WO2000048603A1 - DIBENZO-AZEPINE DERIVATIVES AS αV INTEGRIN RECEPTOR ANTAGONISTS - Google Patents

Abstract

The present invention relates to dibenzo-azepine derivatives and their use as alphaV integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors alphaVbeta3, alphaVbeta5, and/or alphaVbeta6 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, wound healing, viral disease, tumor growth, and metastasis.

Description

TITLE OF THE INVENTION

DLBENZO-AZEPINE DERIVATIVES AS αV INTEGRIN RECEPTOR

ANTAGONISTS

FIELD OF THE INVENTION

The present invention relates to dibenzo-azepine deπvatives, their synthesis, and their use as αv integπn receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integπn receptors ccvβ3, ocvβ5, and/or αvβό and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, wound healing, viral disease, tumor growth, and metastasis.

BACKGROUND OF THE INVENTION It is believed that a wide vaπety of disease states and conditions can be mediated by acting on integπn receptors and that integπn receptor antagonists represent a useful class of drugs. Integπn receptors are heterodimeπc transmembrane receptors through which cells attach and communicate with extracellular matnces and other cells. (See S.B. Rodan and G.A. Rodan, "Integπn Function In Osteoclasts", Journal of Endocrinology, Vol. 154, S47- S56 (1997), which is incorporated by reference herein in its entirety).

In one aspect of the present invention, the compounds herein are useful for inhibiting bone resorption. Bone resorption is mediated by the action of cells known as osteoclasts. Osteoclasts are large mult ucleated cells of up to about 400 mm in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. Osteoclasts are actively motile cells that migrate along the surface of bone, and can bind to bone, secrete necessary acids and proteases, thereby causing the actual resorption of mineralized tissue from the bone. More specifically, osteoclasts are believed to exist in at least two physiological states, namely, the secretory state and the migratory or motile state. In the secretory state, osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polaπzed, form a ruffled border, and secrete lysosomal enzymes and protons to resorb bone. The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the migratory or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption until they again attach to bone αv Integπns are involved osteoclast attachment, activation and migration The most abundant αv integrin in osteoclasts, e.g., in rat, chicken, mouse and human osteoclasts, is an integπn receptor known as αvβ3, which is thought to interact in bone with matπx proteins that contain the RGD sequence Antibodies to αvβ3 block bone resorption in vitro indicating that this integrin plays a key role in the resorptive process. There is increasing evidence to suggest that αvβ3 ligands can be used effectively to inhibit osteoclast mediated bone resorption in vivo in mammals. The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, peπodontal disease, hyperparathyroidism, peπarticular erosions in rheumatoid arthπtis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis. All of these conditions are characterized by bone loss, resulting from an imbalance between bone resorption, i.e. breakdown, and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site; for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year vertebrae immediately following menopause, a condition which leads to increased fracture πsk. In the United States, there are currently about 20 million people with detectable fractures of the vertebrae due to osteoporosis In addition, there are about 250,000 hip fractures per year attπbuted to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture. Individuals suffenng from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.

Additionally, αvβ3 ligands have been found to be useful in treating and/or inhibiting restenosis, i.e. recurrence of stenosis after corrective surgery on the heart valve, atherosclerosis, diabetic retinopathy, macular degeneration, and angiogenesis, i.e. formation of new blood vessels, and inhibiting viral disease.

Moreover, it has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor, thus, inhibition of angiogenesis can cause tumor regression in animal models (See Harrison's Pnnciples of Internal Medicine, 12th ed., 1991, which is incorporated by reference herein in its entirety). Therefore, αvβ3 antagonists which inhibit angiogenesis can be useful in the treatment of cancer by inhibiting tumor growth (See, e.g., Brooks et al., Cell, 79:1157-1164 (1994), which is incorporated by reference herein in its entirety). Moreover, compounds of this invention can also inhibit neovasculaπzation by acting as antagonists of the integπn receptor, αvβ5. A monoclonal antibody for αvβ5 has been shown to inhibit VEGF-induced angiogenesis in rabbit cornea and the chick choπoallantoic membrane model (See M.C Fπedlander, et.al., Science 270: 1500-1502 (1995), which is incorporated by reference herein in its entirety). Thus, compounds that antagonize αvβ5 are useful for treating and preventing macular degeneration, diabetic retinopathy, tumor growth, and metastasis

Additionally, compounds of the instant invention can inhibit angiogenesis and inflammation by acting as antagonists of the integπn receptor, αvβ6, which is expressed dunng the later stages of wound healing and remains expressed until the wound is closed (See Chπstofidou-Solomidou, et al., "Expression and Function of Endothehal Cell αv Integπn Receptors in Wound-Induced Human Angiogenesis in Human Skin/SCLD Mice Chimeras, Amencan Journal of Pathology, Vol. 151, No. 4, pp. 975-983 (October 1997), which is incorporated by reference herein in its entirety). It is postulated that αvβ6 plays a role in the remodeling of the vasculature duπng the later stages of angiogenesis. Also, αvβ6 participates in the modulation of epithelial inflammation and is induced m response to local injury or inflammation (See Xiao-Zhu Huang, et al., "Inactivation of the Integπn β6 Subunit Gene Reveals a Role of Epithelial Integπns in Regulating Inflammation in the Lungs and Skin," Journal of Cell Biology, Vol. 133, No.4, pp 921-928 (May 1996), which is incorporated by reference herein in its entirety). Accordingly, compounds that antagonize αvβ6 are useful in treating or preventing cancer by inhibiting tumor growth and metastasis.

In addition, certain compounds of this invention antagonize both the αvβ3 and αvβ5 receptors. These compounds, referred to as "dual αvβ3/αvβ5 antagonists," are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, viral disease, tumor growth, and metastasis. In addition, certain compounds of this invention are useful as mixed αvβ3, αvβ5, and αvβό receptor antagonists.

Peptidyl as well as peptidomimetic antagonists of the αvβ3 integπn receptor have been descnbed both in the scientific and patent literature For example, reference is made to W.J. Hoekstra and B.L. Poulter, Curr. Med. Chem. 5: 195-204 (1998) and references cited therein; WO 95/32710, WO 95/37655; WO 97/01540, WO 97/37655; WO 98/08840; WO 98/18460; WO 98/18461 ; WO 98/25892; WO 98/31359; WO 98/30542; EP 853084; EP 854140; EP 854145; and US Patent No 5,780,426. Evidence of the ability of αvβ3 integπn receptor antagonists to prevent bone resorption in vitro and in vivo has been presented (see V.W. Engleman et al, "A Peptidomimetic Antagonist of the αvβ3 Integπn Inhibits Bone Resorption inVitro and Prevents Osteoporosis in Vivo," J Clin. Invest 99. 2284-2292 (1997); S.B. Rodan et al., "A High Affinity Non-Peptide αvβ3 Ligand Inhibits Osteoclast Activity In Vitro and InVivo " J. Bone Miner. Res. 11 : S289 (1996); J.F. Gourvest et al., "Prevention of OVX-Induced Bone Loss With a Non-peptidic Ligand of the αvβ3 Vitronectin Receptor," Bone 23: S612 (1998); M.W. Lark et al., "An Orally Active Vitronectin Receptor αvβ3 Antagonist Prevents Bone Resorption In Vitro and In Vivo the Ovaπectomized Rat," Bone 23: S219 (1998)).

The αvβ3 integπn receptor recognizes the Arg-Gly-Asp (RGD) tπpeptide sequence in its cognate matπx and cell surface glycoproteins (see J. Samanen, et al., "Vascular Indications for Integπn αv Antagonists," Curr. Pharmaceut. Design 3: 545-584 (1997)). A benzazepine nucleus has been employed among others by Genentech and SmithKline Beecham as a conformationally constrained Gly-Asp mimetic to elaborate nonpeptide αvβ3 integπn receptor antagonists substituted at the N-termmus with heterocyclic arginme mimetics (see R.M. Keenan et al, "Discovery of Potent Nonpeptide Vitronectin Receptor (αvβ3) Antagonists," J. Med. Chem. 40: 2289-2292 (1997); R.M. Keenan et al., "Benzimidazole Deπvatives As Arginme Mimetics in 1,4-Benzodιazepιne Nonpeptide Vitronectin Receptor (αvβ3) Antagonists," Bioorg. Med. Chem. Lett. 8- 3165-3170 (1998); and R.M. Keenan et al., "Discovery of an Imidazopyπdine-

Contaimng 1,4-Benzodιazepιne Nonpeptide Vitronectin Receptor (αvβ3) Antagonist With Efficacy in a Restenosis Model," Bioorg. Med. Chem. Lett. 8: 3171-3176 (1998). Patents assigned to SmithKlme Beecham that disclose such benzazepme- based αvβ3 integπn receptor antagonists include WO 96/00574, WO 96/00730, WO 96/06087, WO 96/26190, WO 97/24119, WO 97/24122, WO 97/24124, and WO 98/15278 and to Genentech include WO 97/34865. The dibenzocycloheptene nucleus has also been employed as a Gly-Asp mimetic to afford αvβ3 antagonists (see WO 97/01540 and WO 98/30542 both assigned to SmithKline Beecham). However, there still remains a need for small-molecule, selective αv integrin receptor antagonists that display improved potency, pharmacodynamic, and pharmacokinetic properties, such as oral bioavailability and significant duration of action. Such compounds would prove to be useful for the treatment, prevention, or suppression of various pathologies enumerated above that are mediated by αv binding and cell adhesion and activation.

It is therefore an object of the present invention to provide dibenzo- azepine derivatives which are useful as αv integrin receptor antagonists.

It is another object of the present invention to provide dibenzo-azepine derivatives which are useful as αvβ3 receptor antagonists.

It is another object of the present invention to provide dibenzo-azepine derivatives which are useful as αvβ5 receptor antagonists. It is another object of the present invention to provide dibenzo-azepine derivatives which are useful as αvβό receptor antagonists.

It is another object of the present invention to provide dibenzo-azepine derivatives which are useful as dual αvβ3/αvβ5 receptor antagonists.

It is another object of the present invention to provide dibenzo-azepine derivatives which are useful as mixed αvβ3, αvβ5, and αvβό receptor antagonists.

It is another object of the present invention to provide pharmaceutical compositions comprising αv integrin receptor antagonists.

It is another object of the present invention to provide methods for making the pharmaceutical compositions of the present invention. It is another object of the present invention to provide methods for eliciting an αv integrin receptor antagonizing effect in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.

It is another object of the present invention to provide compounds and pharmaceutical compositions useful for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, tumor growth, and metastasis.

It is another object of the present invention to provide compounds and pharmaceutical compositions useful for treating osteoporosis. It is another object of the present invention to provide methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, tumor growth, and metastasis It is another object of the present invention to provide methods for treating osteoporosis.

These and other objects will become readily apparent from the detailed descπption which follows.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I

(I)

or a pharmaceutically acceptable salt thereof,

wherein U and V each independently represent N or CR6, provided that no more than one U represents N and no more than one V represents N;

X is O; S(O)0-2; NR4; or CR1R2;

Y is selected from the group consisting of

-(CH₂)0-4-,

-(CH₂)0-4-O-(CH₂)l-4-, -(CH₂)0-4-NR⁴-(CH₂)l-4-, -(CH2)0-4-S-(CH2)l-4-, -(CH )0-4-SO-(CH₂)i-4-,

-(CH2)0-4-SO₂-(CH₂)l-4-,

-(CH₂)0-4-O-(CH₂)i-₄-O-(CH₂)o-4-,

-(CH2)0-4-O-(CH₂)l-4-NR⁴-(CH₂)0-4-,

-(CH₂)0-4-NR⁴-(CH₂)1-₄-NR4-(CH₂)0-4-

-(CH₂)0-4-O-(CH₂)i-₄-S-(CH₂)o-4-,

-(CH₂)0-4-S-(CH₂)i-₄-S-(CH₂)0-4-,

-(CH₂)0-4-NR⁴-(CH₂)i-₄-S-(CH )0-4-,

-(CH₂)0-4-NR⁴-(CH₂)i-₄-O-(CH₂)0-4-, -(CH₂)0-4-S-(CH₂)i-₄-O-(CH₂)o-4-, and

-(CH₂)0-4-S-(CH₂)i-₄-NR⁴-(CH₂)0-4-,

wherein any methylene (CH₂) carbon atom m Y, other than in R⁴, can be substituted by one or two R-> substituents;

Z is selected from the group consisting of

a 5- or 6-membered monocychc aromatic or nonaromatic πng system having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the non-aromatic πng nitrogen atoms are unsubstituted or substituted with one R ' substituent and the πng carbon atoms are unsubstituted or substituted with one or two R6 substituents, and

a 9- to 14-membered polycychc πng system, wherein one or more of the πngs is aromatic, and wherein the polycychc πng system has 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S, and wherein the non-aromatic ring nitrogen atoms are unsubstituted or substituted with one R substituent and the πng carbon atoms are unsubstituted or substituted with one or two R" substituents;

R! and R^ are each independently selected from the group consisting of hydrogen, halo, Ci-8 alkyl, C₂-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl Ci-6 alkyl,

C3-8 cycloheteroalkyl Ci-6 alkyl, aryl, aryl C\.β alkyl, ammo C[. alkyl, Ci-4 acylamino Ci-6 alkyl,

(Ci-6 alkyl) 1-2 amino Ci-6 alkyl, hydroxy Cι_6 alkyl,

Ci-6 alkoxy Ci-6 alkyl,

Ci-6 alkylthio Ci-6 alkyl, hydroxycarbonyl C 1-6 alkyl,

Cj-4 alkoxycarbonyl Cι_6 alkyl, and tπfluoromethyl;

each R3 is independently selected from the group consisting of hydrogen, halo, aryl,

