HYDROXY ACID INTEGRIN ANTAGONISTS

Abstract: The present invention relates to compounds, pharmaceutical compositions and method of using alpha v beta 3 and/or alpha v beta 5 selective integrin antagonists.

Description: HYDROXY ACID INTEGRIN ANTAGONISTS The present application claims priority under Title 35, United States Code, §119 of United States Provisional applications Serial No. 60/235,616 filed September 27, 2000 and Serial No. 60/60/241 ,656 filed October 10, 2000. Field of the Invention The present invention relates to pharmaceutical agents which are ctvβ 3 and/or αvβs integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by α v β3 and/or v βs integrins. Background of the Invention Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked α and β polypeptide subunits. Currently eleven different α subunits have been identified and six different β subunits have been identified. The various a subunits can combine with various β subunits to form distinct integrins. The integrin identified as β 3 (also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis (Ross, et al., J. Biol, Chem., 1987, 262, 7703), Paget's disease, humoral hypercalcemia of malignancy (Carron et al., Cancer Res. 1998, 58, 1930), osteopenia (Lark et al., J Bone Miner Res. 2001 ,16, 319), endometriosis (Healy et al., Hum. Reproductive Update, 1998, 4, 736), angiogenesis, including tumor angiogenesis (Cheresh, Cancer Metastasis Rev., 1991 , 10, 3-10 and Brooks, et al., Cell, 1994, 79, 1157), retinopathy including macular degeneration (Friedlander et al., Proc. Natl. Acad. Sci USA 1996, 93, 9764), arthritis, including rheumatoid arthritis (Badger et al., Arthritis Rheum, 2001 , 44, 128), periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis and artherosclerosis, (Brown et al., Cardiovascular Res., 1994, 28, 1815). The compounds of the present invention are αvββ antagonists and can be used, alone or in combination with other therapeutic agents, in the treatment or modulation of various conditions or disease states described above. Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials. Thus, compounds which selectively antagonize αvββ would be beneficial for treating such conditions. The integrin αvβs plays a role in neovascularization. Antagonists of the αvβ δ integrin will inhibit neovascularization and will be useful for treating and preventing angiogenesis metastasis, tumor growth, macular degeneration and diabetic retionopathy. M.C. Friedlander, et al., Science, 270, 1500-1502 (1995) disclose that a monoclonal antibody for αvβs inhibits VEFG-induced angogenesis in the rabbit cornea and the chick chorioallantoic membrane model. Therefore, it would be useful to antagonize both the vβs and the αvββ receptor. Such "mixed vβs/αvββ antagonists" or "dual αvββ/αvβs antagonists" would be useful for treating or preventing angiogenesis, tumor metastasis, tumor growth, diabetic retinopathy, macular degeneration, atherosclerosis and osteoporosis. It has been shown that the αvββ integrin and other αv containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to αvβ3 also bind to αvβs, ocvβ . and nbβ3- Antagonism of platelet n b ββ (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin αvββ, it would be beneficial to develop compounds which are selective antagonists of αvβ3 as opposed to αnbβ3- Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor. Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the αvβ 3 integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin vβ3 expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the αvββ integrin cell adhesion receptor to impede tumor metastasis would be beneficial. Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of αvβ3 provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of αvβ3 antagonists causes dramatic regression of various histologically distinct human tumors. The adhesion receptor integrin α ββ was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells. Antagonists of αvββ inhibit this process by selectively promoting apoptosis of cells in neovasculature. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, αvββ antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571). It has been reported that the cell surface receptor αvβ 3 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it results in osteoporosis (loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of α ββ have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411 - 1413]. Antagonism of αvββ leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast v ββ which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis. The role of the αvββ integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vase. Surg. Vol. 19(1) (1994) 125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial. White (Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses αvβ 3 for entering host cells. The integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit αvβ 3 would find usefulness as antiviral agents. Summary of the Invention The compounds of this invention are 1) αvβ3 integrin antagonists; or 2) αvβs integrin antagonists; or 3) mixed or dual αvβs/αvβs antagonists. The present invention includes compounds which inhibit the respective integrins and also includes pharmaceutical compositions comprising such compounds. The present invention further provides for methods for treating or preventing conditions mediated by the vββ and/or αvβs receptors in a mammal in need of such treatment comprising administering a therapeutically effective amount of the compounds of the present invention and pharmaceutical compositions of the present invention. Administration of such compounds and compositions of the present invention inhibits angiogenesis, tumor metastasis, tumor growth, osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, retinopathy, macular degeneration, arthritis, periodontal disease, smooth muscle cell migration, including restenosis and artherosclerosis, and viral diseases. The present invention relates to a class of compounds represented by the Formula I. or a pharmaceutically acceptable salts thereof wherein X is Y is selected from the group consisting of N-R 1 , 0, and S; A is N or C; R 1 is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle, monocyclic heterocycles, and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or R taken together with R forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl; or R 1 taken together with R 8 forms a 5 membered heteroaromatic ring optionally substituted with one or more substituent selected from lower alkyl, phenyl and hydroxy; or R 1 taken together with R 8 forms a 5 membered heteroaromatic ring fused with a phenyl group; R 8 (when not taken together with R 1 ) and R 9 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, monocyclic heterocycles, monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl, monocyclic and bicyclic heterocyclicalkyls, -SO 2 R 10 wherein R 10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles; and O c R wherein R 10 is defined as above; or or NR and R taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of 0, N and S; or wherein Y' is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl, aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl, alkynyl, alkenyl, -S-R 11 and -OR 11 wherein R 11 is selected from the group consisting of H, alkyl, aralkyl, aryl, alkenyl, and alkynyl, or R 11 taken together with R 8 forms a 4-12 membered mononitrogen and monosulfur or monooxygen containing heterocyclic ring optionally substituted with lower alkyl, hydroxy, keto, phenyl, carboxyl or carboxyl ester, and fused phenyl, or R 11 taken together with R 8 is thiazole, oxazole, benzoxazole, or benzothiazole; R 8 is defined as above; or Y 1 (when Y 1 is carbon) taken together with R 8 forms a 4-12 membered mononitrogen or dinitrogen containing ring optionally substituted with alkyl, aryl, keto or hydroxy; or wherein R 1 and R 8 taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, phenyl, or carboxyl derivatives; and R 9 is selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, or acyloxymethoxycarbonyl; or wherein R 1 and R 8 taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with hydroxy, keto, phenyl, or alkyl; and R 9 are both selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl; R 2 , R 3 and R 4 are independently selected from one or more substituent selected from thegroup consisting of H, alkyl, hydroxy, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino, alkylamino, acylamino, dialkylamino, cyano, alkylthio, alkylsulfonyl, carboxyl derivatives, trihaloacetamide, acetamide, aryl, fused aryl, cycloalkyl, thio, monocyclic heterocycles, fused monocyclic heterocycles, and X, wherein X is defined above; R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carboxyl derivatives, haloalkyl, cycloalkyl, monocyclic heterocycles, monocyclic heterocycles optionally substituted with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino, amido, alkyl optionally substituted with one or more of halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkylamino, dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonic acid, phosphonic acid derivatives, phosphinic acid derivatives, aryl, arylthio, arylsulfoxide, or arylsulfone all optionally substituted on the aryl ring with halo, alkyl, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl, monocyclic heterocycles, and fused monocyclic heterocycles, monocyclic heterocyclicthio, monocyclic heterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can be optionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy, fused aryl, or alkyl, alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl, aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycles. It is another object of the invention to provide pharmaceutical compositions comprising compounds of the Formula I. Such compounds and compositions are useful in selectively inhibiting or antagonizing the v β 3 and/or αv βs integrins and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the αv β 3 and/or v βs integrin. The invention further involves treating or inhibiting pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget's disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials. Detailed Description In its broadest sense, the invention relates to compounds represented by Formula I or a pharmaceutically acceptable salts thereof wherein X is Y is selected from the group consisting of N-R 1 , 0, and S; A is N or C; R is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle, monocyclic heterocycles, and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or R taken together with R forms a 4- 12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl; or R 1 taken together with R 8 forms a 5 membered heteroaromatic ring optionally substituted with one or more substituent selected from lower alkyl, phenyl and hydroxy; or R 1 taken together with R 8 forms a 5 membered heteroaromatic ring fused with a phenyl group; R (when not taken together with R ) and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, monocyclic heterocycles, monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl, monocyclic and bicyclic heterocyclicalkyls, -SO 2 R 10 wherein R 10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles; and O ,10 R >10 w ,herei .n r R, 10 i •s defined as above; or or NR and R taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of 0, N and S; or wherein Y' is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl, aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl, alkynyl, alkenyl, -S-R 11 and -OR 11 wherein R 11 is selected from the group consisting of H, alkyl, aralkyl, aryl, alkenyl, and alkynyl, or R 11 taken together with R forms a 4-12 membered mononitrogen and monosulfur or monooxygen containing heterocyclic ring optionally substituted with lower alkyl, hydroxy, keto, phenyl, carboxyl or carboxyl ester, and fused phenyl, or R 11 taken together with R 8 is thiazole, oxazole, benzoxazole, or benzothiazole; R 8 is defined as above; or Y 1 (when Y 1 is carbon) taken together with R 8 forms a 4-12 membered mononitrogen or dinitrogen containing ring optionally substituted with alkyl, aryl, keto or hydroxy; or 1 8 wherein R and R taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, phenyl, or carboxyl derivatives; and R 9 is selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, or acyloxymethoxycarbonyl; or wherein R and R taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with hydroxy, keto, phenyl, or alkyl; and R 9 are both selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl; R 2 , R 3 and R 4 are independently selected from one or more substituent selected from thegroup consisting of H, alkyl, hydroxy, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino, alkylamino, acylamino, dialkylamino, cyano, alkylthio, alkylsulfonyl, carboxyl derivatives, trihaloacetamide, acetamide, aryl, fused aryl, cycloalkyl, thio, monocyclic heterocycles, fused monocyclic heterocycles, and X, wherein X is defined above; R , R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carboxyl derivatives, haloalkyl, cycloalkyl, monocyclic heterocycles, monocyclic heterocycles optionally substituted with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino, amido, alkyl optionally substituted with one or more of halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkylamino, dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonic acid, phosphonic acid derivatives, phosphinic acid derivatives, aryl, arylthio, arylsulfoxide, or arylsulfone all optionally substituted on the aryl ring with halo, alkyl, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl, monocyclic heterocycles, and fused monocyclic heterocycles, monocyclic heterocyclicthio, monocyclic heterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can be optionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy, fused aryl, or alkyl, alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl, aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycles. In another embodiment, the invention is represented by Formula II π or a pharmaceutically acceptable salt thereof, wherein R Ϊ and R 2 are selected from a group consisting of hydrogen, hydroxy alkyl haloalkyl and halo. The invention further relates to pharmaceutical compositions containing therapeutically effective amounts of the compounds of Formula I or II. The invention also relates to a method of selectively inhibiting or antagonizing the αv β 3 integrin and/or the αv βs integrin and more specifically relates to a method of inhibiting bone resorption, periodontal disease, osteoporosis, humoral hypercalcemia of malignancy, Paget's disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, smooth muscle cell migration and restenosis by administering a therapeutically effective amount of a compound of the Formula I to achieve such inhibition together with a pharmaceutically acceptable carrier. As used herein, the terms "alkyl" or "lower alkyl" refer to a straight chain or branched chain hydrocarbon radicals having from about 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like. As used herein the terms "alkenyl" or "lower alkenyl" refer to unsaturated acyclic hydrocarbon radicals containing at least one double bond and 2 to about 6 carbon atoms, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons. Examples of such groups are ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like. As used herein the terms "alkynyl" or "lower alkynyl" refer to acyclic hydrocarbon radicals containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. The term "cycloalkyl" as used herein means saturated or partially unsaturated cyclic carbon radicals containing 3 to about 8 carbon atoms and more preferably 4 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-l-yl, and the like. The term "aryl" as used herein denotes aromatic ring systems composed of one or more aromatic rings. Preferred aryl groups are those consisting of one, two or three aromatic rings. The term embraces aromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and the like. As used herein, the term "cyano" is represented by a radical i The terms "hydroxy" and "hydroxyl" as used herein are synonymous and are represented by a radical The term "lower alkylene" or "alkylene" as used herein refers to divalent linear or branched saturated hydrocarbon radicals of 1 to about 6 carbon atoms. As used herein the term "alkoxy" refers to straight or branched chain oxy containing radicals. Examples of alkoxy