[0010] The starting material used in the present invention is a commercially available amino acid or a COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-YI (Wiley
It is prepared by routine methods found in standard reference books (Interscience Publishing). The coupling method for forming an amide bond here is a method generally well known in the art. The method of peptide synthesis is described in THE PRACTICE OF PE by Bodansky et al.
PTIDE SYNTHESIS, Springer-Verlag, Berlin, 1884; E. Gross and J. Meienhofer
THE PEPTIDES, Vol. 1, 1-284 (1979); and JMStewart and JDYoung
SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed., Pierce Chemical Co., Rockford, Il
l., 1984, which are general descriptions of the technology and are hereby expressly incorporated herein. Synthetic methods for the preparation of compounds of the present invention frequently employ protecting groups to mask reactive functionality or to minimize unnecessary side reactions. Such protecting groups are generally described in Green, TW, PROTECTIVE GROUPS IN ORGANIC SYNTHESES, Jone Wikey & Son
s, New York (1981). The term "amino protecting group" generally refers to Bo
Refers to c, acetyl, benzoyl, Fmoc and Cbz groups and their derivatives known in the art. . Methods of protection and deprotection and substitution of amino protecting groups with other moieties are well known.

The acid addition salt of the compound of formula I can be prepared by standard methods in a suitable solvent in a suitable solvent such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid. , Maleic acid, succinic acid and methanesulfonic acid. Certain compounds form acceptable inner salts or zwitterions. Cationic salts are prepared by treatment of the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or an appropriate organic amine.
^{Li +, Na +, K +} , Ca ++, Mg ++ and NH ₄ ⁺ in such a cation is a specific example of the cations to provide a pharmaceutically acceptable salt. Halides, sulfates, phosphoates, alkanoates (acetates and trifluoroates), benzoates and sulfonates (such as mesylate) are examples of anions that provide pharmaceutically acceptable salts. The invention also provides a pharmaceutical composition comprising a compound according to Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Thus, the compounds of formula I may be utilized in the manufacture of a medicament. Pharmaceutical compositions of the compound of formula I prepared as described above are formulated for parenteral administration as a solution or lyophilized powder. The powder is reconstituted before use with the addition of a suitable diluent or pharmaceutically acceptable carrier. Liquid formulations may be buffered, isotonic, aqueous solutions. Examples of suitable diluents are standard isotonic saline, standard water or 5% dextrose in buffered sodium or ammonium acetate solution. Such formulations are particularly suitable parenterally, but can also be used for oral administration or in a metered dose inhaler or inhaler nebulizer. The addition of excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate is preferred. Alternatively, these compounds are encapsulated, tableted, or prepared in an emulsion or syrup for oral administration. A pharmaceutically acceptable solid or liquid carrier is
It is added to enhance or stabilize the composition or to facilitate the preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, gypsum, magnesium or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier also contains 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 from about 20 mg to about 20 mg per unit dose.
It is about 1 g. Pharmaceutical formulations are prepared according to the usual pharmaceutical techniques, including powdering, mixing, granulating and compressing, tableting if necessary; or filling for powdering, mixing and hard gelatin capsule formation. When a liquid carrier is used, it will be in the form of a syrup, elixir, emulsion or aqueous or non-aqueous suspension. Such liquid formulations can be administered directly orally or filled into soft gelatin capsules. For rectal administration, the compounds of the invention can also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycol and formed into suppositories.

