USE OF THIOAMIDE OXAZOLIDINONES FOR THE TREATMENT OF BONE RESORPTION AND OSTEOPOROSIS

Abstract: The use of thioamide oxazolidinones for the treatment of bone resorption and osteoporosis is provided

Description: USE OF THIO AMIDE OXAZOLIDINONES FOR THE TREATMENT OF BONE RESORPTION AND OSTEOPOROSIS Background of the Invention 1. Field of the Invention The present invention is directed to a new use for known compounds. More specifically, the invention relates to the use of thioamide oxazolidinones for the treatment of bone resorption, osteoporosis and other bone diseases. 2. Technology Description Bone is not a static tissue. It is subject to constant breakdown and resynthesis in a complex process mediated by osteoblasts, which produce new bone, and osteoclasts, which destroy bone. The activities of these cells are regulated by a large number of cytokines and growth factors, many of which have now been identified and cloned. Mundy has described the current knowledge related to these factors (Mundy, G. R. Clin Orthop 324:24-28, 1996; Mundy, G. R. J Bone Miner Res 8:S505-10, 1993). Although there is a great deal of information available on the factors which influence the breakdown and resorption of bone, information on growth factors that stimulate the formation of new bone is more limited. Investigators have searched for sources of such activities, and have found that bone tissue itself is a storehouse for factors that have the capacity for stimulating bone cells. Thus, extracts of bovine bone tissue obtained from slaughterhouses contain not only structural proteins which are responsible for maintaining the structural integrity of bone, but also biologically active bone growth factors which can stimulate bone cells to proliferate. Among these latter factors are transforming growth factor .beta., the heparin-binding growth factors (e.g., acidic and basic fibroblast growth factor), the insulin-like growth factors (e.g., insulinlike growth factor I and insulin-like growth factor II), and a recently described family of proteins called bone morphogenetic proteins (BMPs). All of these growth factors have effects on other types of cells, as well as on bone cells. The BMPs are novel factors in the extended transforming growth factor .beta, superfamily. They were first identified by Wozney J. et al. Science ( 1988) 242- 1528- 34, using gene cloning techniques, lollowing earlier descriptions characterizing the biological activity in extracts of dcnuneralized bone (Uπst M Science ( 1965) 150 893- 99) Recombinant BMP2 and BMP4 can induce new bone lormation when they are injected locally into the subcutaneous tissues ol rats (Wozney J Molec Reprod Dcv ( 1992) 32: 160-67) These tactors are expressed by normal osteoblasts as they diiferentiate, and have been shown to stimulate osteoblast differentiation and bone nodule formation in vitro as well as bone formation in vivo (Harris S et al. J. Bone Miner Res (1994) 9:855-63). This latter property suggests potential usefulness as therapeutic agents in diseases that result in bone loss The cells that are responsible for forming bone are osteoblasts As osteoblasts differentiate from precursors to mature bone-forming cells, they express and secrete a number of enzymes and structural proteins of the bone matrix, including Type-1 collagen, osteocalcin, osteopontin and alkaline phosphatase (Stern G. et al Curr Oprn Cell Biol (1990) 2:1018-27; Harris S. et al. (1994), supra). They also synthesize a number of growth regulatory peptides that are stored in the bone matrix, and are presumably responsible for normal bone formation. These growth regulatory peptides include the BMPs (Harris S. et al. (1994), supra). In studies of primary cultures of fetal rat calvarial osteoblasts, BMPs 1, 2, 3, 4, and 6 are expressed by cultured cells prior to the formation of mineralized bone nodules (Harris S. et al. (1994), supra). Like alkaline phosphatase, osteocalcin and osteopontin, the BMPs are expressed by cultured osteoblasts as they proliferate and differentiate. Although the BMPs are potent stimulators of bone formation in vitro and in vivo, there are disadvantages to their use as therapeutic agents to enhance bone healing. Receptors for the bone morphogenetic proteins have been identified in many tissues, and the BMPs themselves are expressed in a large variety of tissues in specific temporal and spatial patterns. This suggests that BMPs may have effects on many tissues in addition to bone, potentially limiting their usefulness as therapeutic agents when administered systemically. Moreover, since they are peptides, they would have to be administered by miection These disadvantages impose severe limitations to the development of BMPs as therapeutic agents There is a plethora ol conditions that are characterized by the need to enhance bone lormation Perhaps the most obvious is the case ol bone lracturcs, where it would be desirable to stimulate bone growth and to hasten and complete bone repair Agents that enhance bone lormation would also be uselul in facial reconstruction procedures Other bone deficit conditions include bone segmental delects, peπodontal disease, metastatic bone disease, osteolytic bone disease and conditions where connective tussue repair would be beneficial, such as heahng or regeneration ol