groups encompassed include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t-butoxy and the like. As used herein the terms "arylalkyl" or "aralkyl" refer to a radical of ^— R 22 — R 21 the formula < 1 wherein R is aryl as defined above and R is an alkylene as defined above. Examples of aralkyl groups include benzyl, pyridylmethyl, naphthylpropyl, phenethyl and the like. As used herein the term "nitro" is represented by a radical — N0 2 . As used herein the term "halo" or "halogen" refers to bromo, chloro, fluoro or iodo. As used herein the term "haloalkyl" refers to alkyl groups as defined above substituted with one or more of the same or different halo groups at one or more carbon atom. Examples of haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl and the like. As used herein the term "carboxyl" or "carboxy" refers to a radical of the formula -COOH. As used herein the term "carboxyl ester" refers to a radical of the formula - COOR 23 wherein R 23 is selected from the group consisting of H, alkyl, aralkyl or aryl as defined above. As used herein the term "carboxyl derivative" refers to a radical of the formula C — Y R 2 wherein Y 6 and Y 7 are independently selected from the group consisting of O, N or S and R 23 is selected from the group consisting of H, alkyl, aralkyl and aryl as defined above. As used herein the term "amino" is represented by a radical of the formula - NH 2 . As used herein the term "alkylsulfonyl" or "alkylsulfone" refers to a O radical of the — S — R wherein R is alkyl as defined above. O As used herein the term "alkylthio" refers to a radical of the formula -SR 24 wherein R 24- is alkyl as defined above. As used herein the term "sulfonic acid" refers to a O radical of the | — S — O R wherein R is alkyl as defined above. O As used herein the term "sulfonamide" or "sulfonamido" refers to a radical are as defined above. As used herein the term "fused aryl" refers to an aromatic ring such as the aryl groups defined above fused to one or more phenyl rings. Embraced by the term "fused aryl" is the radical naphthyl and the like. As used herein the terms "monocyclic heterocycle" or "monocyclic heterocyclic" refer to a monocyclic ring containing from 4 to about 12 atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 of the atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur with the understanding that if two or more different heteroatoms are present at least one of the heteroatoms must be nitrogen. Representative of such monocyclic heterocycles are imidazole, furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole, thiazole, thiadiazole, and the like. As used herein the term "fused monocyclic heterocycle" refers to a monocyclic heterocycle as defined above with a benzene fused thereto. Examples of such fused monocyclic heterocycles include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole and the like. As used herein the term "methylenedioxy" refers to the radical and the term "ethylenedioxy" refers to the radical As used herein the term "4-12 membered dinitrogen containing heterocycle refers to a radical of the formula wherein m is 1 or 2 and R 19 is H, alkyl, aryl, or aralkyl and more preferably refers to 4-9 membered ring and includes rings such as imidazoline. As used herein the term "5-membered optionally substituted heteroaromatic ring" includes for example a radical of the formula and "5-membered heteroaromatic ring fused with a phenyl" refers to such a "5- membered heteroaromatic ring" with a phenyl fused thereto. Representative of such 5-membered heteroaromatic rings fused with a phenyl is benzimidazole. As used herein the term "bicycloalkyl" refers to a bicyclic hydrocarbon radical containing 6 to about 12 carbon atoms which is saturated or partially unsaturated. O II As used herein the term "acyl" refers to a radical of the formula X 26 wherein R is alkyl, alkenyl, alkynyl, aryl or aralkyl and optionally substituted thereon as defined above. Encompassed by such radical are the groups acetyl, benzoyl and the like. I— SH . As used herein the term "thio" refers to a radical of the formula * As used herein the term "sulfonyl" refers to a radical of the formula O II I S — fi wherein R 27 is alkyl, aryl or aralkyl as defined above. o As used herein the term "haloalkylthio" refers to a radical of the formula -S- 9R 9 R wherein R is haloalkyl as defined above. As used herein the term "aryloxy" refers to a radical of the formula I — C*R^ wherein R 29 is aryl as defined above. As used herein the term "acylamino" refers to a radical of the formula O p30 Kil l I I wherein R is alkyl, aralkyl or aryl as defined above. As used herein the term "amido" refers to a radical of the formula O II < ~ w C— NH 2 . As used herein the term "alkylamino" refers to a radical of the formula - NHR 32 wherein R 32 is alkyl as defined above. As used herein the term "dialkylamino" refers to a radical of the formula NR R wherein R and R are the same or different alkyl groups as defined above. As used herein the term "trifluoromethyl" refers to a radical of the formula f— C F 3 . As used herein the term "trifluoroalkoxy" refers to a radical of the formula is a bond or an alkylene as defined above. As used herein the term "alkylaminosulfonyl" or "aminosulfonyl" refers to a O R 3 fi 6 — N H s II ii < 36 radical of the formula O wherein R is alkyl as defined above. As used herein the term "alkylsulfonylamino" or ""alkylsulfonamide" refers to a radical of the formula is alkyl as defined above. As used herein the term "trifluoromethylthio" refers to a radical of the formula * As used herein the term "trifluoromethylsulfonyl" refers to a radical of the formula As used herein the term "4-12 membered mono-nitrogen containing monocyclic or bicyclic ring" refers to a saturated or partially unsaturated monocyclic or bicyclic ring of 4-12 atoms and more preferably a ring of 4-9 atoms wherein one atom is nitrogen. Such rings may optionally contain additional heteroatoms selected from nitrogen, oxygen or sulfur. Included within this group are morpholine, piperidine, piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene and the like. As used herein the term "benzyl" refers to the radical hCH2 ^ As used herein the term "phenethyl" refers to the radical I— CH 2 CH 2 — P As used herein the term "4-12 membered mono-nitrogen containing monosulfur or monooxygen containing heterocyclic ring" refers to a ring consisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein at least one atom is a nitrogen and at least one atom is oxygen or sulfur. Encompassed within this definition are rings such as thiazoline and the like. As used herein the term "arylsulfonyl" or "arylsulfone" refers to a radical of the formula wherein R 37 is aryl as defined above. As used herein the terms "alkylsulf oxide" or "arylsulfoxide" refer to radicals of the formula wherein R 38 is, respectively, alkyl or aryl as defined above. As used herein the term "arylthio" refers to a radical of the formula < ' "SR42 wherem R is aryl as defined above. As used herein the term "monocyclic heterocycle thio" refers to a radical of the formula a monocyclic heterocycle radical as defined above. As used herein the terms "monocyclic heterocycle sulfoxide" and "monocyclic heterocycle sulfone" refer, respectively, to radicals is a monocyclic heterocycle radical as defined above. As used herein the term "alkylcarbonyl" refers to a radical of the formula O 50 " " C wherein R 50 is alkyl as defined above. As used herein the term "arylcarbonyl" refers to a radical of the formula O pp ςi* ' I 51 wherein R is aryl as defined above. As used herein the term "alkoxycarbonyl" refers to a radical of the formula O p p 52 wherein R is alkoxy as defined above. As used herein the term "aryloxycarbonyl" refers to a radical of the formula O p ςoil O— C I ' 51 wherein R is aryl as defined above. As used herein the term "haloalkylcarbonyl" refers to a radical of the O ς I I D bd 53 formula wherein R is haloalkyl as defined above. As used herein the term "haloalkoxycarbonyl" refers to a radical of the O D 0ύ „ formula 4wherein R is haloalkyl as defined above. As used herein the term "alkylthiocarbonyl" refers to a radical of the O formula wherein R is alkyl as defined above. As used herein the term "arylthiocarbonyl" refers to a radical of the formula is aryl as defined above. As used herein the term "acyloxymethoxycarbonyl" refers to a radical of the O 54 " formula 2 wherein R 54 is acyl as defined above. As used herein the term "arylamino" refers to a radical of the formula R 51 - NH- wherein R 51 is aryl as defined above. As used herein the term "acyloxy" refers to a radical of the formula R 55 -O- wherein R 55 is acyl as defined above. As used herein the term "alkenylalkyl" refers to a radical of the formula R 50 — R 7 — wherein R 50 is an alkenyl as defined above and R 57 is alkylene as defined above. As used herein the term "alkenylene" refers to a linear hydrocarbon radical of 1 to about 8 carbon atoms containing at least one double bond. As used herein the term "alkoxyalkyl" refers to a radical of the formula R 56 - is alkylene as defined above. As used herein the term "alkynylalkyl" refers to a radical of the formula R 59 — R 60 — wherein R 59 is alkynyl as defined as above and R 60 is alkylene as defined as above. As used herein the term "alkynylene" refers to divalent alkynyl radicals of 1 to about 6 carbon atoms. As used herein the term "allyl" refers of a radical of the formula -CH 2 CH=CH 2 . As used herein the term "aminoalkyl" refers to a radical of the formula H 2 N- R l wherein R l is alkylene as defined above. As used herein the term "benzoyl" refers to the aryl radical C 6 H 5 -CO-. As used herein the term "carboxamide" or "carboxamido" refer to a radical of the formula -CO-NH 2 . As used herein the term "carboxyalkyl" refers to a radical HOOC--R 62 — wherein R 62 is alkylene as defined as above. As used herein the term "carboxylic acid" refers to the radical — COOH . As used herein the term "ether" refers to a radical of the formula R O wherein R 63 is selected from the group consisting of alkyl, aryl and heteroaryl. As used herein the term "haloalkylsulfonyl" refers to a radical of the O 64 'I R 64 S— II formula O wherein the R 64 is haloalkyl as defined above. As used herein the term "heteroaryl" refers to an aryl radical contain at least one heteroatom. As used herein the term "hydroxyalkyl" refers to a radical of the formula HO- R _- wherein R 65 is alkylene as defined above. As used herein the term "keto" refers to a carbonyl group joined to 2 carbon atoms. As used herein the term "lactone" refers to an anhydro cyclic ester produced by intramolecular condensation of a hydroxy acid with the elimination of water. As used herein the term "olefin" refers to an unsaturated hydrocarbon radical of the type C n H 2n . As used herein the term "sulfone" refers to a radical of the formula R 66 -S0 2 — As used herein the term "thioalkyl" refers to a radical of the formula R — S wherein R 77 is alkyl as defined above. As used herein the term "thioether" refers to a radical of the formula H — S wherein R 78 is alkyl, aryl or heteroaryl. As used herein the term "trifluoroalkyl" refers to an alkyl radical as defined above substituted with three halo radicals as defined above. The term "composition" as used herein means a product which results from the mixing or combining of more than one element or ingredient. The term "pharmaceutically acceptable carrier", as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent. The term "therapeutically effective amount" shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician. The following is a list of abbreviations and the corresponding meanings as used interchangeably herein: 1H-NMR = proton nuclear magnetic resonance AcOH = acetic acid BOC = tert-butoxycarbonyl BuLi = butyl lithium Cat. = catalytic amount CH 2 C1 2 = dichloromethane CH 3 CN = acetonitrile CH 3 I = iodomethane CHN analysis = carbon/hydrogen/nitrogen elemental analysis CHNC1 analysis = carbon/hydrogen/nitrogen/chlorine elemental analysis CHNS analysis = carbon/hydrogen/nitrogen/sulfur elemental analysis DEAD = diethylazodicarboxylate DIAD = diisopropylazodicarboxylate DI water = deionized water DMA = N,N-dimethylacetamide DMAC = N,N-dimethylacetamide DMF = N,N-dimethylformamide EDC = l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et = ethyl Et 2 O = diethyl ether Et 3 N = triethylamine EtOAc = ethyl acetate EtOH = ethanol FAB MS = fast atom bombardment mass spectroscopy g = gram(s) HOBT = 1-hydroxybenzotriazole hydrate HPLC = high performance liquid chromatography i-Pr = iso propyl i-Prop = iso propyl K 2 CO 3 = potassium carbonate KMnO = potassium permanganate KOH = potassium hydroxide KSCN = potassium thiocyanate L = Liter LiOH = lithium hydroxide Me = methyl MeOH = methanol mg = milligram MgSO 4 = magnesium sulfate ml = milliliter mL = milliliter MS = mass spectroscopy NaH - sodium hydride NaHCO 3 = sodium bicarbonate NaOH = sodium hydroxide NaOMe = sodium methoxide NH 4 + HCO " = ammonium formate NMR = nuclear magnetic resonance Pd = palladium Pd/C = palladium on carbon Ph = phenyl Pt = platinum Pt/C = platinum on carbon RPHPLC = reverse phase high performance liquid chromatography RT = room temperature t-BOC = tert-butoxycarbonyl TFA = trifluoroacetic acid THF = tetrahydrofuran TLC - thin layer chromatography TMS = trimethylsilyl Δ = heating the reaction mixture The compounds as shown above can exist in various isomeric forms and all such isomeric forms are meant to be included. Tautomeric forms are also included as well as pharmaceutically acceptable salts of such isomers and tautomers. In the structures and formulas herein, a bond drawn across a bond of a ring can be to any available atom on the ring. The term "pharmaceutically acceptable salt" refers to a salt prepared by contacting a compound of Formula I or II with an acid whose anion is generally considered suitable for human consumption. For use in medicine, the salts of the compounds of this invention are non-toxic "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-methylgucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/disphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention cany 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. All of the pharmacologically acceptable salts may be prepared by conventional means. (See Berge et al., J Pharm. Sci.. 66(1), 1-19 (1977) for additional examples of pharmaceutically acceptable salts.) The compounds of the present invention can have chiral centers and occur as racemates, racemic mixtures, diastereomeric mixtures, and as individual diastereomers or enantiomers, with all isomeric forms 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 present invention; further included are all mixtures of the enantiomers or diastereomers. Also included within the scope of the invention are polymorphs, or hydrates or other modifiers of the compounds of invention. The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. For example, prodrugs of a carboxylic acid may include an ester, an amide, an ortho-ester, or heterocycles such as tetrazole. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described 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 derivatives are described, 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. For the selective inhibition or antagonism of α v β 3 and/or αvβs integrins, compounds of the present invention may be administered orally, parenterally, or by inhalation spray, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, transmuscular infusion techniques or intraperitonally. The compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts. Accordingly, the present invention provides a method of treating conditions mediated by selectively inhibiting or antagonizing the vβ 3 and/or αv βs cell surface receptor which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted in the above formulas, wherein one or more compound is administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and if desired other active ingredients. Another aspect of the invention provides a method for inhibiting bone resorption, treating osteoporosis, inhibiting humoral hypercalcemia of malignancy, treating Paget's disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), inhibiting angiogenesis including tumor angiogenesis, treating retinopathy including macular degeneration and diabetic retinopathy, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including restenosis. Based