Uses of the Invention The compounds of formula I are useful as protease inhibitors, in particular as cysteine and serine protease inhibitors, more particularly as cysteine protease inhibitors, even more particularly as cysteine protease inhibitors of the papain superfamily. More particularly, it is useful as a cysteine protease inhibitor of the cathepsin family, most particularly as a cathepsin K inhibitor. Also, the present invention
Provided are useful compositions and formulations of the compounds, including pharmaceutical compositions and formulations of the compounds. The compounds of the present invention involve proteases, especially cysteine proteases, and are associated with schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and Pneumocystis carini (Pne
umocystis carinii), Trypsanoma curuzi, Trypsanoma brucei, and Crisidia fasciculator (C)
rithisia fusiculata), and in particular diseases associated with cathepsin K, most particularly gingival diseases including osteoporosis, gingivitis and periodontal disease,
Arthritis, more particularly osteoarthritis and rheumatoid arthritis, Paget's disease,
It is useful for treating bone and cartilage loss disorders, including malignant hypercalcemia and metabolic bone disorders. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic tumorigenesis are effectively treated with the compounds of the present invention. The present invention provides for the administration of the compounds of the invention to animals, especially mammals, and most particularly humans in need thereof, at pathological levels of proteases, especially cysteine and serine proteases, more particularly cysteine proteases. More particularly, it provides a method for treating a disease caused by a cysteine protease of the cathepsin family, as a cysteine protease inhibitor of the papain superfamily. The present invention is particularly caused by pathological levels of cathepsin K, characterized in that a cathepsin K inhibitor comprising a compound according to the invention is administered to an animal in need thereof, in particular a mammal, most especially a human. A method for treating a disease is provided. The invention relates in particular to schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy and Pneumocystis carinii, Pneumocystis carinii, in which proteases, in particular cysteine proteases, are involved. (Trypsanoma
curuzi), diseases including infections by trypsanoma brucei and Crithisia fusiculata, and especially those involving cathepsin K, most particularly osteoporosis, gingivitis and periodontal disease The present invention provides a method for treating bone and cartilage loss diseases including gingival disease, arthritis, more particularly osteoarthritis and rheumatoid arthritis, and Paget's disease, malignant hypercalcemia and metabolic bone disease.

Further, the present invention provides a method for treating an effective amount of a compound of Formula I, alone or in combination with other bone resorption inhibitors such as bisphosphonates (eg, alendronate), hormone exchange therapy, antiestrogens or calcitonin. To a method for treating osteoporosis or suppressing bone loss, characterized by administering to a subject. In addition, treatment with a compound of the present invention and an anabolic agent such as the bone morphogenetic protein, iproflavone can be used to prevent bone loss or increase bone mass. For acute treatment, parenteral administration of the compounds of formula I is preferred. Intravenous infusion of the compound in 5% dextrose in water or saline or similar formulation with appropriate excipients is most effective, but intramuscular bolus injection is also useful.
Typically, parenteral dosages will be between about 0.01 and about 100 mg / kg, preferably between 0.1 and 20 mg / kg, to maintain the drug concentration in the plasma at an effective cathepsin K inhibitory concentration. The compounds are administered one to four times daily, for a total daily dosage of about 0.4 to 400 mg / kg / day. The exact amount of the compound of the invention that is therapeutically effective and the best route of administration for the compound will be readily determined by one of ordinary skill in the art by comparing blood levels of the drug to therapeutically effective concentrations. The compounds of the invention may also be administered orally to a patient in a manner such that the drug concentration inhibits bone resorption or achieves the other therapeutic indications disclosed herein. Typically, a pharmaceutical composition containing the compound will be administered orally at between about 0.1 and about 50 mg / kg in a manner consistent with the condition of the patient. Preferably, the oral dosage is about 0.
5 to about 20 mg / kg. When the compounds of the present invention are administered in accordance with the present invention, there can be expected no unacceptable toxic effects.