Ci-8 alkyl,

C2-8 alkenyl, C₂-8 alkynyl, aryl Cι_6 alkyl,

C3_8 cycloalkyl, hydroxyl, oxo, tπfluoromethyl,

Ci-6 alkoxy, aryl C -6 alkoxy,

Ci-6 alkylthio, aryl Ci-6 alkylthio, aminocarbonyl,

(Ci-6 alkyl)i_2 aminocarbonyl, arylammocarbonyl, aryl Ci-6 alkylaminocarbonyl, aryloxycarbonylamino,

Ci-6 alkoxycarbonylammo, aryl Ci-6 alkoxycarbonylammo, arylcarbonylamino Ci-6 alkylcarbonylammo, aryl C 1-6 alkylcarbonylammo,

(Ci-6 alkyl) 1-2 aminocarbonyloxy, Ci-6 alkylsulfonylammo, arylsulfonylamino, aryl C -6 alkylsulfonylammo, Cj- alkylsulfonyl, aryl Ci-6 alkylsulfonyl, Ci-6 alkylcarbonyl, and aryl Ci-6 alkylcarbonyl, or two R3 substituents, when on the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R^ are either unsubstituted or substituted with one to three R* substituents, and provided that each R^ is selected such that in the resultant compound the carbon atom or atoms to which R^ IS attached is itself attached to no more than one heteroatom,

each R⁴ is independently selected from the group consisting of hydrogen,

Ci-8 alkyl, C2-8 alkenyl,

C2-8 alkynyl, aryl Ci-6 alkyl,

Ci-4 alkoxy C - alkyl,

C3-8 cycloalkyl, C 1-6 alkylsulfonyl, arylsulfonyl, arylCi-6 alkylsulfonyl, Ci- alkoxycarbonyl, aryloxycarbonyl, aryl Ci- alkoxycarbonyl,

Ci- alkylcarbonyl, arylcarbonyl, aryl C _ alkylcarbonyl, hydroxycarbonyl Cι_ alkyl, Ci-4 alkoxycarbonyl Ci-6 alkyl,

(aryl) 1-2 aminocarbonyl, (aryl Ci-6 alkyl) i -2 aminocarbonyl, and (Cι_6 alkyl)i-2 aminocarbonyl;

wherein any of the alkyl groups of R⁴ are either unsubstituted or substituted with one to three R^ substituents;

R5 is selected from the group consisting of hydrogen, Ci-8 alkyl, aryl, aryl C\-β alkyl,

Ci-6 alkylcarbonyloxy Ci-4 alkyl, aryl Ci-6 alkylcarbonyloxy C -4 alkyl, Ci- alkylaminocarbonylmethylene, and

Ci-6 dialkylammocarbonylmethylene;

each R" is independently selected from the group consisting of hydrogen, halo,

C 1-8 alkyl,

C2-8 alkenyl,

C2-8 alkynyl,

C3- cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl Ci-6 alkyl, C3-8 cycloheteroalkyl Ci- alkyl, aryl, aryl Ci-6 alkyl, amino, amino Cι_6 alkyl, Ci-4 acylammo, Ci-4 acylammo Ci- alkyl, (Ci-6 alkyl) 1-2 amino, (Ci- alkyl)i-2 ammo Ci- alkyl,

Ci-4 alkoxy, Ci-4 alkoxy Ci- alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl, Ci-4 alkoxycarbonyl,

C -4 alkoxycarbonyl Ci-6 alkyl, hydroxycarbonyl -C 1-6 alkyloxy, hydroxy, hydroxy Cι_ alkyl, nitro, cyano, tπfluoromethyl, 2,2,2-tπfluoroethyl, tπfluoromethoxy, tπfluoroethoxy,

Ci-6 alkyl-S(O)i-₂, (Ci-6 alkyl) ι_2 aminocarbonyl, Ci-6 alkyloxycarbonylamino, (Cι_6 alkyl)i-2 aminocarbonyloxy, (aryl Ci- alky l-2 amino,

(aryl) 1-2 amino, aryl Ci- alkylsulfonylammo, and Ci-6 alkylsulfonylammo, or two R" substituents, when on the same aliphatic carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; and

R is selected from the group consisting of hydrogen, Ci-8 alkyl, C2-8 alkenyl, C₂-8 alkynyl, C3-8 cycloalkyl,

C3-8 cycloheteroalkyl, C3-8 cycloalkyl Ci- alkyl, C3-8 cycloheteroalkyl Ci-6 alkyl, arylCi-6 alkyl, arylcarbonyl,

Ci-6 alkylcarbonyl, arylCi-6 alkylcarbonyl, aryloxycarbonyl, Ci-6 alkoxycarbonyl, and arylC 1-6 alkoxycarbonyl.

The present invention also relates to pharmaceutical compositions compπsing the compounds of the present invention and a pharmaceutically acceptable earner The present invention also relates to methods for making the pharmaceutical compositions of the present invention

The present invention also relates to methods for eliciting an αv integπn receptor antagonizing effect in a mammal in need thereof by admmisteπng the compounds and pharmaceutical compositions of the present invention The present invention also relates to methods for inhibiting bone resorption, restenosis, atherosclerosis, inflammation, viral disease, diabetic retinopathy, macular degeneration, angiogenesis, wound healing, tumor growth, and metastasis by admmisteπng the compounds and pharmaceutical compositions of the present invention The present invention also relates to methods for treating osteoporosis by administering the compounds and pharmaceutical compositions of the present invention

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds useful as αv integπn receptor antagonists. Representative compounds of the present invention are descnbed by structural formula I:

(I)

or a pharmaceutically acceptable salt thereof;

wherein U and V each independently represent N or CR6, provided that no more than one U represents N and no more than one V represents N;

X is O; S(O)0-2; NR⁴; or CR1R2,

Y is selected from the group consisting of

-(CH₂)0-4-, -(CH₂)0-4-O-(CH₂)i-4-, -(CH₂)0-4-NR⁴-(CH₂)l-4-,

-(CH₂)0-4-S-(CH₂)l-4-, -(CH₂)0-4-SO-(CH₂)l-4-, -(CH₂)0-4-SO2-(CH₂)l-4-, -(CH2)0-4-O-(CH₂)l-4-O-(CH )0-4- -(CH₂)0-4-O-(CH₂)l-4-NR⁴-(CH₂)0-4-,

-(CH₂)0-4-NR -(CH₂)l-4-NR⁴-(CH₂)0-4-,

-(CH₂)0-4-O-(CH₂)l-4-S-(CH2)0-4-,

-(CH₂)0-4-S-(CH₂)l-4-S-(CH₂)0-4-,

-(CH2)0-4-NR -(CH₂)l-4-S-(CH₂)0-4-,

-(CH₂)0-4-NR⁴-(CH₂)l-4-O-(CH₂)0-4-,

-(CH₂)0-4-S-(CH₂) 1 -4-O-(CH2)0-4-, ^and

-(CH₂)0-4-S-(CH₂)l-4-NR⁴-(CH₂)0-4-;

wherein any methylene (CH2) carbon atom in Y, other than in R⁴, can be substituted by one or two R^ substituents;

Z is selected from the group consisting of

a 5- or 6-membered monocyc c aromatic or nonaromatic πng system having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the non-aromatic πng nitrogen atoms are unsubstituted or substituted with one R^ substituent and the πng carbon atoms are unsubstituted or substituted with one or two R6 substituents, and

a 9- to 14-membered polycychc nng system, wherein one or more of the πngs is aromatic, and wherein the polycychc nng system has 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S, and wherein the non-aromatic nng nitrogen atoms are unsubstituted or substituted with one R substituent and the πng carbon atoms are unsubstituted or substituted with one or two R^ substituents;

R! and R2 are each independently selected from the group consisting of hydrogen, halo,

Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3- cycloalkyl C - alkyl, C3-8 cycloheteroalkyl Ci- alkyl, aryl, aryl Ci-6 alkyl, amino Ci-6 alkyl,

Ci-4 acylamino Cι_6 alkyl,

(Ci-6 alkyl) 1-2 amino Cι_6 alkyl, hydroxy Ci-6 alkyl, Ci-6 alkoxy Ci-6 alkyl,

Ci- alkylthio Ci-6 alkyl, hydroxycarbonyl Cι_ alkyl,

Ci-4 alkoxycarbonyl Ci-6 alkyl, and trifluoromethyl;

each R3 is independently selected from the group consisting of hydrogen, halo, aryl, C 1-8 alkyl,

C2-8 alkenyl,

C2-8 alkynyl, aryl Ci-6 alkyl,

C3-8 cycloalkyl, hydroxyl, oxo, trifluoromethyl,

Ci-6 alkoxy, aryl Ci-6 alkoxy, Ci-6 alkylthio, aryl C}-6 alkylthio, aminocarbonyl,

(Ci-6 alkyl)i-2 aminocarbonyl, arylaminocarbonyl. aryl Ci-6 alkylaminocarbonyl, aryloxycarbonylamino, Cj-6 alkoxyc arbon y 1 ami n o , aryl Ci-6 alkoxycarbonylammo, arylcarbonylamino

Ci-6 alkylcarbonylammo, aryl Ci-6 alkylcarbonylammo, (Ci-6 alkyl) 1-2 aminocarbonyloxy, Ci-6 alkylsulfonylammo, arylsulfonylammo, aryl Ci-6 alkylsulfonylammo, Ci- alkylsulfonyl, aryl Ci- alkylsulfonyl, Ci-6 alkylcarbonyl, and aryl C 1-6 alkylcarbonyl, or two R3 substituents, when on the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R^ are either unsubstituted or substituted with one to three R! substituents, and provided that each R3 IS selected such that in the resultant compound the carbon atom or atoms to which R^ IS attached is itself attached to no more than one heteroatom,

each R⁴ is independently selected from the group consisting of hydrogen,

Ci-8 alkyl,

C2-8 alkenyl,

C2-8 alkynyl, aryl Ci-6 alkyl, Ci-4 alkoxy C 1-6 alkyl,

C3-8 cycloalkyl,

Ci-6 alkylsulfonyl, arylsulfonyl, arylCj-6 alkylsulfonyl, Ci-6 alkoxycarbonyl, aryloxycarbonyl, aryl Cι_6 alkoxycarbonyl,

Ci-6 alkylcarbonyl, arylcarbonyl, aryl Ci- alkylcarbonyl, hydroxycarbonyl Cι_6 alkyl, Ci-4 alkoxycarbonyl Ci- alkyl, (aryl) 1-2 aminocarbonyl, (aryl Ci-6 alkyl)ι_2 aminocarbonyl, and

(Ci-6 alkyl) 1-2 aminocarbonyl;

wherein any of the alkyl groups of R4 are either unsubstituted or substituted with one to three R^ substituents;

R5 is selected from the group consisting of hydrogen,

Ci-8 alkyl, aryl, aryl Cι_6 alkyl,

Ci-6 alkylcarbonyloxy Ci-4 alkyl, aryl Cι_ alkylcarbonyloxy Ci-4 alkyl,

Ci-6 alkylaminocarbonylmethylene, and

Ci-6 dialkylaminocarbonylmethylene;

each R6 is independently selected from the group consisting of hydrogen, halo,

Ci-8 alkyl, C2-8 alkenyl,

C2-8 alkynyl,

C3-8 cycloalkyl,

C3-8 cycloheteroalkyl,

C3-8 cycloalkyl Cj-6 alkyl, C3_8 cycloheteroalkyl Ci- alkyl, aryl, aryl Cι_6 alkyl, amino, amino Ci-6 alkyl,

Ci-4 acylamino, Ci-4 acylamino Ci- alkyl, (Ci-6 alkyl) 1-2 amino, (Ci-6 alkyl) 1-2 amino Ci- alkyl, C 1-4 alkoxy,

Cι_4 alkoxy Ci-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Cι_6 alkyl, Ci-4 alkoxycarbonyl, Ci-4 alkoxycarbonyl Ci-6 alkyl, hydroxycarbonyl-Ci-6 alkyloxy, hydroxy, hydroxy C 1- alkyl, nitro, cyano, trifluoromethyl, 2,2,2-trifluoroethyl, trifluoromethoxy, trifluoroethoxy, Ci-₆ alkyl-S(O)i-₂,

(Ci-6 alkyl)i-2 aminocarbonyl, Ci-6 alkyloxycarbonylamino, (Cι_6 alkyl)i-2 aminocarbonyloxy, (aryl Cι_6 alkyl) 1-2 amino, (aryl) 1-2 amino, aryl Ci- alkylsulfonylamino, and C -6 alkylsulfonylamino; or two R" substituents, when on the same aliphatic carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; and

R IS selected from the group consisting of hydrogen, Ci-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl,

C3-8 cycloheteroalkyl, C3-8 cycloalkyl Ci-6 alkyl, C3-8 cycloheteroalkyl Ci-6 alkyl, arylCi-6 alkyl, arylcarbonyl,

Cι_ alkylcarbonyl, arylC -6 alkylcarbonyl, aryloxycarbonyl, Ci-6 alkoxycarbonyl, and arylCi-6 alkoxycarbonyl.

In the compounds of the present invention, U and V are preferably CR6

In the compounds of the present invention, X is preferably oxygen or sulfur. More preferably X is oxygen.

In the compounds of the present invention, W is preferably C=O or CH?.