upon standard laboratory experimental techniques and procedures well known and appreciated by those skilled in the art, as well as comparisons with compounds of known usefulness, the compounds of Formula I or II can be used in the treatment of patients suffering from the above pathological conditions. One skilled in the art will recognize that selection of the most appropriate compound of the invention is within the ability of one with ordinary skill in the art and will depend on a variety of factors including assessment of results obtained in standard assay and animal models. Treatment of a patient afflicted with one of the pathological conditions comprises administering to such a patient an amount of compound of the Formula I which is therapeutically effective in controlling the condition or in prolonging the survivability of the patient beyond that expected in the absence of such treatment. As used herein, the term "inhibition" of the condition refers to slowing, interrupting, arresting or stopping the condition and does not necessarily indicate a total elimination of the condition. It is believed that prolonging the survivability of a patient, beyond being a significant advantageous effect in and of itself, also indicates that the condition is beneficially controlled to some extent. As stated previously, the compounds of the invention can be used in a variety of biological, prophylactic or therapeutic areas. It is contemplated that these compounds are useful in prevention or treatment of any disease state or condition wherein the αv β 3 and/or αv βs I ntegrin plays a role. The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions. 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 1.0 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, 200 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 lmg to about 100 mg of active ingredient. Intravenous doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin 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 may be continuous rather than intermittant throughout the dosage regiment. For administration to a mammal in need of such treatment, the compounds in a therapeutically effective amount are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and or polyvinyl alcohol, and tableted or encapsulated for convenient administration. Alternatively, the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The pharmaceutical compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. The following Schemes are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit. Those with skill in the art will readily understand that known variations of the conditions and processes described in the Schemes can be used to make the embodiments of the invention. Scheme 1 Preparation of S - 3 - aminobutyrolactone hydrochloride salt 2 eq. Diborane in THF, O C 4NHα indioxane Commercially available Solid, crystallizes from reaction fromAldrich mixture) Scheme 2 Ooirirercially available Solid, crystallizes fromreaction fromAldrich rrixture) l.BCC-Gy-O l Bu BCF, NMM -10 0 C,DIv_F, 30trin SCHEME 3 2. dilute HCI X = e.g H, OH, F, OAIkyl, OAtyl, etc. Scheme 4 HCI 2. HCI Scheme 5 Commercially available Solid, crystallizes from reaction from Aldrich mixture) l. BOC-Gly-O'Bu IBCF. NMM Scheme 6 Scheme 7 4NHQ, BOH, RT 3 his 3 ϋOHorNaOH, FTT 4 TFAtopHabout4,hplc M = H,0H, F,CF 3 ,etc X=H,OH,CF 3 ,etc IBCF, NMM, DMF M = H, OH, F, CF 3 , etc X = H, OH, CF 3 , etc Scheme 8 M=H, H,F,CF 3 ,etc M=H,OH,F,CF 3 ,etc P=H,OH,GF 3 ,etc P=H,OH,CF 3 ,ete. When A= mtrcgen ton When A = mtrogen then M=H,OH,F,CF 3 ete M=H,OH,F,CF 3 etc P= no substitution P=nosub_ututιon The following Examples are intended to be illustrative and not intended to limit the scope of the invention. EXAMPLE 1 Ex la Solid, crystallizes from reaction mixture) Synthesis of 3-amino-5-oxo-3S-furan hydrochloride A solution of the Boc-aspartimol-γ-benzylester (0.5 g, Tetrahedron Lett .32, (7), 923, 1991) in dry benzene (10 .0 mL) containing p-toluenesulfonic acid (0.32 g) was heated to reflux for 1.5 h. under anhydrous conditions. The reaction mixture was cooled, diluted with ether and filtered the precipitate. It was washed with ether, and dried to give 0.38 g of the desired lactone as its p-toluenesufonate salt: 1H-NMR (DMSO-d 6 ) 5 8.14 (br, 2H), 7.46 (d, 2H, J = 8.0 Hz), 7.09 (d, 2H, J = 8.0 Hz), 4.46 (m, 1H), 4.24 (m, 1H), 4.1 9(m, 1H), 2.96 (dd, 1H), 2.47 (dd, 2H), 2.2 (, 3H); MS: m/z 102 (MH + ) Ex lb Alternate preparation of of 3-amino-5-oxo-3S-furan hydrochloride. N-tBoc-L-aspartic acid, β-benzyl ester (10.0 mmole) was dissolved inlO mL of tetrahydrofuran (THF) and added drop-wise over a period of 30 min to a 0° C. solution of BH 3 -THF (20 mL, 20.0 mmole) under argon. After the mixture was stirred for an additional 1-2 hr at 0° C, the reaction was quenched by drop-wise addition of 10% acetic acid in methanol and the solvent evaporated. The oil residue was dissolved in ethyl acetate and extracted with IN HCI, water, and 1M NH 4 HCO 3 . The ethyl acetate layer was dried (Na 2 SO 4 ) and volatiles evaporated to give an oil that could be crystalized from isopropanol/hexane (mp 56-57° C):1H NMR (CDCL 3 ) δ 1.45 (s, 9H), 2.65 (d, 2H), 3.68 (d, 2H), 5.12 (s, 2H), 5.25 (m, 1H), 7.35 (m, 5H). The resulting 3-N-tBoc-amino-4-hydroxy-butyric acid benzyl ester (20 g. 64 mmole) was stirred in 200 mL dichloromethane at room temperature for 16 hr in the presence of a catalytic amount of camphor sulfonic acid. Solvent was removed in vacuo and the crude product purified by flash chromatography (Merck 60 silica gel, ethyl acetate/hexane/1% triethylamine). The N-tBoc-3-aminolactone was isolated as a white solid (5.4 g). The 3-N-tBoc-aminolactone (5.0 g, 25 mmole) isolate was dissolved in 20 mL 4N HCl/dioxane. After 45 minutes at 25° C, 10 mL of 4N HCl/dioxane was added and after 1 hr the excess HCI was removed in vacuo. The resulting solution deposited white crystals upon standing. These were filtered and dried to give 2.9 g of the desired product as the hydrochloride salt. 1H NMR (d 6 DMSO) δ 2.55 (dd, Jι=18.3 Hz, J 2 =2.5 Hz), 3.0 (dd, 1H, J_=8.5 Hz, J 2 =18.3 Hz), 4.1 (m, 1H), 4.35 (dd, 1H, Jι=10.5 Hz, J 2 =2.7 Hz), 4.5 (dd, 1H, J 1= 10.5 Hz, J 2 =6.5 Hz); MS (FAB) 102.1 (M +H). Ex lc 3-amino-5-oxo-3S-furan hydrochloride (2.9 g, 21 mmol) was dissolved in DMF (123 mL) and cooled to 0°C under a nitrogen atmosphere. N-Boc-Gly-OSu (5.4 g, 20 mmol) was added, followed by 4-methylmorpholine (2.3 mL, 21 mmol). After the solution was stirred 18 hours, it was diluted with brine and extracted twice with EtOAc. The combined organic layers were washed with H 2 O, dried (Νa 2 SO 4 ), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: EtOAc) to give a colorless oil (4.7 g, 87%). 1H NMR (CDC1 3 ) δ 1.46 (s, 9H), 2.51 (dd, IH), 2.89 (dd, IH), 3.82 (s, 2H), 4.25 (dd, IH), 4.54 (dd, IH), 4.72 (m, IH). Ex Id The colorless oil from Ex lc (3.2 g, 12.4 mmol) was dissolved in 4N HCI dioxane (30 mL). After stirring 2.5 hours at ambient temperature, the excess HCI was removed in vacuo. The white solid material was filtered and dried (2.4 g, 98%). 1H NMR (CD 3 OD) δ 2.51 (dd, IH), 2.92 (dd, IH), 3.68 (s, 2H), 4.28 (dd, IH), 4.57 (dd, IH), 4.63 (m, IH). EI-MS m/z 159 (MH + ). Ex le ACID A The amine hydrochloride from Ex Id (950 mg, 4.9 mmol) and Acid A (1.4 g, 4.9 mmol) were combined and slurried in DMF/CH 2 C1 2 (12 mL, 1:1) at ambient temperature under a nitrogen atmosphere. 1,3-Diisopropylcarbodiimide (0.9 mL, 5.9 mmoL) was added, followed by 4-methylmorpholine (0.5 mL, 4.9 mmol). After stirring 18 hours, the solution was filtered through a pad of Celite and the filtrate concentrated in vacuo. The resulting oil was purified by reverse-phase HPLC (H 2 O/CH 3 CN) to afford the title compound as a white solid (671 mg, 20%). 1H NMR (DMSO-d 6 ) δ 2.37 (dd, IH), 2.90 (dd, IH), 3.16 (dd, 2H), 3.35 (dd, 2H), 3.82 (d, 2H), 4.09 (m, 2H), 4.48 (m, 2H), 6.75 (t, IH) 7.11 (t, IH), 7.14 (m, IH), 8.18 (s, 2H), 8.54 (d, IH), 8.63 (t, IH), 9.71 (s, IH). EI-MS m/z 392 (MH + ). Anal. Calcd for C 17 H 21 N 5 O 6 +2.5 TFA +0.5 H 2 O: C, 38.55; H, 3.60. Found: C, 38.55; H, 3.87. The desired hydroxy-acid was obtained by dissolving the product of Ex le (200 mg, 0.29 mmol) in water (7 mL). The pH of the solution was brought to about 11 by addition of dilute aqueous NaOH. Upon completion of the reaction, as determined by analytical reverse-phase HPLC, the solution was brought to a pH of about 8 by addition of TFA and concentrated in vacuo. Purification of the resulting residue by reverse-phase HPLC (H 2 O/CH 3 CN) afforded the title compound as a white solid (50 mg, 17%). 