Biological Assays The compounds of the present invention can be tested in one of several biological assays to determine the concentration of a compound required to have a given pharmacological effect. Determination of Cathepsin K Proteolytic Catalytic Activity All assays for cathepsin K were performed with human recombinant enzymes. Standard analytical conditions for measuring rate constants are fluorogenic peptide substrates, typically Cbz-
Using Phe-Arg-AMC, pH 5.5 containing 20 mM cysteine and 5 mM EDTA.
Measured in 00 mM sodium acetate. Stock substrate solutions were prepared at a concentration of 10 or 20 mM in DMSO with an analytical final substrate concentration of 20 μM. All analyzes contained 10% DMSO. Independent experiments showed that this level of DMSO did not affect enzyme activity or rate constants. All analyzes were performed at room temperature. Product fluorescence (
(Excitation at 360 nM; emission at 460 nM) was monitored by a Perceptive Biosystems Cytofluor II fluorescence plate reader. A product progress curve occurred over 20-30 minutes following formation of the AMC product.

Inhibition Studies Potential inhibitors were evaluated using the progress curve method. The analysis was performed in the presence of various concentrations of the test compound. The reaction was initiated by the addition of an enzyme inhibitor and substrate to the buffer solution. Data analysis was performed by one of two procedures, depending on the appearance of the progress curve in the presence of the inhibitor. The apparent inhibition constant (Ki, app) of the compound whose progress curve was linear was calculated by Equation 1 (Br
andt et al., Biochemistry, 1989, 28, 140): ν = VmA / [Ka (1 + I / Ki, app) + A] (1) where ν is the reaction rate at which the maximum rate is Vm, A is the substrate concentration of Michaelis constant Ka, and I is the inhibitor concentration. For compounds whose progress curves showed a downward curve characteristic of time-dependent inhibition, the data from the individual sets were analyzed by equation 2 to obtain k _obs . [AMC] = ν _ss + (ν ₀ −ν _ss ) [1-exp (−k _obs t)] / k _obs (2) where [AMC] is the concentration of the product formed up to time t , V ₀ is the initial reaction velocity and v _ss is the final steady state velocity. The value of k _obs was analyzed as a linear function of inhibitor concentration, _yielding an apparent second-order rate constant (k _obs / inhibitor concentration or k _obs / [I]) describing time-dependent inhibition. All discussions of this speed handling are well documented (M
orrion et al., Adv. Enzymol. Relat. Areas Mol. Biol., 1988, 61, 201).

Human Osteoclast Resorption Assay A portion of the cell suspension derived from osteoclasts is removed from liquid nitrogen storage, rapidly warmed at 37 ° C, and centrifuged in RPMI-1640 medium (1000 rpm, 5 minutes, 4 ° C). ). The medium was aspirated and replaced with the murine anti-HLA-DR antibody, diluted 1: 3 in RPMI-1640 medium and incubated on ice for 30 minutes. The cell suspension was mixed frequently. Cells were washed twice with cold RPMI-1640 by centrifugation (1000 rpm, 5 minutes, 4 ° C.) and transferred to sterile 15 mL centrifuge tubes. Mononuclear cell numbers were counted in a Neubauer improved calculator plate calculation chamber. Remove enough magnetic beads (5 / mononuclear cells) coated with goat anti-mouse IgG from storage bottle and in 5 mL of fresh medium, which has been washed with toxic azide preservative
Placed. 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 on the beads were fixed on a magnet, and the remaining cells (osteoblast-rich fraction) were decanted into a sterile 50 mL centrifuge tube.
Fresh media was added to the cells coated on the beads to remove any trapped osteoclasts. This washing step was repeated 10 times. Bead coated cells were discarded. The osteoclasts were counted using a large hole disposable plastic Pasteur pipette, filling the sample into the chamber and counting in a counting chamber. Cells were pelleted by centrifugation and the density of osteoclasts was adjusted to 15 × 10 ⁴ / mL in EMEM medium.
Supplemented with 10% fetal calf serum and 1.7 g / l sodium bicarbonate.
Each 3 mL of cell suspension (per treatment) was decanted into a 15 mL centrifuge tube. Cells were pelleted by centrifugation. 3 mL of the treatment was added to each tube as appropriate (EM
Diluted to 50 μM in EM medium). In addition, an appropriate vehicle control and a positive control (10
87MEM1 diluted to 0 μM / mL) and an isotype control (IgG2a diluted to 100 uM / mL) were included. The tubes were incubated at 37 ° C. for 30 minutes. Pour 0.5 mL aliquots of cells onto sterile dentin sections in a 48-well plate.
The cells were cultured at 7 ° C for 2 hours. Each treatment was screened in quadruplicate. Sections were prepared using warm PBS (
Washed with 6 changes of 10 mL / well in a 6-well plate, then placed in fresh treatments or controls and incubated at 37 ° C for 48 hours. Sections are washed with phosphate-buffered saline, fixed with 2% glutaraldehyde (in 0.2 M sodium cacodylate) for 5 minutes, then washed with water and cultured in buffer solution at 37 ° C. for 5 minutes did. Sections were washed with cold water and cold buffered acetic acid solution / fast red garnet (fast r
ed garnet) for 5 minutes at 4 ° C. Remove excess buffer,
The sections were washed with water and dried with air. TRAP-positive osteoclasts were counted with a bright-field microscope and then removed from the dentin surface by sonication. Pit volumes were measured using a Nikon / Lasertec ILM21W confocal microscope.