In the compounds of the present invention, Y is preferably selected from the group consisting of

-(CH₂)0-4-, -(CH₂)0-4-O-(CH₂)l-4-,

-(CH₂)0-4-NR⁴-(CH₂)l-4-

-(CH₂)0-4-S-(CH₂)l-4-,

-(CH₂)0-4-SO-(CH₂)l-4-,

-(CH₂)0-4-SO2-(CH2)l-4-

-(CH₂)0-4-O-(CH₂)l-4-O-(CH₂)0-4-,

-(CH₂)0-4-O-(CH₂)l-4-NR⁴-(CH₂)0-4-,

-(CH₂)0-4-NR⁴-(CH₂)l-4-NR⁴-(CH2)0-4-, and

-(CH₂)0-4-NR⁴-(CH₂)l-4-O-(CH₂)0-4-;

wherein any methylene (CH2) carbon atom in Y, other than in R⁴, can be substituted by one or two R^ substituents. More preferably Y is selected from the group consisting of

-(CH₂)0-4-,

-(CH₂)0-4-O-(CH₂)l-4-,

-(CH₂)0-4-NR⁴-(CH₂)l-4-,

-(CH₂)0-4-S-(CH₂)l-4-, and

-(CH₂)0-4-NR⁴-(CH₂)l-4-O-(CH₂)0-4-;

wherein any methylene (CH2) carbon atom in Y, other than in R⁴, can be substituted by one or two R^ substituents. Most preferably Y is preferably selected from the group consisting of

-(CH₂)0-4-,

-(CH₂)0-4-NR⁴-(CH₂)n- or -(CH₂)0-4-NR⁴-(CH2)l-4-O-(CH2)0-4-;

wherein any methylene (CH₂) carbon atom in Y, other than in R⁴, can be substituted by one or two R^ substituents.

In the compounds of the present invention, Z is preferably is preferably selected from the group consisting of

wherein R7 is as defined above and the πng carbon atoms are unsubstituted or substituted with one or two R6 substituents as defined above More preferably Z is selected from the group consisting of

wherein R7 is as defined above and the ring carbon atoms are unsubstituted or substituted with one or two R6 substituents as defined above Most preferably Z is

wherein R7 is as defined above and the ring carbon atoms are unsubstituted or substituted with one or two R6 substituents as defined above.

In the compounds of the present invention, R! and R2 are preferably independently selected from the group consisting of hydrogen, C 1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, and aryl -3 alkyl.

More preferably R* and R² are independently selected from hydrogen and C 1-3 alkyl.

In the compounds of the present invention, each R^ is preferably selected from the group consisting of hydrogen, aryl,

Ci-8 alkyl, aryl Ci-6 alkyl, fluoro, hydroxy, oxo, trifluoromethyl, aminocarbonyl, arylaminocarbonyl, aryl Ci-6 alkylaminocarbonyl, and

(Ci-6 alkyl) 1-2 aminocarbonyl.

More preferably R3 is hydrogen or oxo.

In the compounds of the present invention, each R⁴ is preferably selected from the group consisting of hydrogen, C 1-8 alkyl, aryl Ci- alkyl, C3_8 cycloalkyl, Ci-4 alkoxy Ci- alkyl, Ci- alkylsulfonyl, arylCi-6 alkylsulfonyl,

Ci-6 alkoxycarbonyl, aryl Ci-6 alkoxycarbonyl, Cι_6 alkylcarbonyl, arylcarbonyl, aryl C 1-6 alkylcarbonyl,

(aryl) 1-2 aminocarbonyl, (aryl Ci-6 alkyl) i -2 aminocarbonyl, and (Ci-6 alkyl) -2 aminocarbonyl.

More preferably, R⁴ is selected from the group consisting of hydrogen,

C 1-4 alkyl, aryl Cι_4 alkyl, and

Ci-4 alkoxy Ci-4 alkyl. Most preferably R4 is hydrogen or methyl.

In the compounds of the present invention, R^ is preferably selected from the group consisting of hydrogen, methyl, and ethyl. More preferably, R^ is hydrogen.

In the compounds of the present invention, each R6 is preferably selected from the group consisting of hydrogen, cyano, halo,

C i-4 alkyl, aryl, aryl Ci-3 alkyl,

Ci-4 acylamino, Ci-4 alkoxy, Ci-4 alkylthio, aminocarbonyl,

(Ci-6 alkyl) 1-2 aminocarbonyl, C 1-4 alkoxycarbonyl, tπfluoromethyl, and tnfluoromethoxy.

In the compounds of the present invention, R7 is preferably hydrogen, Ci-3 alkyl, or aryl Cι_3 alkyl. More preferably R7 IS hydrogen.

Illustrative but non miting examples of compounds of the present invention that are useful as αv tegnn receptor antagonists are:

{ l l-Oxo-3-[3-(pyπdιn-2-ylamιno)-l-propoxy]-HH-dιbenzo[l,4]oxazepιn-10-yl}- acetic acid ethyl ester;

{ l l-Oxo-3-[3-(pyπdιn-2-ylamιno)-l-propoxy]-HH-dιbenzo[l,4]oxazepm-10-yl}- acetic acid;

{ 3-[3-(Pyπdιn-2-ylamιno)-l-propoxy]-l lH-dιbenzo[l,4]oxazepιn-10-yl }-acetιc acid ethyl ester;

{ 3-[3-(Pyπdιn-2-ylamιno)-l-propoxy]-l lH-dιbenzo[l,4]oxazepιn-10-yl}-acetιc acid;

or a pharmaceutically acceptable salt thereof.

Further illustrative of the present invention are the compounds selected from the group consisting of

{ l l-Oxo-3-[3-(pyπdιn-2-ylamιno)-l-propoxy]-HH-dιbenzo[l,4]oxazepιn-10-yl }- acetic acid;

{3-[3-(Pyπdιn-2-ylamιno)-l-propoxy]-l lH-dιbenzo[l,4]oxazepιn-10-yl }-acetιc acid; or a pharmaceutically acceptable salt thereof.

For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. The compounds of the present invention can have chiral centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers, with all isomeric forms being included in the present invention. Therefore, where a compound is chiral, the separate enantiomers or diastereomers, substantially free of the other, are included within the scope of the invention; further included are all mixtures of the two enantiomers.

Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form, known as keto-enol tautomeis The individual tautomers as well as mixtures thereof are encompassed within the compounds of the present invention

Compounds of the present invention may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example, by the use of an optically active acid as a resolving agent, or by HPLC using a chiral stationary phase Alternatively, any enantiomer of a compound of the present invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

Also included within the scope of the invention are polymorphs and hydrates of the compounds of the instant invention.

The present invention includes within its scope prodrugs of the compounds of this invention In general, such prodrugs will be functional deπvatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administeπng" shall encompass the treatment of the vaπous conditions descnbed with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug deπvatives are descnbed, for example, in "Design of Prodrugs," ed H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu The term "therapeutically effective amount" shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.

The term " αv integπn receptor antagonist," as used herein, refers to a compound which binds to and antagonizes either the αvβ3 receptor, the αvβ5 receptor, or the αvβό receptor, or a compound which binds to and antagonizes combinations of these receptors (for example, a dual αvβ3/αvβ5 receptor antagonist)

The term "bone resorption," as used herein, refers to the process by which osteoclasts degrade bone The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1- propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.)

The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range

The term "alkynyl" shall mean straight or branched chain alkynes of two to ten total carbon atoms, or any number within this range

The term "cycloalkyl" shall mean cyclic πngs of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

The term "cycloheteroalkyl," as used herein, shall mean a 3- to 8- membered fully saturated heterocyclic nng containing one or two heteroatoms chosen from N, O, or S. Examples of cycloheteroalkyl groups include, but are not limited to, pipeπdmyl, pyrro dinyl, azetidinyl, morphohnyl, and piperazinyl. The term "alkoxy," as used herein, refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., Cι_5 alkoxy), or any number within this range (i.e., methoxy, ethoxy, etc.). The term "alkylthio," as used herein, refers to straight or branched chain alkylsulfides of the number of carbon atoms specified (e.g., -5 alkylthio), or any number withm this range (i.e., methylthio, ethylthio, etc.).

The term "aryl," as used herein, refers to a monocychc or polycychc system compπsing at least one aromatic ring, wherein the monocy c or polycychc system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O, or S, and wherein the monocyhc or polycyhc system is either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Ci-io alkyl, C3-8 cycloalkyl, aryl, aryl Ci-8 alkyl, ammo, ammo-Ci-8 alkyl, Ci-3 acylammo, Ci-3 acylamino-Ci- 8 alkyl, Ci-6 alkylammo, Ci-6 alkylamino Ci-8 alkyl, Ci-6 dialkylamino, Ci-6 dιalkylamιno-Ci-8 alkyl, Cj-4 alkoxy, Cι_4 alkoxy C -6 alkyl, Ci-4 alkylthio, Ci-4 alkylthio Ci-6 alkyl hydroxycarbonyl, hydroxycarbonyl Cι_6 alkyl, Cι_5 alkoxycarbonyl, Ci-3 alkoxycarbonyl Ci-6 alkyl, hydroxycarbonyl Ci-6 alkyloxy, hydroxy, hydroxy Ci-6 alkyl, cyano, nitro, trifluoromethyl, tnfluoromethoxy, tπfluoroethoxy, oxo, thioxo, or Cj-5 alkylcarbonyloxy. Examples of aryl include, but are not limited to, phenyl, naphthyl, pyπdyl, quinolyl, pyrrolyl, pyrazolyl, pyrazinyl, pynmidyl, lmidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, mdolyl, thienyl, furyl, dihydrobenzofuryl, benzo(l,3) dioxolane, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, and isothiazolyl, which are either unsubstituted or substituted with one or more groups independently selected from hydrogen, halogen, Ci_io alkyl, C3-8 cycloalkyl, aryl, aryl Ci-8 alkyl, amino, amino Ci-8 alkyl, Ci-3 acylammo, -3 acylamino Ci-8 alkyl, Cι_6 alkylamino, C\- 6 alkylamιno-Ci-8 alkyl, Ci- dialkylammo, Cι_6 dialkylammo Ci-8 alkyl, Cι_4 alkoxy, Ci-4 alkoxy Ci- alkyl, hydroxycarbonyl, hydroxycarbonyl Ci-6 alkyl, Ci-5 alkoxycarbonyl, Ci-3 alkoxycarbonyl Cι_6 alkyl, hydroxycarbonyl Ci-6 alkoxy, hydroxy, hydroxy Ci-6 alkyl, cyano, tπfluoromethyl, oxo or Ci-5 alkylcarbonyloxy Preferably, the aryl group is unsubstituted, mono-, di-. tn- or tetra-substituted with one to four of the above-named substituents; more preferably, the aryl group is unsubstituted, mono-, di- or tn-substituted with one to three of the above-named substituents; most preferably, the aryl group is unsubstituted, mono- or di-substituted with one to two of the above-named substituents

Whenever the term "alkyl" or "aryl" or either of their prefix roots appears in a name of a substituent (e.g , aryl Ci-6 alkyl), it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Ci-8) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root. The terms "arylalkyl" and "alkylaryl" include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include, but are not limited to, toluene, ethylbenzene, propylbenzene, methylpyπdine, ethylpyπdine, propylpyπdine and butylpyπdme.

In the compounds of the present invention, two R! substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group In the compounds of the present invention, two R^ substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a carbonyl group. In such instances, the limitation, that in the resultant compound the carbon atom or atoms at which R3 IS attached is itself attached to no more than one heteroatom, does not apply Also, two R^ substituents, when on the same carbon atom, can be taken together with the carbon atom to which they are attached to form a cyclopropyl group

The term "halo" shall include lodo, bromo, chloro, and fluoro.

The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur (S) atom The term "oxo" means "=O" The term "carbonyl" means "C=O." The term "thioxo" means "C=S." The letter "O" signifies oxygen; the letter "S" signifies sulfur; and the letter "N" signifies nitrogen.

The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different

Under standard nonmenclature used throughout this disclosure, the terminal portion of the designated side chain is descnbed first, followed by the adjacent functionality toward the point of attachment. For example, a Ci-5 alkylcarbonylammo Ci- alkyl substituent is equivalent to

O

II

-Cτ-₆ alkyl-NH-C-C .g alkyl .

In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the vaπous substituents, i.e. X, Y, Z, R , R2, R3_? R4 _anc\ R5, and the subscπpts m, n, and p are to be chosen in conformity with well-known pnnciples of chemical structure connectivity

Representative compounds of the present invention typically display submicromolar affinity for the integπn receptors, particularly the αvβ3, αvβ5, and/or αvβό receptors. Compounds of this invention are therefore useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy. Pharmacologically effective amounts of the compounds, including pharamaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts. The compounds of the present invention are administered in dosages effective to antagonize the αvβ3 receptor where such treatment is needed, as, for example, in the prevention or treatment of osteoporosis. Further exemplifying the invention is the method wherein the αv mtegπn receptor antagonizing effect is an αvβ3 antagonizing effect An illustration of the invention is the method wherein the αvβ3 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis. Preferably, the αvβ3 antagonizing effect is the inhibition of bone resorption

An example of the invention is the method wherein the αv integnn receptor antagonizing effect is an αvβ5 antagonizing effect. More specifically, the αvβ5 antagonizing effect is selected from inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, tumor growth, or metastasis

Illustrating the invention is the method wherein the αv integπn receptor antagonizing effect is a dual αvβ3/αvβ5 antagonizing effect. More particularly, the dual αvβ3/αvβ5 antagonizing effect is selected from inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, or metastasis.

Illustrating the invention is the method wherein the αv integπn receptor antagonizing effect is an αvβό antagonizing effect. More particularly, the αvβό antagonizing effect is selected from inhibition of angiogenesis, inflammatory response, or wound healing

Illustrating the invention is the method wherein the αvβ3 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of atherosclerosis, inflammation, viral disease, or inhibition of tumor growth and metastasis. Preferably, the αvβ3 antagonizing effect is the inhibition of bone resorption.