1H NMR (CD 3 OD) δ 2.43 (dd, IH), 2.55 (dd, IH), 3.22 (dd, 2H), 3.35 (dd, 2H), 3.49 (m, 2H), 3.92 (d, 2H), 4.12 (m, IH), 4.21 (m, IH), 6.74 (t, IH) 7.07 (t, IH), 7.12 (m, IH). EI-MS m/z 410 (MH + ). Anal. Calcd for C 17 H 23 N 5 O 7 +1.5 TFA +0.1 EtOAc: C, 41.58; H, 4.33; N, 11.89. Found: C, 41.43; H, 4.21; N, 11.61. EXAMPLE 2 Ex 2a ACID B The amine hydrochloride from Ex Id (950 mg, 4.9 mmol) and Acid B (1.3 g, 4.9 mmol) were combined and slurried in DMF/CH 2 C1 2 (12 mL, 1:1) at ambient temperature under a nitrogen atmosphere. 1,3-Diisopropylcarbodiimide (0.9 mL, 5.9 mmoL) was added, followed by 4-methylmorpholine (0.5 mL, 4.9 mmol). After stirring 18 hours, the solution was filtered through a pad of Celite and the filtrate concentrated in vacuo. The resulting oil was purified by reverse-phase HPLC (H 2 O/CH 3 CN) to afford the title compound as a light yellow solid (760 mg, 25%). 1H NMR (DMSO-d 6 ) δ 1.89 (m, 2H), 2.37 (dd, IH), 2.89 (dd, IH), 3.16 (dd, 2H), 3.28 (m, 4H), 3.84 (d, 2H), 4.09 (m, IH), 4.48 (m, 2H), 6.75 (t, IH) 7.11 (t, IH), 7.14 (m, IH), 8.32 (s, 2H), 8.54 (d, IH), 8.63 (t, IH), 9.89 (s, IH). EI-MS m/z 376 (MH + ). Anal. Calcd for C 17 H 21 N 5 O 5 +2 TFA +0.3 H 2 O: C, 41.43; H, 3.91; N, 11.50. Found: C, 41.21; H, 4.07; N, 11.74. Lactone Product Ex 2b The desired hydroxy-acid was obtained by dissolving the lactone product of Ex 2a (200 mg, 0.29 mmol) in water (7 mL). The pH of the solution was brought to about 11 by addition of dilute aqueous NaOH. Upon completion of the reaction, as determined by analytical reverse-phase HPLC, the solution was brought to a pH of about 8 by addition of TFA and concentrated in vacuo. Purification of the resulting residue by reverse-phase HPLC (H 2 O/CH 3 CN) afforded the title compound as a white solid (50 mg, 17%). 1H NMR (CD 3 OD) d 2.03 (m, 2H), 2.55 (dd, IH), 2.67 (dd, IH), 3.43 (m, 4H), 3.61 (m, 2H), 4.04 (d, 2H), 4.32 (m, IH), 6.83 (t, IH) 7.17 (t, IH), 7.22 (m, IH). EI-MS m/z 394 (MH + ). Anal. Calcd for C 17 H 23 N 5 O 6 +3 TFA: C, 37.56; H, 3.56; N, 9.52. Found: C, 36.37; H, 3.61; N, 9.80. EXAMPLE 3 Ex 3a ACID C The amine hydrochloride from Ex Id (950 mg, 4.9 mmol) and Acid C (1.0 g, 3.7 mmol) were combined and slurried in DMF/CH 2 C1 2 (12 mL, 1:1) at ambient temperature under a nitrogen atmosphere. 1,3-Diisopropylcarbodiimide (0.9 mL, 5.9 mmoL) was added, followed by 4-methylmorpholine (0.5 mL, 4.9 mmol). After stirring 18 hours, the solution was filtered through a pad of Celite and the filtrate concentrated in vacuo. The resulting oil was purified by reverse-phase HPLC (H 2 O/CH 3 CN) to afford the title compound as a light yellow solid (150 mg, 7%). 1H NMR (DMSO-d 6 ) d 2.39 (dd, IH), 2.90<(dd, IH), 3.17 (dd, 2H), 3.38 (dd, 2H), 3.87 (d, 2H), 4.10 (m, 2H), 4.48 (m, 2H), 7.36 (m, IH), 7.52 (t, IH), 7.70 (m, IH), 7.75 (m, IH), 8.38 (s, 2H), 8.62 (d, IH), 8.83 (t, IH), 10.08 (s, IH). EI-MS m z 376 (MH + ). Anal. Calcd for C 17 H 21 N 5 O 5 +2 TFA +0.5 H 2 O: C, 41.18; H, 3.95; N, 11.44. Found: C, 40.86; H, 3.90; N, 11.83. Lactone Product Ex 3b The desired hydroxy-acid was obtained by dissolving the lactoneproduct of Ex 3a (200 mg, 0.29 mmol) in water (7 mL). The pH of the solution was brought to about 11 by addition of dilute aqueous NaOH. Upon completion of the reaction, as determined by analytical reverse-phase HPLC, the solution was brought to a pH of about 8 by addition of TFA and concentrated in vacuo. Purification of the resulting residue by reverse-phase HPLC (H 2 O/CH 3 CN) afforded the title compound as a white solid (50 mg, 17%). 1H NMR (DMSO-d 6 ) d 2.31 (dd, IH), 2.52 (dd, IH), 3.16 (m, 2H) . 3.34 (m, 2H), 3.36 (m, 2H), 3.86 (d, 2H), 4.08 (m, 2H), 7.36 (m. IH) 7.52 (t, IH), 7.68 (m, IH), 7.74 (m, IH), 7.83 (d, IH), 8.38 (s, 2H), 8.72 (t, IH), 10.08 (s, IH). EI-MS m/z 394 (MH + ). Anal. Calcd for C 17 H 23 N 5 O 6 +7 TFA +1 CH 3 CN +4 H 2 O: C, 30.38; H, 3.17; N, 6.44. Found: C, 30.19; H, 2.90; N, 6.69. EXAMPLE 4 The desired hydroxy-acid was obtained using substantially the procedure of Example 3, substituting the following lactone product: EXAMPLE 5 ACID E The amine hydrochloride from Ex lc (950 mg, 4.9 mmol) and Acid B (1.0 g, 3.5 mmol) were combined and slurried in DMF/CH 2 C1 2 (12 mL, 1:1) at ambient temperature under a nitrogen atmosphere. 1,3-Diisopropylcarbodiimide (0.9 mL, 5.9 mmoL) was added, followed by 4-methylmorpholine (0.5 mL, 4.9 mmol). After stirring 18 hours, the solution was filtered through a pad of Celite and the filtrate concentrated in vacuo. The resulting oil was purified by reverse-phase HPLC (H 2 O/CH 3 CN) to afford the title compound as a light yellow solid (600 mg, 30%). 1H NMR (DMSO-d 6 ) d 1.89 (m, 2H), 2.39 (dd, IH), 2.89 (dd, IH), 3.28 (m, 4H), 3.84 (d, 2H), 4.09 (m, IH), 4.48 (m, 2H), 7.37 (m,lH), 7.53 (t, IH), 7.70 (m, IH), 7.74 (m, IH), 8.29 (s, 2H), 8.61 (d, IH), 8.83 (t, IH), 9.93 (s, IH). EI-MS m/z 360 (MH + ). Anal. Calcd for C 17 H 2 ιN 5 O 4 +1 TFA +1 H 2 O +1 DMF: C, 46.81 ; H, 5.54; N, 14.89. Found: C, 46.69; H, 5.21; N, 14.69. Lactone Product Ex 5b The desired hydroxy-acid was obtained by dissolving the lactone product of Ex 5a (200 mg, 0.29 mmol) in water (7 mL). The pH of the solution was brought to about 11 by addition of dilute aqueous NaOH. Upon completion of the reaction, as determined by analytical reverse-phase HPLC, the solution was brought to a pH of about 8 by addition of TFA and concentrated in vacuo. Purification of the resulting residue by reverse-phase HPLC (H 2 O/CH 3 CN) afforded the title compound as a white solid (50 mg, 17%). 1H NMR (CD 3 OD) d 2.55 (dd, IH), 2.68 (dd, IH), 3.62 (m, 2H), 4.08 (d, 2H), 4.33 (m, IH), 7.78 (s, IH), 8.06 (s, IH), 8.18 (s, IH). EI-MS m/z 406 (MH + ). Anal. Calcd for Cι 5 Hι 8 N 5 O 5 F 3 +1.5 TFA: C, 37.51; H, 3.41; N, 12.15. Found: C, 37.35; H, 3.24; N, 12.01. EXAMPLE 6 Ex 6a Preparation of BOC-NH-CH(CH 2 COOBzL)-CH 2 -OH: This compound was prepared according to the literature Tet Letts. 32, (7)923, 1991. Ex 6b A solution of Boc-aspartimol-γ-benzylester (1.0 g, 0.0032 mol) in EtOH (10.0 mL) containing p-toluenesulfonic acid (0.65 g) was heated to reflux for 12 h under anhydrous conditions. After removal of the solvent under reduced pressure, the residue was dissolved in DMF (10.0 mL), cooled in an ice bath, added N- methylmorpholine (0.6 mL), and BOC-Gly-ONSu (0.9 g). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was then poured into cold water (25 mL) and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with 5% citric acid (2 x 25 mL), water, (2 X 25 mL), dried (Na.SO 4 ) and concentrated to dryness. The resulting intermediate (0.75 g) was dissolved in EtOH (5.0 mL), added 4N HCl/dioxane (5.0 mL), and stirred at room temperature for 3 h. After removal of the solvents, the residue was dried in a desiccator over NaOH pallets for 4 h, and used in the following step without purification. To a solution of (5-fluoro-tetrahydro pyrimide)-3-amino-5-hydroxybenzoic acid (1.0 g, 0.00345 mol) in DMF (5.0 mL) at - 20 °C, was added isobutylchloroformate (0.45 mL), followed by the addition of N-methylmorpholine (0.4 mL). After stirrring for 20 min, a solution of the free amine generated by the addition of N-methylmorpholine (0.42 mL) to a solution of the product from step B in DMF (5.0 mL). was added. The resulting mixture was stirred at room temperature for 16 h. The solvents were distilled in vacuo, and the product was purified by reverse-phase HPLC using 10-90% acetonitrile/water at a flow rate of 70 mL/min. The appropriate fractions (MH + m z = 440) were combined and freeze dried to obtain 0.22 g of the desired ester This material was stirred with IN LiOH (1.0 mL) for 1 h, diluted with water (5 .0 mL), cooled, and acidified with trifluoroacetic acid. The resulting mixture was purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min) at flow rate of 70 mL/min. The appropriate fractions as revealed by mass spectrum of