General Nuclear magnetic resonance spectra were recorded at 250 or 400 MHz using a Bruker AM 250 or Bruker AC 400 spectrometer, respectively. CDCl ₃ is heavy chloroform, DMSO-d ₆ is heavy (hexadeuterio) dimethyl sulfoxide, and CD ₃ OD is heavy (tetradeuterio)
Methanol. Chemical shift is 100 from the internal standard tetramethylsilane.
(D) Recorded in parts per downfield. The abbreviations for NMR are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet, dt = doublet of triplet, ap
p = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectrum
) Is a Perkin-Elmer 683 infrared spectrometer with a Fourier transform infrared spectrum (Fourier
Transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in the transfer mode and were recorded in inverse wavenumber (cm ^-1 ). Mass spectroscopy used either VG 70 FE, PE Syx API III or VG ZAB HF instruments and used fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analysis is Perkin-Elm
Measured using an er 240C elemental analyzer. Melting points were measured using a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures were recorded in degrees Celsius. Analtech Silica Gel GF and Merck Silica Gel 60 F-254 Thin Film
Used for thin film chromatography. Both flash and gravity chromatography were performed on Merck Kieselgel 60 (230-400 mesh) silica gel. Certain materials shown here were purchased from Aldrich Chemical, Milwaukee, Chemical Dynamics Scorp, South Plainfield, New Jersey and Advanced Chemtech, Louisville, Kentucky.

EXAMPLES In the following synthetic examples, the temperatures are in degrees Celsius (° C.). Unless otherwise noted, all starting materials were obtained from commercial sources. Without further elaboration, one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. These examples illustrate the invention and do not limit the scope of the invention. See the claims for what we have.

Example 1 (6-RS) -6- [N- (N-benzofuran-2-oil-L-leucine) amino]
Preparation of -1,3-dioxepin-5-one a) 5,6-Epoxy-1,3-dioxepin cis-4,7-dihydro-1,3-dioxepin (5.0 g) in dichloromethane (300 mL) at 0 ° C. , 49.9 mmol, 4.77 mL) was added meta-chloroperoxybenzoic acid (22.0 g, 74.9 mmol). The mixture was warmed to room temperature and stirred for 16 hours. The solution was then washed successively with 0.5N NAOH (2 ×), water and brine. Dry the organic layer (MgSO ₄ ), filter and concentrate to give the title compound as a white solid (2.06 g, 36%). ¹ H NMR (400 MH
_{z, CDCL 3) δ4.87 (d} -1H), 4.45 (d-1H), 4.24 (dd-2
H), 4.02 (dd, 2H), 3.23 (dd, 2H). b) 5-azido-6-hydroxy-1,3-dioxepine _{MeOH / H 2 O (8:} 1,36mL) in the compound of Example 1 (a) (2.06g, 17.8
mmol), ammonium chloride (2.85 g, 53.3 mmol) was added, followed by sodium azide (3.46 g, 53.3 mmol). After stirring at reflux for 16 hours, the solution was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, then dried (MgSO _4), filtered, concentrated and the title compound of off-white and solid (1.49 g, 53%) was obtained as a. ¹ H NMR (400 MHz, CDCL ₃ ) δ 4.5
5 (dd-2H), 3.82 (bs-1H), 3.72-3.51 (m-5H),
3.32 (m, 1H).