More particularly illustrating the invention is a pharmaceutical composition compπsmg any of the compounds descnbed above and a pharmaceutically acceptable earner. Another example of the invention is a pharmaceutical composition made by combining any of the compounds descnbed above and a pharmaceutically acceptable earner Another illustration of the invention is a process for making a pharmaceutical composition compnsmg combining any of the compounds descnbed above and a pharmaceutically acceptable carrier Further illustrating the invention is a method of treating and/or preventing a condition mediated by antagonism of an αv integrin receptor in a mammal in need thereof, compπsing administering to the mammal a therapeutically effective amount of any of the compounds descnbed above. Preferably, the condition is selected from bone resorption, osteoporosis, restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, viral disease, cancer, tumor growth, and metastasis More preferably, the condition is selected from osteoporosis and cancer. Most preferably, the condition is osteoporosis.

More specifically exemplifying the invention is a method of eliciting an αv integrin antagonizing effect in a mammal in need thereof, compπsing admmisteπng to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions descnbed above. Preferably, the αv integnn antagonizing effect is an αvβ3 antagonizing effect, more specifically the αvβ3 antagonizing effect is selected from inhibition of bone resorption, inhibition of restenosis, inhibition of atherosclerosis, inhibition of angiogenesis, inhibition of diabetic retinopathy, inhibition of macular degeneration, inhibition of inflammation, inhibition of viral disease, or inhibition of tumor growth or metastasis. Most preferably, the αvβ3 antagonizing effect is inhibition of bone resorption. Alternatively, the αv mtegnn antagonizing effect is an αvβ5 antagonizing effect, an αvβό antagonizing effect, or a mixed αvβ3, αvβ5, and αvβό antagonizing effect. Examples of αvβ5 antagonizing effects are inhibition of restenosis, atherosclerosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, or tumor growth Examples of αvβό antagonizing effects are inhibition of angiogenesis, inflammatory response, and wound healing Additional examples of the invention are methods of inhibiting bone resorption and of treating and/or preventing osteoporosis in a mammal in need thereof, compπsing administeπng to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions decnbed above Additional illustrations of the invention are methods of treating hypercalcemia of malignancy, osteopenia due to bone metastases, peπodontal disease, hyperparathyroidism, peπarticular erosions in rheumatoid arthntis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment in a mammal in need thereof, compπsing administeπng to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above More particularly exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of osteoporosis in a mammal need thereof. Still further exemplifying the invention is the use of any of the compounds described above in the preparation of a medicament for the treatment and/or prevention of bone resorption, tumor growth, cancer, restenosis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation, viral disease, and/or angiogenesis.

Also exemplifying the invention are compositions further compnsmg an active ingredient selected from the group consisting of a ) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b.) an estrogen receptor modulator, c ) a cytotoxic/antiprohferative agent, d.) a matnx metalloprotemase inhibitor, e ) an inhibitor of epi dermal-den ved, fibroblast-deπved, or platelet- den ved growth factors, f.) an inhibitor of VEGF, g.) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tιe-2, or Tιe-1, h.) a cathepsin K inhibitor, and l.) a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor; and mixtures thereof. (See B. Millauer et al., "Dominant-Negative Inhibition of Flk-1 Suppresses the Growth of Many Tumor Types in Vivo", Cancer Research, 56, 1615-1620 (1996), which is incorporated by reference herein in its entirety).

Preferably, the active ingredient is selected from the group consisting of: a ) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b.) an estrogen receptor modulator, and c.) a cathepsin K inhibitor; and mixtures thereof.

Nonhmiting examples of such bisphosphonates include alendronate, etidronate, pamidronate, nsedronate, ibandronate, and pharmaceutically acceptable salts and esters thereof. A particularly preferred bisphosphonate is alendronate, especially alendronate monosodium tπhydrate

Nonhmitmg examples of estrogen receptor modulators include estrogen, progesterm, estradiol, droloxifene, raloxifene, and tamoxifene. Nonhmiting examples of cytotoxic/antiprohferative agents are taxol, vincπstine, vinblastme, and doxorubicin.

Cathepsin K, formerly known as cathepsin 02, is a cysteme protease and is described in PCT International Application Publication No WO 96/13523, published May 9, 1996; U.S. Patent No. 5,501,969, issued March 3, 1996; and U.S Patent No. 5,736,357, issued Apnl 7, 1998, all of which are incorporated by reference herein in their entirety. Cysteine proteases, specifically catheps s, are linked to a number of disease conditions, such as tumor metastasis, inflammation, arthπtis, and bone remodeling. At acidic pH's, cathepsms can degrade type-I collagen. Cathepsin protease inhibitors can inhibit osteoclastic bone resorption by inhibiting the degradation of collagen fibers and are thus useful in the treatment of bone resorption diseases, such as osteoporosis.

The present invention is also directed to combinations of the compounds of the present invention with one or more agents useful in the prevention or treatment of osteoporosis. For example, the compounds of the instant invention may be effectively administered in combination with effective amounts of other agents such as an organic bisphosphonate, an estrogen receptor modulator, or a cathepsin K inhibitor.

Additional illustrations of the invention are methods of treating tumor growth or metastasis in a mammal in need thereof, compπsing administeπng to the mammal a therapeutically effective amount of a compound descnbed above and one or more agents known to be cytotoxic/antiprohferative. Also, the compounds of the present invention can be administered in combination with radiation therapy for treating tumor growth and metastasis.

In addition, the integnn αvβ3 antagonist compounds of the present invention may be effectively administered in combination with a growth hormone secretagogue in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases. These diseases include conditions which can benefit from a reduction in bone resorption. A reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result in bone augmentation. A reduction in bone resorption can alleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions These diseases include: osteoporosis (including estrogen deficiency, immobilization, glucocorticoid-induced and senile), osteodystrophy, Paget^'s disease, myositis ossificans, Bechterew's disease, malignant hypercalcemia, metastatic bone disease, penodontal disease, cholelithiasis, nephro thiasis, urohthiasis, uπnary calculus, hardening of the artenes (sclerosis), arthπtis, bursitis, neuritis and tetany. Increased bone resorption can be accompanied by pathologically high calcium and phosphate concentrations in the plasma, which would be alleviated by this treatment. Similarly, the present invention would be useful in increasing bone mass in patients with growth hormone deficiency. Thus, preferred combinations are simultaneous or alternating treatments of an αvβ3 receptor antagonist of the present invention and a growth hormone secretagogue, optionally including a third component compπsing an organic bisphosphonate, preferably alendronate monosodium tπhydrate.

In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times dunng the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment, and the term "administeπng" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating integπn -mediated conditions includes in pπnciple any combination with any pharmaceutical composition useful for treating osteoporosis.

As used herein, the term "composition" is intended to encompass a product compnsmg the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intrapeπtoneal, topical (e.g., ocular eyedrop), subcutaneous, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an αvβ3 antagonist. The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the seventy of the condition to be treated, the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinanly skilled physician, veteπnaπan or clinician can readily determine and prescπbe the effective amount of the drug required to prevent, counter or arrest the progress of the condition

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0 1 to 5.0 mg/kg/day For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0 1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute duπng a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered m divided doses of two, three or four times daily Furthermore, preferred compounds for the present invention can be administered in mtranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skm patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen

In the methods of the present invention, the compounds herein descnbed in detail can form the active ingredient, and are typically administered m admixture with suitable pharmaceutical diluents, excipients or earners (collectively referred to herein as 'earner' matenals) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert earner such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert earner such as ethanol, glycerol, water and the hke Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like Lubπcants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention can also be administered in the form of hposome delivery systems, such as small umlamellar vesicles, large unilamellar vesicles and multilamellar vesicles Liposomes can be formed from a vaπety of phosphohpids, such as cholesterol, stearylamme or phosphatidylcholines. Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual earners to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug earners. Such polymers can include polyvmylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycohc acid, copolymers of polylactic and polyglycohc acid, polyepsilon caprolactone, polyhydroxy butyπc acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

In the schemes and examples below, vaπous reagent symbols and abbreviations have the following meanings

BOP Benzotnazol-l-yloxytns(dιmethylamιno)- phosphonium hexafluorophosphate CH₂Cb Methylene chloπde.

CHC1₃- Chloroform. CH3OH: Methanol DEAD Diethyl azodicarboxylate

DMF. N,N-Dιmethylformamιde.

DMSO- Dimethylsulfoxide.

EDC: l-(3-Dιmethylamιnopropyl)-3-ethylcarbodπmιde ^»HC1

EtOAc: Ethyl acetate.

EtOH: Ethanol.

FABLRMS: Fast-atom bombardment low-resolution mass spectrum.

HOBT. 1 -Hydroxybenzotn azole .

HPLC: High Performance Liquid Chromatography.

L1AIH4: Lithium aluminum chlonde.

MgSO4: Magnesium sulfate.

NaCNBH3; Sodium cyanoborohydπde.

Na2C03: Sodium carbonate.

NaOH: Sodium hydroxide.

Na2SO4: Sodium sulfate.

NMM. N-methylmorpholme. NMR: Nuclear magnetic resonance. NH4CI: Ammonium chlonde.

Pd/C: Palladium on activated carbon catalyst.

Ph: Phenyl.

Ph3P: Tnphenylphosphine.

SιO₂: Silica gel. TFA- Tπfluoroacetic acid. THF: Tetrahydrofuran. TLC: Thin-Layer Chromatography.

The novel compounds of the present invention can be prepared according to the procedures depicted below in Schemes 1 and 2 using appropriate starting matenals which are either available from commercial sources or readily made according to methods well-descπbed in the published chemical literature.

The following general synthetic methods can be employed to prepare the compounds of the present invention. Compounds wherein both W and X represent oxygen can be prepared according to the methods of Scheme 1. The required dibenzooxazepinone intermediate L3 is prepared in a 3-step sequence from 2-fluoronιtrobenzene and methyl 4-methoxysalιcylate. Alkylation of the seven- membered nng amide nitrogen is effected with an alkyl bromo- or lodoacetate the presence of an appropπate base, such as sodium or potassium hydride, in a suitable solvent, such as tetrahydrofuran, N,N-dιmethylformamιde, or dimethyl sulfoxide Compounds wherein X is sulfur and W is oxygen can be made in a similar fashion but using methyl 4-methoxythiosahcylate in place of methyl 4-methoxysahcylate to elaborate the dibenzothiazepinone substrate Compounds wherein X represents (SO)i-2 can be prepared by treatment of the dibenzothiazepinone intermediate with one or two molar equivalents of a suitable oxidizing agent, respectively, such as meta- chloroperbenzoic acid (MCPBA), magnesium monoperoxyphthalate, sodium metapeπodate, sodium perborate, or Oxone, in a suitable reaction solvent, such as diethyl ether, tetrahydrofuran, methylene chlonde, chloroform, or methanol. Compounds wherein W is (H)2 can be prepared by treatment of the precursor wherein

W is oxygen with a suitable reducing agent, such as lithium aluminum hydπde, diborane, or borane-methyl sulfide in a suitable solvent, such as diethyl ether, tetrahydrofuran, or methylene chlonde.

Compounds wherein Z-Y represents Z-(CH2)m- - can be prepared by alkylation of a phenolic intermediate such as L-5 (obtainable by demethylation of the anisole intermediate L4) using Mitsunobu-type conditions (tπphenylphosp e, dialkyl azodicarboxylate) (Synthesis 1981, 1-28; Organic Reactions 1992, 42, 335-656) in the presence of the alcohol reagent, Z(optιonally protected)-(CH2)m- H. Removal of any Z-protectmg group followed by further manipulation, such as catalytic hydrogenation in the presence of a palladium catalyst or catalytic transfer hydrogenation and/or removal of any C-termmus carboxyhc acid protecting group, such as by alkaline hydrolysis, affords the desired final compounds of the present invention.

Compounds wherein Z-Y represents Z-(CH2)πrS- can be prepared by alkylation of a thiophenol precursor corresponding to L5 with an alkyl hahde, such as Z(optιonally protected)-(CH2)m-I> ^ιn the presence of a suitable inorganic or organic base, followed by removal of any Z-protecting group and further manipulation, such as catalytic hydrogenation and/or removal of any C-termmus carboxyhc acid protecting group, such as by alkaline hydrolysis The thiophenol intermediate can be prepared from the phenol by means of the Newman-Karnes procedure Treatment of the Z(optιonally protected)-(CH2)m-S- intermediate with one or two equivalents of a suitable oxidizing agent, such as MCPBA in methylene chlonde, and subsequent N- and C-termmi deprotection, give the compounds of the present invention wherein Z-Y represents Z-(CH₂)m-S(O)- and Z-(CH₂)m-S(O)2, respectively.

Compounds wherein Z-Y represents Z-(CH2)m-N(R4)-C(=O)- are prepared by converting a phenolic intermediate, such as 1^5, into its benzoic acid derivative This can be accomplished, for example, by converting the phenol into its tnfluoromethanesulfonate ester followed by carbonyl insertion with carbon monoxide in the presence of potassium acetate, a palladium catalyst, such as palladium acetate, and l,l '-bιs(dιphenylphosphιno)ferrocene (dppf). Alternatively, the tnfluoromethanesulfonate ester can be converted into its benzomtnle deπvative with copper(I) cyanide in DMF, which is then hydrolyzed to the benzoic acid under standard conditions. Amide bond formation is then earned out using standard coupling reagents, such as BOP, under conditions well-known to practitioners of the art of synthetic organic chemistry. Final N- and C-termini deprotection affords the desired final compounds of the present invention. The compounds illustrated in the examples below are not to be construed as forming the only genus that is considered as the invention. They serve to further illustrate details for the preparation of the compounds of the present invention Those skilled in the art will readily understand that known vaπations of the conditions and processes of the following synthetic procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted.