the fractions (MH + m/z = 412) were combined and freeze dried to obtain the desired acid (0.14 g) as its trifluoroacetate salt: 1H-NMR (CD 3 OD) δ 7.21 (m, IH), 7.16 (t, IH, J = 1.6 Hz), 6.82 (t, IH, I = 1.6 Hz), 5.20 (d, IH, J H>F = 44 Hz, J = 2.4Hz), 4.26 (m, IH), 3.99 (d, 2H, J = 1.2 Hz), 3.70- 3.45 (m, 6H), and 2.64 - 2.48 (2dd, 2H, = 6.4 Hz, J 2 = 16 Hz); HR-MS: m/z calcd for C 17 H 23 N 5 O 6 F (MH + ) 412.1632, found 412.1630. EXAMPLE 7 CF 3 COOH Title compound was prepared as described according to Example 6, substituting of (5-fluoro-tetrahydro pyrimide)-3-amino-benzoic acid for of (5- fluoro-tetrahydro pyrimide)-3-amino-5-hydroxybenzoic acid. 1H-NMR (CD 3 OD) δ 7.82 (m, IH), 7.74 (m ,1H), 7.58 9m IH), 7.42 9m IH), 5.21 (d, IH, J H,F = 46.4 Hz, J = 2.0Hz), 4.27 (m, IH), 4.03 (q, 2H), 3.65 - 3.49 (m, 6H), 2.62 (dd, IH, J = 6.2 Hz)), 2.51 (dd, IH, J = 6.2 Hz); HR-MS: m/z calcd for C 17 H 23 N 5 O 5 F (MH + ) 396.1683, found 396.1710. Activitity of the compounds of the present invention can be tested in the following assays. Compounds of the present invention antagonize the α v β 3 integrin with an IC 50 of O.lnM to 100 μM in the 293-cell assay. Similarly these compounds also antagonized the α v β 5 integrin with an IC 50 of < 50 μM in the cell adhesion assay. VITRONECTIN ADHESION ASSAY Human vitronectin receptors θ v β 3 and v β 5 are purified from human placenta as previously described [Pytela et al., Methods in Enzvmology, 144:475- 489 (1987)]. Human vitronectin is purified from fresh frozen plasma as previously described [Yatohgo et al.. Cell Structure and Function. 13:281-292 (1988)]. Biotinylated human vitronectin is prepared by coupling NHS-biotin from Pierce Chemical Company (Rockford, IL) to purified vitronectin as previously described [Charo et al. J. Biol. Chem.. 266(3): 1415-1421 (1991)]. Assay buffer, OPD substrate tablets, and RIA grade BSA are obtained from Sigma (St. Louis, MO). Anti-biotin antibody is obtained from Sigma (St. Luois, MO). Nalge Nunc- hnmuno microtiter plates were obtained from Nalge Company (Rochester, NY). This assay is essentially the same as previously reported [Niiya et al., Blood. 70:475-483 (1987)]. The purified human vitronectin receptors o» v β 3 and α v β 5 are diluted from stock solutions to 1.0 μg/mL in Tris-buffered saline containing 1.0 mM Ca ++ , Mg ++ , and Mn ++ , pH 7.4 (TBS +++ ). The diluted receptors are immediately transferred to Nalge Nunc-Immuno microtiter plates at 100 μL/well (100 ng receptor/well). The plates are sealed and incubated overnight at 4°C to allow the receptors to bind to the wells. All remaining steps are at room temperature. The assay plates are emptied and 200 μL of 1% RIA grade BSA in TBS +++ (TBS +++ /BSA) are added to block exposed plastic surfaces. Following a 2 hour incubation, the assay plates are washed with TBS +++ using a 96 well plate washer. Logarithmic serial dilution of the test compound and controls are made starting at a stock concentration of 2 mM and using 2 nM biotinylated vitronectin in TBS +++ /BS A as the diluent. This premixing of labeled ligand with test (or control) ligand, and subsequent transfer of 50 μL aliquots to the assay plate is carried out with a CETUS Propette robot; the final concentration of the labeled ligand is 1 nM and the highest concentration of test compound is 1.0 x 10 "4 M. The competition occurred for two hours after which all wells are washed with a plate washer as before. Affinity purified horseradish peroxidase labeled goat anti-biotin antibody is diluted 1:2000 in TBS +++ /BSA and 125 μL is added to each well. After 45 minutes, the plates are washed and incubated with OPD/Η 2 O 2 substrate in 100 mM/L Citrate buffer, pH 5.0. The plate is read with a microtiter plate reader at a wavelength of 450 nm and when the maximum-binding control wells reached an absorbance of about 1.0, the final A 45 o are recorded for analysis. The data are analyzed using a macro written for use with the EXCEL spreadsheet program. The mean, standard deviation, and %CN were determined for duplicate concentrations. The mean A 45 o values are normalized to the mean of four maximum-binding controls (no competitor added) (B -MAX). The normalized values are subjected to a four parameter curve fit algorithm [Rodbard et al., Int. Atomic Energy Agency. Vienna, pp 469 (1977)], plotted on a semi-log scale, and the computed concentration corresponding to inhibition of 50% of the maximum binding of biotinylated vitronectin (IC 50 ) and corresponding R is reported for those compounds exhibiting greater than 50% inhibition at the highest concentration tested; otherwise the IC 50 is reported as being greater than the highest concentration tested. PURIFIED ϋb/UIa RECEPTOR ASSAY Human fibrinogen receptor (α v β 3 ) is purified from outdated platelets. (Pytela, R., Pierschbacher, M.D., Argraves, S., Suzuki, S., and Rouslahti, E. "Arginine-Glycine-Aspartic acid adhesion receptors", Methods in Enzymology 144(1987):475-489.) Human vitronectin is purified from fresh frozen plasma as described in Yatohgo, T., Izumi, M., Kashiwagi, H., and Hayashi, M., "Novel purification of vitronectin from human plasma by heparin affinity chromatography," Cell Structure and Function 13(1988):281-292. Biotinylated human vitronectin is prepared by coupling NHS-biotin from Pierce Chemical Company (Rockford, IL) to purified vitronectin as previously described. (Charo, IF., Nannizzi, L., Phillips, D.R., Hsu, M.A., Scarborough, R.M., "Inhibition of fibrinogen binding to GP ϋb/Tfla by a GP ma peptide". J. Biol. Chem. 266(3X1991 : 1415-1421.) Assay buffer, OPD substrate tablets, and RIA grade BSA are obtained from Sigma (St. Louis, MO). Anti-biotin antibody is obtained from Sigma (St. Louis, MO). Nalge Nunc-Immuno microtiter plates are obtained from (Rochester, NY). ADP reagent is obtained from Sigma (St. Louis, MO). This assay is essentially the same reported in Niiya, K., Hodson, E., Bader, R., Byers-Ward, V. Koziol, J.A., Plow, E.F. and Ruggeri, Z.M., "Increased surface expression of the membrane glycoprotein πb/THa complex induced by platelet activation: Relationships to the binding of fibrinogen and platelet aggregation", Blood 70(1987):475-483. The purified human fibrinogen receptor ( v β 3 ) is diluted from stock solutions to 1.0 μg/mL in Tris-buffered saline containing 1.0 mM Ca ++ , Mg ++ , and Mn ++ , pH 7.4 (TBS +++ ). The diluted receptor is immediately transferred to Nalge Nunc-Immuno microtiter plates at 100 μL/well (100 ng receptor/well). The plates are sealed and incubated overnight at 4°C to allow the receptors to bind to the wells. All remaining steps are at room temperature. The assay plates are emptied and 200 μL of 1% RIA grade BSA in TBS +++ (TBS ++ 7BSA) are added to block exposed plastic surfaces. Following a 2 hour incubation, the assay plates are washed with TBS +++ using a 96 well plate washer. Logarithmic serial dilution of the test compound and controls are made starting at a stock concentration of 2 mM and using 2 nM biotinylated vitronectin in TBS +++ /BSA as the diluent. This premixing of labeled ligand with test (or control) ligand, and subsequent transfer of 50 μL aliquots to the assay plate is carried out with a CETUS Propette robot; the final concentration of the labeled ligand is 1 nM and the highest concentration of test compound is 1.0 x 10 "4 M. The competition occurred for two hours after which all wells are washed with a plate washer as before. Affinity purified horseradish peroxidase labeled goat anti-biotin antibody is diluted 1:2000 in TBS +++ /BSA and 125 μL are added to each well. After 45 minutes, the plates are washed and incubated with ODD/H 2 O 2 substrate in 100 mM/L citrate buffer, pH 5.0. The plate was read with a microtiter plate reader at a wavelength of 450 nm and when the maximum-binding control wells reached an absorbance of about 1.0, the final A 45 o are recorded for analysis. The data are analyzed using a macro written for use with the EXCELI spreadsheet program. The mean, standard deviation, and %CV are determined for duplicate concentrations. The mean A 450 values are normalized to the mean of four maximum-binding controls (no competitor added)(B-MAX). The normalized values are subjected to a four parameter curve fit