C) 5-Amino-6-hydroxy-1,3-dioxepin To a stirred solution of the compound of Example 1 (b) (1.38 g, 8.7 mmol) in MeOH (44 mL) was added triethylamine (2.64 g). , 26.1 mmol, 3.6 mL), then 1
3-Propanedithiol (2.82 g, 26.1 mmol, 2.6 mL) was added. After stirring at room temperature for 16 hours, the solution was dried at 60 ° C. under reduced pressure to give the title compound as a yellow oil (1.16 g, 100%). MS (ESI): 133.8 (M + H) ^<+> . d) trans-5- [N- (N-tert-butoxycarbonyl-L-leucine) amino]
-1,3-Dioxepin-6-ol The compound of Example 1 (c) (1.16 g, 8.7 mmol) in DMF (20 mL), N-tert
To a stirred solution of -butoxycarbonyl-L-leucine (2.5 g, 9.57 mmol) and 1-hydroxybenzotriazole (0.235 g, 1.74 mmol) was added 1-
(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.8 g,
9.57 mmol) was added. After stirring at room temperature for 16 hours, the solution was diluted with ethyl acetate,
Washed successively with saturated aqueous sodium bicarbonate, water (2 ×) and brine.
The organic layer was dried (MgSO _4), filtered, and concentrated. The residue was purified by column chromatography (silica gel; ethyl acetate / hexane) to give the title compound as a white solid (2
. 86 g, 87%). MS (ESI): 381.2 (M + H) ^<+> . e) trans-5- [N- (L-leucine) amino] -1,3-dioxepin-6
All Compound of Example 1 (d) (3.04 g, 8.00 mmol) in ethyl acetate (50 mL)
To the solution was added 10% palladium on carbon (1.5 g). After stirring at room temperature under a hydrogen atmosphere for 16 hours, the mixture was filtered through celite. The filtrate was concentrated to give the title compound as a yellow oil (1.97 g, 100%). MS (ESI): 247.3
(M + H) ⁺ .

F) trans-5- [N- (N-benzofuran-2-oil-L-leucine) amino) -1,3-dioxepin-6-ol The compound of Example 1 (e) in DMF (3 mL) (0.200 g, 0.816 mmol), benzofuran-2-carboxylic acid (0.146 g, 0.898 mmol) and 1-hydroxybenzotriazole (0.022 g, 0.163 mmol) in a stirred solution.
-(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.172 g, 0.898 mmol) was added. After stirring at room temperature for 16 hours, the solution was diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate, water (2x) and brine. The organic layer was dried (MgSO _4), filtered, and concentrated. The residue was purified by column chromatography (silica gel; methanol / dichloromethane) to give the title compound as a white solid (0.296 g, 93%). MS (ESI): 391
(M + H) ⁺ . g) (6-RS) -6- [N- (N-benzofuran-2-oil-L-leucine) amino] -1,3-dioxepin-5-one of Example 1 (f) in dichloromethane (4 mL). Compound (0.296 g, 0.759
mmol) was added Dess-Martin reagent (0.483 g, 1.13 mmol). After stirring at room temperature for 2 hours, a solution of sodium thiosulfate (2 mL of 10% in water) and saturated aqueous sodium bicarbonate (2 mL) was added to the solution as well. The aqueous phase was extracted with dichloromethane (2x). Combine the organic phases, wash with brine and dry (Mg
SO ₄ ), filtered and concentrated. The residue was subjected to column chromatography (silica gel;
Purify with ethyl acetate / hexane to give the title compound as a white solid (0.290 g, 98
%). MS (ESI): 388.7 (M + H) ^<+> .