SCHEME 1

EXAMPLE 1

4-Methoxy-2-(2-nitrophenoxy)-benzoic acid methyl ester (1-1)

A solution of 2-fluoronitrobenzene (3.978 g, 28.19 mmol), methyl 4- methoxysalicylate (5.131 g, 28.15 mmol), and potassium carbonate (7.800 g, 56.43 mmol) in DMF (30 mL) was warmed to 50°C overnight. The solvent was removed in vacuo and the residue dissolved in dichloromethane and water. The water was extracted twice more with dichloromethane and the combined organic extracts washed with brine and dried (Na2SO4). The solvent was removed in vacuo to afford the title compound IA as a pale yellow oil (9.36 g). ^JH NMR (CDCI3, 400 MHz) δ 8.01 (d, 1H, J = 8.8 Hz), 7.97 (dd, 1H, J = 1.6, 8.1 Hz), 7 44 (dt, 1H, J = 1.6, 7.8 Hz), 7.14 (dt, 1H, J = 1.1, 7.8 Hz), 6.82 (dt, 2H, J = 2.6, 8.8 Hz), 6.63 (d, 1H, J = 2.6 Hz), 3.84 (s, 3H), 3.70 (s, 3H); FABLRMS m/e 304 g/mole (M++H, C₁₃H₁₃NO₆ = 304 g/mole); HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H₂O [0.1% H3PO₄] - CH₃CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/mm flow rate) RT = 12.120 min; focus = 215 nm; 98.8% pure.

2-(2-Amιnophenoxy)-4-methoxy-benzoιc acid methyl ester (1-2) A solution of LI (7.360 g, 21.87 mmol) in methanol (200 mL) was added to a suspension of 10% palladium on carbon in ethanol (100 mL). The mixture was treated with hydrogen gas at room temperature and pressure for 3 hours. The reaction mixture was filtered through cehte and the filtrate evaporated in vacuo to afford the title compound L2 as an oil (5.80 g). FABLRMS m/e 273 g/mole (M+, C₁₅H₁₅NO₄ = 273 g/mole).

3-Methoxy- 1 OH-dibenzof 1 ,41oxazepιn- 11 -one (1-3)

A solution of 1^2 (47.80 g, 174.9 mmol) in TΗF (1 L) was treated with sodium hydnde (7.430 g of 60% in oil, 185.7 mmol) in portions and stirred at room temperature for 3 days. The reaction was quenched with aqueous NΗ4CI and extracted three times with diethyl ether. The combined organic extracts were washed with bnne and dπed (Na2SO4). The solvent was removed in vacuo to afford 42 g of crude product. Recrystalhzation from ethyl acetate gave L3 as white crystals (22.8 g)-

*H NMR (CDCI₃, 400 MHz) 5 8.10 (s, 1H), 7.90 (d, 1H, J = 8.8 Hz), 7.24 (dd, 1H, J

= 2.3, 7.0 Hz), 7.12 (m, 2H) 7.02 (dd, 1H, J = 2.6, 7.0 Hz), 6.78 (dd, 1H, J = 2. 6, 8.8

Hz), 6.74 (d, 1H, J = 2.3 Hz), 3.86 (s, 3H);

FABLRMS m e 242 g/mole (M++H, C₁₄H, >NO₃ = 242 g/mole).

(3-Methoxy-l l-oxo-l lH-dιbenzori,4]oxazepm-10-yl)-acetιc acid ethyl ester (1-4)

A solution of L3 (330 mg, 1.37 mmol) in DMF (2 mL) was cooled to 0°C and treated with sodium hydnde (74.0 mg of 60% in oil, 1.85 mmol). The reaction mixture was warmed to room temperature for 30 min and cooled to 0°C. The reaction mixture was treated with ethyl bromoacetate and warmed to room temperature for 30 min., followed by quenching with aqueous NH4CI The solvent was removed in vacuo and the residue diluted in water and extracted with three portions of dichloromethane. The combined organic extracts were washed with bnne and dried (Na2SO4). The solvent was removed in vacuo to afford the title compound

^]H NMR (CDCI₃, 400 MHz) δ 7.82 (d, 1H, J = 8.6 Hz), 7.27-7.15 (m, 4H), 6.75 (dd,

1H, J = 2.4, 8.6 Hz), 6.71 (d, 1H, J = 2 4 Hz), 4.61 (s, 2H), 4.30 (q, 2H, J = 7.1 Hz), 3.84 (s, 3H), 1.32 (t, 3H, J = 7.1 Hz);

FABLRMS m/e 328 g/mole (M++H, C₁₈H₁₇NO₅ = 328 g/mole)

(3-Hydroxy-ll-oxo-llH-dιbenzori,4]oxazepιn-10-yl)-acetιc acid ethyl ester (1-5) A solution of L4 (8.80 g, 26.8 mmol) in dichloromethane (200 mL) was cooled to -5°C and treated with ethanethiol (16.8 g, 270 mmol) and aluminum chlonde (21.5 g, 161 mmol). The reaction was warmed to room temperature and stirred four hours before quenching with aqueous NH4CI solution. The organic layer was washed with bnne and dπed (Na₂SO4). The solvent was removed in vacuo. Preparative centπfugal chromatography (SιO₂, 6mm, 10% EtOH; 90% CH C1₂) afforded L5 as a clear, glassy solid (3.0 g).

FABLRMS m/e 314 g/mole (M++H, C₁₇H₁₅NO₅ = 314 g/mole).

{3-r3-(l-Hydroxy-pyndιn-2-ylammo)-l-propoxyl-l l-oxo-llH-dιbenzo [l,41oxazepιn-10-yl )-acetιc acid ethyl ester (1-6)

A solution of L5 (274 mg, 0.875 mmol) and Ph₃P (264 mg, 1.00 mmol) in DMF (1 mL) was treated with a solution of DEAD (193 mg, 1.11 mmol) and 2-(3-hydroxy-propylamιno)-pyπdιn-l -oxide (186 mg, 1.11 mmol) in DMF (1 mL) at room temperature for 6 days The solvent was removed in vacuo and the residue partitioned between dichloromethane and aqueous Na2CO3 solution. The aqueous layer was extracted with four portions of dichloromethane and the combined organic extracts washed with brine and dried (Na2SO4). The solvent was removed in vacuo Preparative centrifugal chromatography (SιO₂, 2mm, 10% EtOH; 90% CH₂C1₉) afforded L6 (130 mg). ^JH NMR (CDCI3, 400 MHz) δ 8.11 (dd, IH, J = 1.5, 6.6 Hz), 7.81 (d, IH, J = 8.8

Hz), 7.26-7.12 (m, 5H), 6.98 (t, IH, J = 5.5 Hz), 6.77 (dd, IH, J = 2.4, 8.8 Hz), 6.72 (d, IH, J = 2.4 Hz), 6.61 (dd, IH, J = 1.7, 8.4 Hz), 6.54 (dt, IH, J = 1.7, 5.8 Hz), 4.61 (s, 2H), 4.31 (q, 2H, J = 7.1 Hz), 4.13 (t, 2H, J = 5.7 Hz), 3.51 (q, 2H, J = 6.4 Hz), 2.18 (dddd, 2H, J = 6 Hz), 1.33 (t, 3H, J = 7.1 Hz).

{ l l-Oxo-3-[3-(pyndιn-2-ylamιno)-l-propoxyl-l lH-dιbenzori,4^"loxazepιn-10-yl )- acetic acid ethyl ester (1-7) A solution of L6 (125 mg, 0.270 mmol) in 2-propanol (20 mL) was treated with 1,4-cyclohexadιene (296 mg, 3.69 mmol) and 10% palladium on carbon (72 mg). The mixture was heated to reflux overnight. The reaction mixture was filtered through ce te and the filtrate evaporated in vacuo to afford the title compound 1-7 (115 mg). The crude product was used directly in the next reaction.

{ l l-Oxo-3-[3-(pyndιn-2-ylamιno)-l-propoxy1-llH-dιbenzo[l,41oxazepιn-10-yU- acetic acid (1-8)

A solution of 7 (115 mg, 0.256 mmol) in THF (6 mL) was treated with IM aqueous NaOH (2.50 mL) at room temperature for one hour. The reaction was neutralized with IM aqueous HCl (2.50 mL) and the solvents were removed in vacuo. Preparative centπfugal chromatography (SιO₂, 2mm, 10% MeOH; 25%

EtOAc, 65% CHCI3) afforded L8 (70 mg).

^]H NMR DMSO-dβ, 400 MHz) δ 7.96-7.94 (m, IH), 7.59 (d, IH, J = 8.6 Hz), 7.49 (dd, IH, J = 2.2, 7.5 Hz), 7.36-7.29 (m, 2H), 7.18-7.14 (m, 2H), 6.89 (d, IH, J = 2.5 Hz), 6.84 (dd, IH, J = 2.5, 8.6 Hz), 6.56 (t, IH, J = 5.7 Hz), 6.46-6.43 (m, 2H), 4.23 (s, 2H), 4.12 (t, 2H, J = 6.2 Hz), 3.39-3.33 (m, 3H), 2.00-1.96 (m, 2H). FABLRMS m e 420 g/mole (M++H, C₂₃H₂₁N₃O5 = 420 g/mole);

Exact MS (ES) (M++H, C₂₃H₂₁N₃O₅ = 420.1554), Found 420.1553; HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H₂O [0.1% H3PO4] - CH₃CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/mm flow rate) RT = 7.967 min; focus = 215 nm; 100% pure. SCHEME 2

EXAMPLE 2

3-Methoxy-10,ll-dihydro-dibenzo[l,41oxazepine (2-1)

A solution of L3 (1.16 g, 4.80 mmol) in THF (50 mL) was treated with a solution of IM L-AIH4 in THF (10.0 mL, 10.0 mmol) and heated to 55°C for 2 hours. The reaction was quenched with aqueous NH4CI and extracted with diethyl ether. The solvents were removed in vacuo to afford 2- 1 (1.05 g).

FABLRMS m e 228 g/mole (M++H, C₁₄H₁₃NO₂ = 228 g/mole).

(3-Methoxy-l lH-dibenzo[l,41oxazepin-10-yl)-acetic acid ethyl ester (2-2)

A solution of 2Λ (2.04 g, 8.97 mmol) in DMSO (10 mL) was cooled to 0°C and treated with sodium hydride (450 mg of 60% in oil, 11.2 mmol). The reaction mixture was warmed to room temperature for 15 min, followed by addition of ethyl bromoacetate (1.67 g, 10.0 mmol) and warming to 50°C overnight. The solvent was removed in vacuo and the residue diluted in water and extracted with three portions of dichloromethane The combined organic extracts were washed with bnne and dried (Na2SO4) The solvent was removed in vacuo Preparative centπfugdl chromatography (SιO₉, 6mm, 50% EtOAc, 50% hexane) afforded 2X2 (2 17 g)

FABLRMS m/e 314 g/mole (M++H, C₁₈H₁₉NO₄ = 314 g/mole)

(3-Hydroxy-l lH-dιbenzo[l,41oxazeριn-10-yl)-acetιc acid ethyl ester (2-3)

A solution of 2^2 (400 mg, 1 27 mmol) in dichloromethane (5 mL) was cooled to -5°C and treated with ethanethiol (419 mg, 6 75 mmol) and aluminum chlonde (81 mg, 6 11 mmol) After 30 min, the reaction was quenched with aqueous NH4CI solution The solvent was removed in vacuo and the residue dissolved in IM

HCl The aqueous layer was extracted with three portions of dichloromethane and the combined organic extracts were washed with bnne and dπed (Na2SO4) The solvent was removed in vacuo Preparative centπfugal chromatography (SιO₉, 4mm, 10% EtOH, 90% CH₂C1₂) afforded 2X (240 mg)

FABLRMS m/e 300 g/mole (M++H, C₁₇H₁₇NO₄ = 300 g/mole)

{3-[3-(l-Hydroxy-pyndιn-2-ylammo)-l-propoxyl-l lH-dιbenzo[l,41 oxazepιn-10-yl }- acetic acid ethyl ester (2-4)

A solution of 2^3 (150 mg, 0 500 mmol) and Ph₃P (204 mg, 0 777 mmol) in DMF (1 mL) was treated with a solution of DEAD (121 mg, 0 698 mmol) and 2-(3-hydroxy-propylamιno)-pyndm-l -oxide (122 mg, 0 725 mmol) in DMF (1 mL) at room temperature for 2 days The solvent was removed in vacuo and the residue partitioned between dichloromethane and aqueous Na2CO3 solution The aqueous layer was extracted with four portions of dichloromethane and the combined organic extracts washed with bnne and dned (Na2SO4) The solvent was removed in vacuo Preparative centrifugal chromatography (SιO₂, 2mm, 10% EtOH, 90% CH₂C1₂) afforded 2X (135 mg)

FABLRMS m/e 450 g/mole (M++H, C₂₅H₂₇N₃O₅ = 450 g/mole) { 3-[3-(Pvndm-2-ylamιno)-l-propoxyl-l lH-dιbenzo[l,41oxazepιn-10-yl }-acetιc acid ethyl ester (2-5)

A solution of 2^4 (135 mg, 0 300 mmol) m 2-propanol (20 mL) was treated with 1,4-cyclohexadιene (296 mg, 3.69 mmol) and 10% palladium on carbon (88 mg) The mixture was heated to reflux overnight. The reaction mixture was filtered through celite and the filtrate evaporated in vacuo to afford the title compound 2-5 (110 mg) The crude product was used directly in the next reaction

FABLRMS m/e 434 g/mole (M++H, C₂₅H₂₇N₃O₄ = 434 g/mole).