algorithm, [Robard et al., Int. Atomic Energy Agency, Vienna, pp 469 (1977)], plotted on a semi-log scale, and the computed concentration corresponding to inhibition of 50% of the maximum binding of biotinylated vitronectin (IC 50 ) and corresponding R was reported for those compounds exhibiting greater than 50% inhibition at the highest concentration tested; otherwise the IC 5 o is reported as being greater than the highest concentration tested. β-[[2-[[5-[(aminoiminomethyl)amino]-l-oxopentyl]amino]-l- oxoethyl]amino]-3-pyridinepropanoic acid [US 5,602,155 Example 1] which is a potent α v β 3 antagonist (IC 50 in the range 3-10 nM) is included on each plate as a positive control. Human Platelet Rich Plasma Assays Healthy aspirin free donors are selected from a pool of volunteers. The harvesting of platelet rich plasma and subsequent ADP induced platelet aggregation assays are performed as described in Zucker, M.B., "Platelet Aggregation Measured by the Photometric Method", Methods inEnzvmology 169(1989): 117-133. Standard venipuncture techniques using a butterfly allowed the withdrawal of 45 mL of whole blood into a 60 mL syringe containing 5 mL of 3.8% trisodium citrate. Following thorough mixing in the syringe, the anti-coagulated whole blood is transferred to a 50 mL conical polyethylene tube. The blood is centrifuged at room temperature for 12 minutes at 200 xg to sediment non-platelet cells. Platelet rich plasma is removed to a polyethylene tube and stored at room temperature until used. Platelet poor plasma is obtained from a second centrifugation of the remaining blood at 2000 xg for 15 minutes. Platelet counts are typically 300,000 to 500,000 per microliter. Platelet rich plasma (0.45 mL) is aliquoted into siliconized cuvettes and stirred (1100 rpm) at 37°C for 1 minute prior to adding 50 uL of pre- diluted test compound. After 1 minute of mixing, aggregation is initiated by the addition of 50 uL of 200 uM ADP. Aggregation is recorded for 3 minutes in a Payton dual channel aggregometer (Payton Scientific, Buffalo, NY). The percent inhibition of maximal response (saline control) for a series of test compound dilutions is used to determine a dose response curve. All compounds are tested in duplicate and the concentration of half -maximal inhibition (IC 50 ) is calculated graphically from the dose response curve for those compounds which exhibited 50% or greater inhibition at the highest concentration tested; otherwise, the IC 50 is reported as being greater than the highest concentration tested.

Claims: What is claimed is: 1. A compound of Formula 1 wherein: X is Y is selected from the group consisting of N-R 1 , 0, and S; A is N or C; R is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle, monocyclic heterocycles, and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or R 1 taken together with R 8 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl; or R 1 taken together with R 8 forms a 5 membered heteroaromatic ring optionally substituted with one or more substituent selected from lower alkyl, phenyl and hydroxy; or R taken together with R forms a 5 membered heteroaromatic ring fused with a phenyl group; o 1 0 R (when not taken together with R ) and R are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, monocyclic heterocycles, monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl, monocyclic and bicyclic heterocyclicalkyls, -SO 2 R 10 wherein R 10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles; and O 3 10 w ,herei •n R r, 10 is defined as above; or or NR 8 and R 9 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of 0, N and S; or wherein Y' is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl, aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl, alkynyl, alkenyl, -S-R 11 and -OR 11 wherein R 11 is selected from the group consisting of H, alkyl, aralkyl, aryl, alkenyl, and alkynyl, or R 11 taken together with R forms a 4-12 membered mononitrogen and monosulfur or monooxygen containing heterocyclic ring optionally substituted with lower alkyl, hydroxy, keto, phenyl, carboxyl or carboxyl ester, and fused phenyl, or R 11 taken together with R 8 is thiazole, oxazole, benzoxazole, or benzothiazole; R 8 is defined as above; or Y 1 (when Y 1 is carbon) taken together with R 8 forms a 4-12 membered mononitrogen or dinitrogen containing ring optionally substituted with alkyl, aryl, keto or hydroxy; or wherein R and R taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, phenyl, or carboxyl derivatives; and R 9 is selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, or acyloxymethoxycarbonyl; or 1 S wherein R and R taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with hydroxy, keto, phenyl, or alkyl; and R 9 are both selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl; R 2 , R 3 and R 4 are independently selected from one or more substituent selected from thegroup consisting of H, alkyl, hydroxy, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino, alkylamino, acylamino, dialkylamino, cyano, alkylthio, alkylsulfonyl, carboxyl derivatives, trihaloacetamide, acetamide, aryl, fused aryl, cycloalkyl, thio, monocyclic heterocycles, fused monocyclic heterocycles, and X, wherein X is defined above; R , R and R are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carboxyl derivatives, haloalkyl, cycloalkyl, monocyclic heterocycles, monocyclic heterocycles optionally substituted with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino, amido, alkyl optionally substituted with one or more of halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkylamino, dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonic acid, phosphonic acid derivatives, phosphinic acid derivatives, aryl, arylthio, arylsulfoxide, or arylsulfone all optionally substituted on the aryl ring with halo, alkyl, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl, monocyclic heterocycles, and fused monocyclic heterocycles, monocyclic heterocyclicthio, monocyclic heterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can be optionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy, fused aryl, or alkyl, alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl, aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycles; and all pharmaceutically acceptable salts, isomers, enantiomers, tautomers, racemates and polymorphs thereof. 2. A compound according to claim 1 wherein: R = H; R° = H; R 7 = H; alkyl, haloalkyl, carboxyalkyl, alkenyl, alkynyl, and phenyl, optionally substituted with one or more halogen atom. 3. A compound according to claim 1 wherein: R >2 , R , and R * are H, OH, or haloalkyl; X is Y is N-R 1 wherein R is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, cyano, and nitro; or R 1 taken together with R 8 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, alkoxy, halogen, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl. 4. A compound selected from the group consisting of: and all pharmaceutically acceptable salts, isomers, enantiomers, tautomers, racemates and polymorphs thereof. 5. A pharmaceutical composition comprising a compound of Claim 1 or 2. 6. A method of inhibiting a condition mediated by the α v β or α v β 5 integrin comprising administering a therapeutically effective amount of a compound of Claim 1 or 2. 7. The method according to Claim 6 wherein the condition treated is selected from the group consisting of tumor metastasis, solid tumor growth, angiogenesis, osteoporosis, humoral hypercalcemia of malignancy, smooth muscle cell migration, restenosis, atheroscelososis, macular degeneration, retinopathy, and arthritis.

Inventors: CHESTER YUAN, DEVADAS BALEKUDRU, JIANG LAN, PENNING THOMAS D, ROGERS THOMAS, RUMINISKI PETER, VANCAMP JENNIFER, CHESTER, YUAN, DEVADAS, BALEKUDRU, JIANG, LAN, PENNING, THOMAS, D., ROGERS, THOMAS, RUMINISKI, PETER, VANCAMP, JENNIFER
Applicants: CHESTER YUAN, DEVADAS BALEKUDRU, JIANG LAN, PENNING THOMAS D, PHARMACIA CORP, ROGERS THOMAS, RUMINISKI PETER, VANCAMP JENNIFER, CHESTER, YUAN, DEVADAS, BALEKUDRU, JIANG, LAN, PENNING, THOMAS, D., PHARMACIA CORPORATION, ROGERS, THOMAS, RUMINISKI, PETER, VANCAMP, JENNIFER
Application year: 2001
Main classification: C07D239
IPC codes: A61K31, A61P1, A61P3, A61P9, A61P19, A61P27, A61P31, A61P35, C07D239