Example 2 (6-RS) -6- [N- [N- (5,6-dimethoxybenzofuran-2-oil)-
Preparation of L-leucinyl] amino] -1,3-dioxepin-5-one Following the procedure of Examples 1 (a) to 1 (g), except that the benzofuran-2-carboxylic acid of step (f) was replaced with dimethoxybenzofuran The title compound was prepared as a white solid (0.247 g, 92%) by replacing the 2-carboxylic acid. MS
(ESI): 448.8 (M + H) ^<+> .

Example 3 Preparation of (6-RS) -6- [N- [N-benzothiophen-2-oil-L-leucinyl) amino] -1,3-dioxepin-5-one Example 1 (a) ) To 1 (g), except that the benzofuran-2-carboxylic acid of step (f) is replaced by benzothiophene-2-carboxylic acid to give the title compound as a white solid (0.147 g, 77%). Prepared as MS (ESI)
: 405.1 (M + H) ^<+> .

Example 4 Preparation of 6- [N- [N- (5,6-dimethoxybenzofuran-2-oil) -L-leucinyl] amino] -1,3-dioxepin-5-one Obtained by liquid chromatography purification of the compound of Example 2 (
(R, R) Whelk-O column; 30: 70-ethanol: hexane). R _T 14.25m
in, MS (ESI): 448.8 (M + H) ⁺ .

Example 5 Preparation of 6- [N- [N- (5,6-dimethoxybenzofuran-2-oil) -L-leucinyl] amino] -1,3-dioxepin-5-one Obtained by liquid chromatography purification of the compound of Example 2 (
(R, R) Whelk-O column; 30: 70-ethanol: hexane). R _T 16.57m
in, MS (ESI): 448.8 (M + H) ⁺ .

Example 6 6- [N- [N- (5,6-methylenedioxybenzothiophene-2-oil) -L
Preparation of -leucinyl] amino] -1,3-dioxepin-5-one Following the process of Examples 1 (a) to 1 (g), the benzofuran-2-
The title compound was prepared as a white solid (0.080 g, 95%) by replacing the carboxylic acid with methylenedioxybenzothiophene-2-carboxylic acid. MS (ESI): 448.79 (M + H) ^<+> . Example 7 Preparation of (6-RS) -6- [N- [N- (5,6-dimethoxybenzothiophen-2-oyl) -L-leucinyl] amino] -1,3-dioxepin-5-one. Following the procedure of Examples 1 (a) -1 (g), except that the benzofuran-
The title compound was prepared as a white solid (0.068 g, 61%) by replacing the 2-carboxylic acid with 5,6-dimethoxybenzothiophene-2-carboxylic acid. MS (ESI): 464.8 (M + H) ^<+> .

Example 8 (6-RS) -6- [N- (N-naphtho [1,2-b] thiophen-2-oil-L-leucinyl) amino] -1,3-dioxepin-5-one Following the procedure of Examples 1 (a) to 1 (g), except that the benzofuran-
The title compound was prepared as a white solid (0.07 g, 51%) by replacing the 2-carboxylic acid with naphtho [1,2-b] thiophene-2-carboxylic acid. M
S (ESI): 454.7 (M + H) ^<+> .