{ 3-[3-(Pvπdιn-2-ylamιno)-l-propoxy1-l lH-dιbenzo[l,41oxazepm-10-yl }-acetιc acid

(2-6)

A solution of 2^ (100 mg, 0.230 mmol) in THF (15 mL) and methanol

(5 mL) was treated with IM aqueous NaOH (5.00 mL) at room temperature for 30 minutes The reaction was neutralized with IM aqueous HCl (5.0 mL) and the solvents were removed in vacuo. Preparative centnfugal chromatography (SιO₉,

2mm, 10% MeOH; 25% EtOAc, 65% CHC1₃) afforded (60 mg)

^lH NMR (CDC1₃, 400 MHz) δ 8.85 (br s, IH), 7.80 (d, IH, J = 5.3 Hz), 7.60 (dt, IH, J = 1.7, 7.9 Hz), 7.04 (dd, IH, J = 1.3, 8.1 Hz), 6.91-6.53 (m, 8H), 4.27 (s, 2H), 4.09 (t, 2H, J = 6.0 Hz), 3.90 (br s, IH), 3.83 (s, 2H), 3.42 (t, 2H, J = 6.0 Hz), 2.11-2.04 (m, 2H); FABLRMS m/e 406 g mole (M++H, C₂₃H₂₃N₃O₄ = 406 g/mole),

Exact MS (ES) (M++H, C₂₃H₂₃N₃O₄ = 406.1761), Found 406.1765; HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H₂O [0.1% H3PO₄] - CH₃CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) RT = 8.431 m , focus = 215 nm; 98.8% pure

SCHEME A

Synthesis of Radioliqand for SPA Assay

A-1

H, dioxαne

SCHEME A, cont'd.

A-5a

όN HCl SCHEME A, cont'd

HC|.H₂N^ ^Cθ2CH2CH3 EDC, HOBT, ^H' HNS0₂C₆H₄l NMM, DMF

A-4

N-(4-Iodo-phenylsulfonylamιno)-L-asparagme (A-2)

To a stirred solution of acid AA (4.39 g, 33.2 mmol), NaOH (1.49 g, 37.2 mmol), dioxane (30 ml) and H2O (30 ml) at 0°C was added pipsyl chloride

(10.34 g, 34.2 mmol) After ~5 minutes, NaOH (1.49, 37.2 mmol) dissolved m 15 ml H2O, was added followed by the removal of the cooling bath. After 2.0 h, the reaction mixture was concentrated. The residue was dissolved m H2O (300 ml) and then washed with EtOAc. The aqueous portion was cooled to 0°C and then acidified with concentrated HCl. The solid was collected and then washed with diethyl ether to provide acid A-2 as a white solid. *H NMR (300 MHz, D2O) δ 7.86 (d, 2H, J=8Hz ), 7.48 (d, 2H, J=8Hz) 3.70 (m, IH),

2.39 (m, 2H).

2(S)-(4-Iodo-phenylsulfonylamιno)-β-alanιne (A-3)

To a stirred solution of NaOH (7.14 g, 181.8 mmol) and H2O (40 ml) at 0°C was added bromine (1.30 ml, 24.9 mmol) dropwise over a ten minute penod After ~5 minutes, acid AX. (9.9 g, 24.9 mmol), NaOH (2 00 g, 49.8 mmol) and H2O (35 ml) were combined, cooled to 0°C and then added in a single portion to the reaction. After stirring for 20 minutes at 0°C, the reaction was heated to 90°C for 30 minutes and then recooled to 0°C The pH was adjusted to ~7 by dropwise addition of concentrated HCl The solid was collected, washed with EtOAc, and then dried in vacuo to provide acid A-3 as a white solid

*H NMR (300 MHz, D2O) δ 8.02 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.36 (m, IH),

3.51 (dd, IH, J=5Hz, 13Hz) 3.21 (m, IH)

Ethyl 2(S)-(4-ιodo-phenylsulfonylamιno)-β-alanιne-hydrochloπde (A-4) HCl gas was rapidly bubbled through a suspension of acid A-3 (4 0 g,

10.81 mmol) in EtOH (50 ml) at 0°C for 10 minutes The cooling bath was removed and the reaction was heated to 60°C After 18 h, the reaction was concentrated to provide ester A-4 as a white solid !H NMR (300 MHz, CD3OD) δ 7.98 (d, 2H, J=8Hz), 7.63 (d, 2H, J=8Hz), 4.25 (q, IH, J=5Hz), 3.92 (m, 2H), 3.33 (m, IH), 3.06 (m, IH), 1.01 (t, 3H, J=7Hz)

Ethyl 4-[2-(2-Amιnopyπdιn-6-yl)ethyllbenzoate (A-5a)

A mixture of ester A-5 (700 mg, 2.63 mmol), (for preparation, see: Scheme 29 of PCT International Application Publication No. WO 95/32710, published December 7, 1995) 10% Pd/C (350 mg) and EtOH were stirred under 1 atm hydrogen gas. After 20 h, the reaction was filtered through a celite pad and then concentrated to provide ester A-5a as a brown oil TLC Rf = 0.23 (sihca, 40% EtOAc/hexanes) iH NMR (300 MHz, CDCI3) δ 7.95 (d, 2H, J=8Hz), 7.26 (m, 3H), 6.43 (d, IH, J=7Hz), 6.35 (d, IH, J=8Hz), 4.37 (m, 4H), 3.05 (m, 2H), 2.91 (m, 2H), 1.39 (t, 3H, J=7Hz).

4-[2-(2-Amιnopyπdιn-6-yl)ethyllbenzoιc acid hydrochlonde (A-6)

A suspension of ester N5a (625 mg, 2.31 mmol) in 6N HCl (12 ml) was heated to 60°C. After -20 h, the reaction was concentrated to give acid A-6 as a tan solid ^AH NMR (300 MHz, CD3OD) δ 7.96 (d, 2H, J=8Hz), 7.80 (m, IH), 7 33 (d, 2H,

J=8Hz). 6.84 (d, IH, J=9Hz), 6.69 (d, IH, J=7Hz), 3.09 (m, 4H) Ethyl 4-[2-(2-Ammopyπdιn-6-yl)ethyl]benzoyl-2(S)-(4-ιodo-phenylsulfonylamιno)-β- alan e (A-7)

A solution of acid 15-6 (400 mg. 1.43 mmol), amine A-4 (686 mg, 1.57 mmol), EDC (358 mg, 1.86 mmol), HOBT (252 mg, 1 86 mmol), NMM (632 μ\, 5.72 mmol) in DMF (10 ml) was stirred for -20 h. The reaction was diluted with EtOAc and then washed with saturated sodium hydrogencarbonate, bnne, dned (MgSOzi) and concentrated Flash chromatography (silica, EtOAc then 5% isopropanol/EtOAc) provided amide A-7 as a white solid. TLC Rf = 0.4 (silica, 10% isopropanol/EtOAc) IH NMR (300 MHz, CD3OD) δ 7.79 (d, 2H, J=9Hz) 7.61 (d, 2H, J=8Hz), 7.52 (d, 2H, J=9Hz), 7.29 (m, IH), 7.27 (d, 2H, J=8Hz), 4.20 (m, IH), 3 95 (q, 2H, J=7Hz), 3.66 (dd, IH, J=6Hz, 14Hz), 3 49 (dd, IH, J=8Hz, 13Hz), 3.01 (m, 2H). 2.86 (m, 2H), 1.08 (t, 3H, J=7Hz).

4-[2-(2-Amιnopyπdm-6-yl)ethyl]benzoyl-2(S)-(4-ιodophenyl-sulfonylammo)-β- alanme (A-8)

A solution of ester AX (200 mg, 0.3213 mmol) and 6N HCl (30 ml) was heated to 60°C. After -20 h, the reaction mixture was concentrated. Flash chromatography (silica, 20:20:1:1 EtOAc/EtOH/ NH4OH/H2O) provided acid N8 as a white solid.

TLC Rf = 0.45 (sihca, 20:20:1:1 EtOAc/EtOH/NH4θH/H2θ)

^JH NMR (400 MHz, DMSO-d6) δ 8.40 (m, IH), 8.14 (Bs, IH), 7.81 (d, 2H, J=8Hz), 7.62 (d, 2H, J=8Hz), 7.48 (d, 2H, J=8Hz), 7.27 (m, 3H), 6.34 (d, IH, J=7Hz), 6.25 (d, IH, J=8Hz), 5.85 (bs, 2H), 3.89 (bs, IH), 3.35 (m, 2H), 2 97 (m, 2H), 2.79 (m, 2H)

4-[2-(2-Ammopyndιn-6-yl)ethyl)benzoyl-2(S)-(4-tnmethylstanny]~ phenylsulfonylamino-β-alanine (A-9)

A solution of iodide N8 (70 mg, 0.1178 mmol), [(CH3)3Sn]2 (49 μl, 0.2356 mmol), Pd(PPh3)4 (5 mg) and dioxane (7 ml) was heated to 90°C. After 2 h, the reaction was concentrated and then purified by preparative HPLC (Delta-Pak Ci8 15 μM 100A°, 40 x 100 mm; 95:5 then 5:95 H2O/CH3CN) to provide the tπfluoroacetate salt The salt was suspended in H2O (10 ml), treated with NH4OH (5 drops) and then lyophihzed to provide amide A-9 as a white solid iH NMR (400 MHz, DMSO-d6) δ 8.40 (m, IH), 8.18 (d, IH, J=8Hz), 7.67 (m, 5H), 7.56 (d, 2H, J=8Hz), 7.29 (d, 2H, J=8Hz), 6.95-7.52 (m, 2H), 6 45 (bs, 2H), 4 00 (m, IH), 3 50 (m, IH), 3.33 (m, IH), 2.97 (m, 2H), 2 86 (m, 2H)

4-[2-(2-Amιnopyndιn-6-yl)ethyl]benzoyl-2(S)-4- ' 25]odo-phenylsulfonylamιno-β- alanme (A-10)

An lodobead (Pierce) was added to a shipping vial of 5 mCi of Na^5j (Amersham, IMS30) and stirred for five minutes at room temperature. A solution of 0.1 mg of N9 in 0.05 mL of 10% H2SO4/CH3OH was made and immediately added to the Na^25jy₁₀₍j₀5_eac! _vιaι_ After stirring for three minutes at room temperature, approximately 0.04-0.05 mL of NH4OH was added so the reaction mixture was at pH 6-7. The entire reaction mixture was injected onto the HPLC for puπfication [Vydac peptide-prote C-18 column, 4.6 x 250 mm, linear gradient of 10% acetonitπle (0.1% (TFA):H2θ (0.1% TFA) to 90% acetonitπle (0.1% TFA):H2θ (0.1% TFA) over 30 minutes, 1 mL/min]. The retention time of A-10 is 17 minutes under these conditions Fractions containing the majonty of the radioactivity were pooled, lyophihzed and diluted with ethanol to give approximately 1 mCi of A-10, which coeluted on HPLC analysis with an authentic sample of A-8.

Instrumentation: Analytical and preparative HPLC was earned out using a Waters 600E Powerlme Multi Solvent Delivery System with 0.1 mL heads with a Rheodyne 7125 injector and a Waters 990 Photodiode Array Detector with a Gilson FC203 Microfraction collector. For analytical and preparative HPLC, a Vydac peptide -protein C-18 column, 4.6 x 250 mm was used with a C-18 Brownlee modular guard column. The acetonitπle used for the HPLC analyses was Fisher Optima grade. The HPLC radiodetector used was a Beckman 170 Radioisotope detector. A Vydac C-18 protein and peptide column, 3.9 x 250 mm was used for analytical and preparative HPLC Solutions of radioactivity were concentrated using a Speedvac vacuum centrifuge. Calibration curves and chemical concentrations were determined using a Hewlett Packard Model 8452A UV/Vis Diode Aπ-ay Spectrophotometer. Sample radioactivities were determined in a Packard A5530 gamma counter.

The test procedures employed to measure αvβ3 and αvβ5 binding and the bone resorption inhibiting activity of the compounds of the present invention are described below. BONE RESORPTION-PIT ASSAY

When osteoclasts engage in bone resorption, they can cause the formation of pits in the surface of bone that they are acting upon Therefore, when testing compounds for their ability to inhibit osteoclasts, it is useful to measure the ability of osteoclasts to excavate these resorption pits when the inhibiting compound is present

Consecutive 200 micron thick cross sections from a 6 mm cylinder of bovine femur diaphysis are cut with a low speed diamond saw (Isomet, Beuler, Ltd , Lake Bluff, II). Bone slices are pooled, placed in a 10% ethanol solution and refπgerated until further use.

Prior to expeπmentation, bovme bone slices are ultrasonicated twice, 20 minutes each in H2O. Cleaned slices are placed in 96 well plates such that two control lanes and one lane for each drug dosage are available. Each lane represents either tnphcate or quadruplicate cultures. The bone slices in 96 well plates are steπhzed by UV irradiation. Pπor to incubation with osteoclasts, the bone slices are hydrated by the addition of 0.1 ml αMEM, pH 6.9 containing 5% fetal bovine serum and 1% penicillin/streptomycin.

Long bones from 7-14 day old rabbits (New Zealand White Hare) are dissected, cleaned of soft tissue and placed in αMEM containing 20 mM HEPES. The bones are m ced using scissors until the pieces are <1 mm and transferred to a 50 ml tube in a volume of 25 ml. The tube is rocked gently by hand for 60 cycles, the tissue is sedimented for 1 min., and the supernatant is removed. Another 25 ml of medium is added to the tissue and rocked again. The second supernatant is combined with the first. The number of cells is counted excluding erythrocytes (typically ~ 2 x 107 cells/ml). A cell suspension consisting of 5 x 106/ml in αMEM containing 5% fetal bovine serum, 10 nM l,25(OH)2D3, and pencilhn-streptomycm is prepared. 200 ml aliquots are added to bovine bone slices (200 mm x 6 mm) and incubated for 2 hrs. at 37°C in a humidified 5% CO2 atmosphere. The medium is removed gently with a micropipettor and fresh medium containing test compounds is added. The cultures are incubated for 48 hrs., and assayed for c-telopeptide (fragments of the al chain of type I collagen) by Crosslaps for culture media (Herlev, Denmark).