The above description 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, and all modifications thereof are within the scope of the claims herein. The various magazines, patents, and other publications cited herein constitute prior art and are hereby incorporated by reference in their entirety.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 19/10 A61P 19/10 29/00 101 29/00 101 43/00 105 43/00 105 111 111 C07D 409/12 C07D 409/12 (81) Designated country 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, TZ, UA, US, UZ, VN, YU, ZA (72) Inventor Daniel Frank Baber United States of America 19002 Beiterson Road, Ambler, PA, No. 290 (72) Inventor Stacy Marie Halbert United States 19438 Harleysville, PA, Montgomery Drive No. 149 (72) Inventor Sirishkumar Nida Marcy United States 19333 Devon, PA, United States Number G 230, Avon Road 291 F-term (reference) 4C063 AA01 BB09 CC80 CC94 DD75 DD76 DD80 4C086 AA01 AA02 AA03 BA10 BB03 GA02 GA04 MA01 MA04 NA14 ZA67 ZA96 ZA97 ZB15 ZC20

Claims (35)

[Claims] (1) Formula (I): I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹¹ , R ¹⁶ and R ¹⁷ , and R ′ are
A group independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, Ar-C _0-6 alkyl and Het-C _0-6 alkyl; R ⁹ Is C _3-6 alkyl, Ar, Het, CH (R ¹⁰ ) Ar, CH (R ¹⁰ ) OAr, NR ¹⁰ R ¹¹ , and CH (
R ¹⁰ ) a group selected from the group consisting of NR ¹¹ R ¹² ; R ¹⁰ is H, C _2-6 alkenyl, C _2-6 alkynyl, C _3-11 cycloalkyl-C _0-6 -alkyl, Ar- C _0-6 alkyl, Ar-C _2-6 alkenyl, Ar-C _2-6 alkynyl, Het-C _0-6
Alkyl, Het-C _2-6 alkenyl, Het-C _2-6 alkynyl and optionally OR ¹³ ,
SR ¹³ , NR ¹³ R ¹⁴ , N (R ′) CO ₂ R ′, CO ₂ R ′, CONR ¹³ R ¹⁴ or N (C = NH) consisting of C _1-6 alkyl optionally substituted by NH ₂ R ¹² is R ¹⁵ , R ¹⁵ C (O), R ¹⁵ C (S), R ¹⁵ OC (O) and R ¹⁵ OC (O) NR ¹¹ CH (R ¹⁰ ) (CO R ¹³ and R ¹⁴ are independently H, C _1-6 alkyl, C _2-6 alkenyl, Ar-C _0-6 alkyl or Het-C _0-6 alkyl R ¹⁵ is a group selected from the group consisting of and R ¹⁶ R ¹⁷ NC _2-6 alkyl; R ¹⁵ is C _1-6 alkyl, C _1-6 alkenyl, Ar-C _0-6 alkyl or Het-C _0-6 alkyl group is selected from the group consisting of; Ar is optionally one or more of Ph-C _0-6 alkyl, Het-C _0-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, Ph- C _0-6 alkoxy, Het-C _0-6 alkoxy, OH,
NR ¹³ R ¹⁴ , Het-SC _0-6 alkyl, (CH ₂ ) _1-6 OH, (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , O (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , (CH ₂ ) _0-6 CO ₂ R ′, O (CH ₂ ) _1-6 CO ₂ R ′, (CH ₂ ) _1-6 SO ₂ , CF ₃ , OCF ₃ or phenyl and naphthyl optionally substituted with halogen Ph is optionally one or more C _1-6 alkyl, C _1-6 alkoxy, OH, (C
H ₂ ) _1-6 NR ¹³ R ¹⁴ , O (CH ₂ ) _1-6 NR ¹³ R ¹⁴ , CO ₂ R ′, CF ₃ or halogen; two C _1-6 alkyl or C _1-6 alkoxy groups may be taken together to form a saturated or unsaturated 5- to 7-membered ring condensed with an Ar ring] and pharmaceutically acceptable salts thereof. 2. The compound according to claim ¹ , wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are H. (3) (6-RS) -6- [N- (N-benzofuran-2-oil-L-leucinyl) amino] -1,3-dioxepin-5-one; (6-RS) -6- [N- [N- (5,6-dimethoxybenzofuran-2-oil) -L-leucinyl] amino
] -1,3-dioxepin-5-one; (6-RS) -6- [N- (N-benzothiophen-2-oil-L-leucinyl) amino] -1,3-dioxepin-5-one; (6-S) -6- [N- [N- (5,6-dimethoxybenzofuran-2-oil) -L-leucinyl] amino]
-1,3-dioxepin-5-one; (6-R) -6- [N- [N- (5,6-dimethoxybenzofuran-2-oil) -L-leucinyl] amino]