Bovine bone slices are exposed to osteoclasts for 20-24 hrs and are processed for staining. Tissue culture media is removed from each bone slice Each well is washed with 200 ml of H2O, and the bone slices are then fixed for 20 minutes in 2.5% glutaraldehyde, 0.1 M cacodylate, pH 7.4 After fixation, any remaining cellular debris is removed by 2 min. ultrasonication in the presence of 0.25 M NH4OH followed by 2 X 15 mm ultrasonication in H2O. The bone slices are immediately stained for 6-8 min with filtered 1% toluidine blue and 1% borax After the bone slices have dned, resorption pits are counted in test and control slices Resorption pits are viewed in a Microphot Fx (Nikon) fluorescence microscope using a polanzing Nikon IGS filter cube. Test dosage results are compared with controls and resulting IC50 values are determined for each compound tested The appropriateness of extrapolating data from this assay to mammalian (including human) disease states is supported by the teaching found in Sato, M., et al., Journal of Bone and Mineral Research, Vol. 5, No. l, pp. 31-40, 1990, which is incorporated by reference herein in its entirety This article teaches that certain bisphosphonates have been used clinically and appear to be effective in the treatment of Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastases, and bone loss due to immobilization or sex hormone deficiency. These same bisphosphonates are then tested in the resorption pit assay descnbed above to confirm a correlation between their known utility and positive performance in the assay.

EIB ASSAY

Duong et al., J. Bone Miner. Res., 8: S378 (1993), descπbes a system for expressing the human integπn αvβ3 It has been suggested that the integπn stimulates attachment of osteoclasts to bone matnx, since antibodies against the mtegnn, or RGD-containing molecules, such as echistatin (European Publication 382 451), can effectively block bone resorption.

Reaction Mixture:

1. 175 μl TBS buffer (50 mM Tris-HCl pH 7.2, 150 mM NaCl, 1% BSA, 1 mM CaC 12, 1 mM MgCtø).

2 25 ml cell extract (dilute with 100 mM octylglucoside buffer to give 2000 cpm/25 μl).

3 ¹²⁵I-echιstatιn (25 μl/50,000 cpm) (see EP 382 451)

4 25 μl buffer (total binding) or unlabeled echistatin (non-specific binding) The reaction mixture was then incubated for 1 h at room temp The unbound and the bound αvβ3 were separated by filtration using a Skatron Cell Harvester. The filters (prewet in 1.5% poly-ethyleneimine for 10 mins) were then washed with the wash buffer (50 mM Tns HCl, ImM CaCl2/MgCl2, pH 7.2). The filter was then counted in a g tsa"mma counter.

SPA ASSAY

MATERIALS-

1. Wheat germ agglutin Scintillation Proximity Beads (SPA): Amersham

2. Octylglucopyranoside: Calbiochem 3. HEPES: Calbiochem

4. NaCl: Fisher

5. CaCl2: Fisher

6. MgCl2: SIGMA

7. Phenylmethylsulfonylfluonde (PMSF): SIGMA 8. Optiplate: PACKARD

9 Compound A-10 (specific activity 500-1000 Ci/mmole)

10. test compound

11. Puπfied integπn receptor: αvβ3 was punfied from 293 cells overexpressing αvβ3 (Duong et al., J. Bone Mm. Res., 8:S378, 1993) according to Pytela (Methods in Enzymology, 144:475,

1987)

12. Binding buffer: 50 mM HEPES, pH 7.8, 100 mM NaCl, 1 mM Ca²⁺ Mg²+, 0.5 mM PMSF

13. 50 mM octylglucoside in binding buffer: 50-OG buffer

PROCEDURE:

1. Pretreatment of SPA beads:

500 mg of lyophihzed SPA beads were first washed four times with 200 ml of 50-OG buffer and once with 100 ml of binding buffer, and then resuspended in 12.5 ml of binding buffer 2 Preparation of SPA beads and receptor mixture

In each assay tube, 2.5 μl (40 mg/ml) of pretreated beads were suspended in 97.5 μl of binding buffer and 20 ml of 50-OG buffer. 5 ml (-30 ng/μl) of puπfied receptor was added to the beads in suspension with stirnng at room temperature for 30 minutes The mixture was then centrifuged at 2,500 rpm in a Beckman GPR Benchtop centπfuge for 10 minutes at 4°C The pellets were then resuspended in 50 μl of binding buffer and 25 μl of 50-OG buffer.

3. Reaction

The following were sequentially added into Optiplate in corresponding wells: (I) Receptor/beads mixture (75 μl) (n) 25 μl of each of the following: compound to be tested, binding buffer for total binding or A-8 for non-specific binding (final concentration 1 μM) (in) A-10 in binding buffer (25 μl, final concentration 40 pM) (iv) Binding buffer (125 μl) (v) Each plate was sealed with plate sealer from PACKARD and incubated overnight with rocking at 4°C

4. Plates were counted using PACKARD TOPCOUNT

5. % inhibition was calculated as follows:

A = total counts

B = nonspecific counts

C = sample counts

% inhibition = [{ (A-B)-(C-B)}/(A-B)]/(A-B) x 100 OCFORM ASSAY

Osteoblast-hke cells (1.8 cells), originally derived from mouse calvaπa, were plated in CORNF G 24 well tissue culture plates in αMEM medium containing nbo- and deoxyπbonucleosides, 10% fetal bovine serum and penicilhn- streptomycin. Cells were seeded at 40,000/well in the morning. In the afternoon, bone marrow cells were prepared from six week old male Balb/C mice as follows-

Mice were sacrificed, tibiae removed and placed in the above medium. The ends were cut off and the marrow was flushed out of the cavity into a tube with a 1 mL syπnge with a 27.5 gauge needle. The marrow was suspended by pipetting up and down. The suspension was passed through > 100 mm nylon cell strainer. The resulting suspension was centrifuged at 350 x g for seven minutes. The pellet was resuspended, and a sample was diluted in 2% acetic acid to lyse the red cells. The remaining cells were counted in a hemacytometer The cells were pelleted and resuspended at 1 x 10" cells/mL. 50 μL was added to each well of 1.8 cells to yield 50,000 cells/well and 1 ,25-dιhydroxy-vιtamm D3 (D3) was added to each well to a final concentration of 10 nM. The cultures were incubated at 37°C in a humidified, 5% CO2 atmosphere After 48 h, the medium was changed. 72 h after the addition of bone marrow, test compounds were added with fresh medium containing D3 to quadruplicate wells. Compounds were added again after 48 h with fresh medium containing D3. After an additional 48 h., the medium was removed, cells were fixed with 10% formaldehyde in phosphate buffered saline for 10 minutes at room temperature, followed by a 1-2 minute treatment with ethano acetone (1: 1) and air dπed The cells were then stained for tartrate resistant acid phosphatase as follows: The cells were stained for 10-15 minutes at room temperature with 50 mM acetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mL Fast Red Violet LB Salt and 0.1 mg/mL Naphthol AS -MX phosphate. After staining, the plates were washed extensively with deionized water and air dned. The number of multinucleated, positive staining cells was counted in each well.

αvβ5 ATTACHMENT ASSAY

Duong et al., J. Bone Miner. Res., 11 ^• S290 (1996), descπbes a system for expressing the human αvβ5 integnn receptor

Mateπals. 1 Media and solutions used in this assay are purchased from BRL/Gibco, except BSA and the chemicals are from Sigma

2 Attachment medium: HBSS with 1 mg/ml heat-mactivated fatty acid free BSA and 2 mM CaCl2 3. Glucosaminidase substrate solution: 3.75 mM p-mtrophenyl N-acetyl-beta-

D-glucosaminide, 0.1 M sodium citrate, 0.25% Triton, pH 5.0. 4 Glycine-EDTA developing solution: 50 mM glycine, 5 mM EDTA, pH 10.5.

Methods.

1. Plates (96 well, Nunc Maxi Sorp) were coated overnight at 4 °C with human vitronectin (3 μg/ml) in 50 mM carbonate buffer (pH 9/.6), using 100 μl/well. Plates were then washed 2X with DPBS and blocked with 2% BSA in DPBS for 2h at room temperature. After additional washes (2X) with DPBS, plates were used for cell attachment assay.

2. 293 (αvβ5) cells were grown in αMEM media in presence of 10% fetal calf serum to 90% confluence. Cells were then lifted from dishes with IX Trypsm/EDTA and washed 3X with serum free αMEM Cells were resuspended in attachment medium (3 X 10^ cells/ml). 3. Test compounds were prepared as a senes of dilutions at 2X concentrations and added as 50 μl/well. Cell suspension was then added as 50 ml/well. Plates were incubated at 37 °C with 55 CO2 for 1 hour to allow attachment. 4. Non-adherent cells were removed by gently washing the plates (3X) with DPBS and then incubated with glucosaminidase substrate solution (100 μl/well), overnight at room temperature in the dark. To quantitate cell numbers, standard curve of glucosaminidase activity was determined for each expenment by adding samples of cell suspension directly to wells containing the enzyme substrate solution. 5. The next day, the reaction was developed by addition of 185 μl/well of glycine/EDTA solution and reading absorbance at 405 nm using a Molecular Devices V-Max plate reader. Average test absorbance values (4 wells per test samples) were calculated. Then, the number of attached cells at each drug concentration was quantitated versus the standard curve of cells using the Softmax program. EXAMPLE OF A PHARMACEUTICAL FORMULATION

As a specific embodiment of an oral composition, 100 mg of any of the compounds of the present invention are formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule

Representative compounds of the present invention were tested and found to bind to human αvβ3 integπn. These compounds were generally found to have IC50 values less than about 100 nM in the SPA assay. Representative compounds of the present invention were tested and generally found to inhibit > 50% the attachment of αvβ5 expressing cells to plates coated with vitronectin at concentrations of about 1 μM.

While the invention has been descnbed and illustrated in reference to certain preferred embodiments thereof, those skilled in the art will appreciate that vanous changes, modifications and substitutions can be made therein without departing from the spiπt and scope of the invention. For example, effective dosages other than the preferred doses as set forth hereinabove may be applicable as a consequence of vaπations in the responsiveness of the mammal being treated for seventy of bone disorders caused by resorption, or for other indications for the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compound selected or whether there are present pharmaceutical earners, as well as the type of formulation and mode of administration employed, and such expected vaπations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be limited only by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula

(I)

or a pharmaceutically acceptable salt thereof;

wherein U and V each independently represent N or CR6, provided that no more than one U represents N and no more than one V represents N;

W is C=O; SO2; or CRlR2_;

X is O; S(O)0-2; NR⁴; or CR1R2;

Y is selected from the group consisting of

-(CH )0-4-,

-(CH₂)0-4-O-(CH₂)l-4-, -(CH₂)0-4-NR⁴-(CH )l-4-

-(CH₂)0-4-S-(CH₂)l-4-, -(CH₂)0-4-SO-(CH₂)l-4-, -(CH2)0-4-SO₂-(CH₂)l-4

^.(CH₂)0-4-O-(CH₂) 1 -4-O-(CH₂)0-4-,

-(CH₂)0-4-O-(CH₂)1-4-NR4-(CH₂)0-4-,

-(CH₂)0-4-NR⁴-(CH₂)l-4-NR⁴-(CH₂)0-4-,

-(CH₂)0-4-O-(CH₂) 1 -4-S-(CH₂)0-4-,

-(CH₂)0-4-S-(CH₂)l-4-S-(CH₂)0-4-,

-(CH₂)0-4-NR⁴-(CH₂)l-4-S-(CH₂)0-4-, -(CH₂)0-4-NR⁴-(CH₂)l-4-O-(CH2)0-4-, -(CH₂)0-4-S-(CH2)l-4-O-(CH₂)0-4-, and

-(CH2)0-4-S-(CH₂)l-4-NR -(CH₂)0-4-,

wherein any methylene (CH2) carbon atom in Y, other than in R⁴, can be substituted by one or two R^ substituents;

Z is selected from the group consisting of

a 5- or 6-membered monocychc aromatic or nonaromatic nng system having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S wherein the non-aromatic πng nitrogen atoms are unsubstituted or substituted with one R^ substituent and the πng carbon atoms are unsubstituted or substituted with one or two R6 substituents, and

a 9- to 14-membered polycychc nng system, wherein one or more of the nngs is aromatic, and wherein the polycychc nng system has 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S, and wherein the non-aromatic nng nitrogen atoms are unsubstituted or substituted with one R^ substituent and the πng carbon atoms are unsubstituted or substituted with one or two R" substituents;

R! and R² are each independently selected from the group consisting of hydrogen, halo,

Ci-8 alkyl,

C2-8 alkenyl,

C2-8 alkynyl,

C3-8 cycloalkyl, C3-8 cycloheteroalkyl,

C3-8 cycloalkyl Cι_6 alkyl,

C3-8 cycloheteroalkyl Ci-6 alkyl, aryl, aryl C[- alkyl, amino Ci-6 alkyl,

Ci-4 acylamino C[-β alkyl,

(Ci-6 alkyl) 1-2 amino -6 alkyl, hydroxy C 1-6 alkyl,

Ci-6 alkoxy Ci-6 alkyl,

Ci-6 alkylthio Ci-6 alkyl, hydroxycarbonyl C -6 alkyl,

Ci-4 alkoxycarbonyl -6 alkyl, and tπfluoromethyl;

each R3 IS independently selected from the group consisting of hydrogen, halo, aryl, Ci-8 alkyl,