-1,3-dioxepin-5-one; (6-RS) -6- [N- [N- (5,6-methylenedioxybenzothiophen-2-oyl) -L-leucinyl] amino] -1, 3-dioxepin-5-one; (6-RS) -6- [N- [N- (5,6-mimethoxybenzothiophen-2-oyl) -L-leucinyl] amino] -1,3-dioxepin- 5-one; and from (6-RS) -6- [N- (N-naphtho [1,2-b] thiophen-2-oil-L-leucinyl) amino] -1,3-dioxepin-5-one The compound of claim 1, wherein the compound is selected from the group consisting of: 4. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient. 5. A pharmaceutical composition comprising the compound according to claim 3, and a pharmaceutically acceptable carrier, diluent or excipient. 6. A method for inhibiting a protease selected from the group consisting of cysteine protease and serine protease, which comprises administering an effective amount of the compound according to claim 1 to a patient in need thereof. 7. A method for inhibiting a protease selected from the group consisting of cysteine protease and serine protease, which comprises administering an effective amount of the compound according to claim 3 to a patient in need thereof. 8. The method according to claim 6, wherein said protease is a cysteine protease. 9. The method according to claim 7, wherein said protease is a cysteine protease. 10. The method according to claim 8, wherein said cysteine protease is cathepsin K. 11. The method according to claim 9, wherein the cysteine protease is cathepsin K. 12. A method for treating a disease characterized by bone loss, which comprises administering an effective amount of the compound according to claim 1 to a patient in need thereof to suppress bone loss. 13. The method according to claim 12, wherein said disease is osteoporosis. 14. The method according to claim 12, wherein said disease is periodontal disease. 15. The method according to claim 12, wherein the disease is gingivitis. 16. Characterization of excessive cartilage or matrix matrix degradation characterized by administering an effective amount of a compound of claim 1 to a patient in need thereof to inhibit excessive cartilage or matrix matrix degradation. To treat the disease. 17. The method according to claim 16, wherein said disease is osteoporosis. 18. The method according to claim 16, wherein said disease is rheumatoid arthritis. 19. A method for treating a disease characterized by bone loss, which comprises administering an effective amount of the compound of claim 3 to a patient in need thereof to suppress bone loss. 20. The method according to claim 19, wherein the disease is osteoporosis. 21. The method according to claim 19, wherein said disease is periodontal disease. 22. The method according to claim 19, wherein the disease is gingivitis. 23. An excessive amount of cartilage or matrix deterioration characterized in that an effective amount of the compound according to claim 3 is administered to a patient in need thereof to suppress excessive cartilage or matrix matrix deterioration. How to treat the disease. 24. The method according to claim 23, wherein the disease is osteoporosis. 25. The method according to claim 23, wherein the disease is rheumatoid arthritis. 26. The method according to claim 1, wherein the preparation is for inhibiting a protease selected from the group consisting of cysteine protease and serine protease.
(3) Use of the compound according to any one of (3). 27. The use according to claim 26, wherein said protease is a cysteine protease. 28. The use according to claim 27, wherein said cysteine protease is cathepsin K. 29. Use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for use in the treatment of a disease characterized by bone loss. 30. The use according to claim 29, wherein said disease is osteoporosis. 31. The use according to claim 29, wherein said disease is periodontal disease. 32. The use according to claim 29, wherein said disease is gingivitis. 33. Use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for use in the treatment of a disease characterized by excessive cartilage or matrix matrix degradation. 34. The use according to claim 33, wherein said disease is osteoporosis. 35. The use according to claim 33, wherein said disease is rheumatoid arthritis.