C2-8 alkenyl,

C2-8 alkynyl, aryl Ci-6 alkyl,

C3-8 cycloalkyl, hydroxyl, oxo, tπfluoromethyl,

Ci-6 alkoxy, aryl Ci-6 alkoxy, Ci-6 alkylthio, aryl Cι_6 alkylthio, aminocarbonyl,

(Ci-6 alkyl) 1-2 aminocarbonyl, arylaminocarbonyl, aryl Ci-6 alkylammocarbonyl, aryloxycarbonylam o, Ci-6 alkoxycarbonylammo, aryl Ci-6 alkoxycarbonylammo, arylcarbonylamino Q-6 alkylcarbonylammo, aryl Q-6 alkylcarbonylammo, (Ci-6 alkyl) 1-2 aminocarbonyloxy, Q-6 alkylsulfonylamino, arylsulfonylamino, aryl Q-6 alkylsulfonylamino, Q-6 alkylsulfonyl, aryl Ci-6 alkylsulfonyl, Q-6 alkylcarbonyl, and aryl C 1-6 alkylcarbonyl; or two R3 substituents, when on the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group, wherein any of the alkyl groups of R^ are either unsubstituted or substituted with one to three R! substituents, and provided that each R^ is selected such that in the resultant compound the carbon atom or atoms to which R^ is attached is itself attached to no more than one heteroatom;

each R⁴ is independently selected from the group consisting of hydrogen,

Ci-8 alkyl,

C2-8 alkenyl,

C2-8 alkynyl, aryl -6 alkyl, Q-4 alkoxy Q-6 alkyl,

C3-8 cycloalkyl,

Q-6 alkylsulfonyl, arylsulfonyl, arylQ-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, aryloxycarbonyl, aryl Q-6 alkoxycarbonyl,

Q-6 alkylcarbonyl, arylcarbonyl, aryl Q-6 alkylcarbonyl, hydroxycarbonyl Q-6 alkyl, Q-4 alkoxycarbonyl Q-6 alkyl, (aryl)i-2 aminocarbonyl, (aryl Q-6 alkyl) i -2 aminocarbonyl, and

(Q-6 alkyl)i-2 aminocarbonyl;

wherein any of the alkyl groups of R4 are either unsubstituted or substituted with one to three R! substituents;

R5 is selected from the group consisting of hydrogen,

C i-8 alkyl, aryl, aryl Q-6 alkyl,

Q-6 alkylcarbonyloxy Q_4 alkyl, aryl Q-6 alkylcarbonyloxy Q-4 alkyl,

Q-6 alkylammocarbonylmethylene, and

Q-6 dialkylaminocarbonylmethylene;

each R" ^ independently selected from the group consisting of hydrogen, halo,

Q-8 alkyl, C2-8 alkenyl,

C2-8 alkynyl,

C3-8 cycloalkyl,

C3-8 cycloheteroalkyl,

C3-8 cycloalkyl Q_6 alkyl, C3-8 cycloheteroalkyl Q-6 alkyl, aryl, aryl Q-6 alkyl, amino, amino Q-6 alkyl, Q-4 acylamino, Q-4 acylamino Q-6 alkyl, (Q-6 alkyl) 1-2 amino, (Q-6 alkyl)i-2 amino Q-6 alkyl, Q-4 alkoxy,

Q-4 alkoxy Q-6 alkyl, hydroxycarbonyl, hydroxycarbonyl Q-6 alkyl, Q-4 alkoxycarbonyl, C 1-4 alkoxycarbonyl C 1-6 alkyl, hydroxycarbonyl-Q-6 alkyloxy, hydroxy, hydroxy Q-6 alkyl, nitro, cyano, trifluoromethyl,

2,2,2-trifluoroethyl, trifluoromethoxy, trifluoroethoxy, Q-6 alkyl-S(O)i-₂,

(Q-6 alkyl)i-2 aminocarbonyl,

Q-6 alkyloxycarbonylamino,

(Q-6 alkyl) 1-2 aminocarbonyloxy,

(aryl Q-6 alkyl) i -2 amino, (aryl) 1-2 amino, aryl Q-6 alkylsulfonylamino, and

Q-6 alkylsulfonylamino; or two R6 substituents, when on the same aliphatic carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; and

R ' is selected from the group consisting of hydrogen, Q-8 alkyl, C2-8 alkenyl,

C2-8 alkynyl,

C3-8 cycloalkyl,

C3-8 cycloheteroalkyl,

C3_ cycloalkyl C -6 alkyl,

C3-8 cycloheteroalkyl Cι_6 alkyl, arylQ-6 alkyl, arylcarbonyl, Ci-6 alkylcarbonyl, arylQ-6 alkylcarbonyl, aryloxycarbonyl,

Ci-6 alkoxycarbonyl, and arylQ-6 alkoxycarbonyl.

2. The compound of Claim 1 of the formula

(II)

wherein W, X, Y, Z, Rl, R2, R3, R4, R5, R6, and R7 are as defined in Claim 1.

3. The compound of Claim 2

wherein X is O or S; W is C=O or CH2; and W, X, Y, Z, Rl , R2, R3, R4, R5, R6, and R7 are as defined in Claim 1.

4. The compound of Claim 3 wherein X is O.

5. The compound of Claim 4 wherein Y is selected from the group consisting of

-(CH₂)0-4-,

-(CH₂)0-4-O-(CH₂)l-4-,

-(CH₂)0-4-NR4-(CH2)1 -4-,

-(CH₂)0-4-S-(CH₂)l-4-,

-(CH₂)0-4-SO-(CH₂)l-4-,

-(CH₂)0-4-SO₂-(CH₂)l-4-,

-(CH₂)0-4-O-(CH₂)l-4-O-(CH2)0-4-,

-(CH2)0-4-O-(CH₂)1-4-NR4-(CH2)0-4-,

-(CH₂)0-4-NR⁴-(CH2)l-4-NR⁴-(CH2)0-4-, and

-(CH2)0-4-NR4-(CH₂)1-4-O-(CH₂)0-4-, wherein any methylene (CH2) carbon atom in Y, other than in R , can be substituted by one or two R^ substituents;

Z is selected from the group consisting of

wherein the πng carbon atoms are unsubstituted or substituted with one or two R6 substituents; Rl and R2 are independently selected from the group consisting of hydrogen, Q-6 alkyl, C3-8 cycloalkyl, C3- cycloheteroalkyl, and aryl Q-3 alkyl;

each R3 is independently selected from the group consisting of hydrogen, aryl,

Q-8 alkyl, aryl Q-6 alkyl, fluoro, hydroxy, oxo, trifluoromethyl, aminocarbonyl, arylaminocarbonyl, aryl Q-6 alkylaminocarbonyl, and (C -6 alkyl) 1-2 aminocarbonyl;

each R4 is independently selected from the group consisting of hydrogen,

Q-8 alkyl, aryl Q-6 alkyl,

C3-8 cycloalkyl,

Q-4 alkoxy Q_6 alkyl,

Q-6 alkylsulfonyl, arylQ-6 alkylsulfonyl, Q-6 alkoxycarbonyl, aryl Q-6 alkoxycarbonyl,

Q-6 alkylcarbonyl, arylcarbonyl, aryl Q-6 alkylcarbonyl, (aryl)ι_2 aminocarbonyl,

(aryl Q-6 alkyl)ι_2 aminocarbonyl, and

(Q-6 alkyl) 1-2 aminocarbonyl;

each R6 IS independently selected from the group consisting of hydrogen, cyano, halo, Q-4 alkyl, aryl, aryl Q_3 alkyl, Q-4 acylamino, Q-4 alkoxy, Q-4 alkylthio, aminocarbonyl,

(Q-6 alkyl)i-2 aminocarbonyl, Q-4 alkoxycarbonyl, tπfluoromethyl, and tπfluoromethoxy; and

R7 IS hydrogen, Q_3 alkyl, or aryl Q-3 alkyl.

6. The compound of Claim 5 wherein Y is selected from the group consisting of

-(CH )0-4-,

-(CH₂)0-4-O-(CH₂)l-4-, -(CH₂)0-4-NR4-(CH₂)1-4-, -(CH₂)0-4-S-(CH₂)l-4-, and -(CH₂)0-4-NR⁴-(CH₂)l-4-O-(CH₂)l-4-;

wherein any methylene (CH2) carbon atom in Y, other than in R⁴, can be substituted by one or two R^ substituents; Z is selected from the group consisting of

wherein the ring carbon atoms are unsubstituted or substituted with one or two R6 substituents;

Rl and R2 are independently selected from hydrogen and Q-3 alkyl; and

R4 IS selected from the group consisting of hydrogen, Q-4 alkyl, aryl Q-4 alkyl, and Q-4 alkoxy Q-4 alkyl.

7. The compound of Claim 6 wherein Y is selected from the group consisting of

-(CH₂)0-4-,

-(CH2)0-4-NR⁴-(CH2)l-4- and -(CH₂)0-4-NR4-(CH₂)1-4-O-(CH2)0-4-;

wherein any methylene (CH2) carbon atom in Y, other than in R⁴, can be substituted by one or two R3 substituents;

R3 IS hydrogen or oxo; and R4 IS hydrogen or methyl.

8. The compound of Claim 7 wherein R^ IS selected from the group consisting of hydrogen, methyl, and ethyl.

9. The compound of Claim 8 wherein R^ IS hydrogen.

10 The compound of Claim 8 selected from the group consisting of

{ l l-Oxo-3-[3-(pyndιn-2-ylamιno)-l-propoxy]-l lH-dιbenzo[l,4]oxazepιn-10-yl [- acetic acid ethyl ester;

{ l l-Oxo-3-[3-(pyπdιn-2-ylamιno)-l-propoxy]-HH-dιbenzo[l,4]oxazepιn-10-yl}- acetic acid;

{3-[3-(Pyπdm-2-ylamιno)-l-propoxy]-l lH-dιbenzo[l,4]oxazepιn-10-yl [-acetic acid ethyl ester;

{3-[3-(Pyndιn-2-ylammo)-l-propoxy]-l lH-dιbenzo[l,4]oxazepιn-10-yl [-acetic acid;

or a pharmaceutically acceptable salt thereof.

11 The compound of Claim 10 selected from the group consisting of

{ l l-Oxo-3-[3-(pyπdm-2-ylamιno)-l-propoxy]-l lH-dιbenzo[l,4]oxazepιn-10-yl }- acetic acid; { 3-[3-(Pyπdιn-2-ylamιno)-l-propoxy]-l lH-dιbenzo[l,4]oxazepιn-10-yl [-acetic acid,

or a pharmaceutically acceptable salt thereof

12 A pharmaceutical composition compπsing a compound according to Claim 1 and a pharmaceutically acceptable earner

13 The composition of Claim 12 which further compπses an active ingredient selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) a cytotoxic/antiprohferative agent, d) a matrix metalloprotemase inhibitor, e) an inhibitor of epidermal-deπved, fibroblast-deπved, or platelet- deπved growth factors, f) an inhibitor of VEGF, g) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tιe-2, or Tie- 1, h) a cathepsin K inhibitor, and l) a prenylation inhibitor, such as a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor, and mixtures thereof

14 The composition of Claim 13 wherein said active ingredient is selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, and c) a cathepsin K inhibitor, and mixtures thereof

15. The composition of Claim 14 wherein said organic bisphosphonate or pharmaceutically acceptable salt or ester thereof is alendronate monosodium tnhydrate.

16. A method of eliciting an αv integπn receptor antagonizing effect in a mammal in need thereof, compnsmg administeπng to the mammal a therapeutically effective amount of a compound according to Claim 1.

17. The method of Claim 16 wherein the αv integπn receptor antagonizing effect is an αvβ3 antagonizing effect.

18 The method of Claim 17 wherein the αvβ3 antagonizing effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, and metastasis.

19. The method of Claim 18 wherein the αvβ3 antagonizing effect is the inhibition of bone resorption.

20. The method of Claim 16 wherein the αv mtegnn receptor antagonizing effect is an αvβ5 antagonizing effect.

21. The method of Claim 20 wherein the αvβ5 antagonizing effect is selected from the group consisting of inhibition of restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, tumor growth, and metastasis.

22. The method of Claim 16 wherein the αv integnn receptor antagonizing effect is a dual αvβ3/αvβ5 antagonizing effect.

23. The method of Claim 22 wherein the dual αvβ3/αvβ5 antagonizing effect is selected from the group consisting of inhibition of bone resorption, restenosis, angiogenesis, diabetic retinopathy, macular degeneration, inflammation, viral disease, tumor growth, and metastasis. 24 A method of eliciting an αv integnn receptor antagonizing effect in a mammal in need thereof, compnsmg administering to the mammal a therapeutically effective amount of the composition of Claim 12

25 A method of treating or preventing a condition mediated by antagonism of an αv integnn receptor in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the composition of Claim 12

26 A method of inhibiting bone resorption in a mammal in need thereof, compnsmg administenng to the mammal a therapeutically effective amount of the composition of Claim 12

27 A method of inhibiting bone resorption in a mammal in need thereof, compnsmg administeπng to the mammal a therapeutically effective amount of the composition of Claim 14

28 A method of inhibiting bone resorption m a mammal in need thereof, compπsing administenng to the mammal a therapeutically effective amount of the composition of Claim 15

29 A method of treating tumor growth in a mammal in need thereof, compnsmg administenng to the mammal a therapeutically effective amount of the composition of Claim 12