cartilage defects or ui|ury. Also of great significance is the chronic condition of osteoporosis, including age-related osteoporosis and osteoporosis associated with post-menopausal hormone status. Other conditions characterized by the need for bone growth include primary and secondary hyperparathyroidism, disuse osteoporosis, diabetes-related osteoporosis, and glucocorticoid-related osteoporosis There are currently no satisfactory pharmaceutical approaches to managing any of these conditions. Bone fractures are still treated exclusively using casts, braces, anchoring devices and other strictly mechanical means. Further bone deterioration associated with post-menopausal osteoporosis has been treated with estrogens or bisphosphonates, which have known side effects. U.S. Pat. No, 5,280,040 discloses compounds described as useful in the treatment of osteoporosis. These compounds putatively achieve this result by preventing bone resorption. Wang, G.-J. et al, J Formos Med Assoc (1995) 94:589-592 report that certain lrpid clearing agents, exemplified by lovastatin and bezafibrate, were able to inhibit the bone resorption resulting from steroid administration in rabbits. There was no effect on bone formation by these two compounds in the absence of steroid treatment The mechanism of the inhibition in bone resorption observed in the presence of steroids (and the mechanism of the effect of steroid on bone per se) is said to be unknown. The authors state that steroid-induced bone loss is associated with a decrease in bone formation attributed to an inhibitory effect of corticosteroid on osteoblast activity and an increase in bone absorption due to direct osteoclast stimulation and to an indirect inhibition of intestinal calcium absorption with a secondary increase in parathyroid hormone production. Other mechanisms mentioned include those attributable to lipid abnormalities and hypcrlipidcmia which lead to circulatory impairment, obstruction of subchondral vessels, ostcocyte necrosis and osteoporosis. In light of the known activities of lovastatin and bezafibrate, the authors attribute the effect on bone loss to their ability to lower lipid levels and overcome the impairment to circulation within the femoral head. There is no suggestion in Wang et al. that lovastatin directly enhances bone formation. An abstract entitled "Lovastatin Prevents Steroid-Induced Adipogenesis and Osteoporosis" by Cui, Q. et al. appeared in the Reports of the ASBMR 18th Annual Meeting (September 1996) J. Bone Mineral Res. (1996) 1 1(S1):S510. The abstract reports that lovastatin diminished triglyceride vesicles that accumulated when osteoprogenitor cells cloned from bone marrow stroma of chickens were treated in culture with dexamethasone. Lovastatin was reported to diminish the expression of certain mRNAs and to allow the cells to maintain the osteogenic phenotype after dexamethasone treatment. Further, chickens that had undergone bone loss in the femoral head as a result of dexamethasone treatment were improved by treatment with lovastatin. Again, there is no suggestion that lovastatin directly enhances bone formation in the absence of steroid treatment. In any event, these data are contrary to reports that dexamethasone and other inducers, such as BMPs, induce osteoblastic differentiation and stimulate osteocalcin mRNA (Bellows, C. G., et al., Develop Biol (1990) 140: 132-38; Rickard, D. J., et al, Develop Biol (1994) 161 :218-28). In addition, Ducy, P. et al., Nature (1996) 382:448- 52 have recently reported that osteocalcin deficient mice exhibit a phenotype marked by increased bone formation and bones of improved flnctional quality, without impairment of bone resorption. Ducy et al. state that their data suggest that osteocalcin antagonists may be of therapeutic use in conjunction with estrogen replacement therapy (for prevention or treatment of osteoporosis). Other references which may suggest the use of vaπous compounds for such treatments include the following: US 5,773,428; WO97/15561 ; WO98/08840; WO96/24350 and DE 4338944. The oxazohdmones are a new class of antibacterial agents useful in treating gram positive bacterial infections Representative ol this class is the compound known as hnezolid, developed by Pharmacia & Upiohn Oxazohdmones having a thiocarbonyl functionality have been described in WO98/54161 and PCT/US98/25308 However, the use of these compounds for the treatment of osteoporosis, bone resorption or other bone diseases has not been disclosed nor suggested Despite the above teachings, there still exists a need in the art for compounds useful for stimulating bone formation without the drawbacks associated with presently known treatments for bone deficit conditions. Brief Summary of the Invention In accordance with the present invention a novel method for treating osteoporosis, bone resorption or other bone diseases without the drawbacks associated with presently known treatments for bone deficit conditions is provided. More specifically, the inventive method comprises the administration of oxazolidinones having a thiocarbonyl functionality to the patient in need thereof. In one embodiment, the present invention provides a method for treating or preventing osteoporosis, bone resorption or any other bone disease in a vertebrate mammal comprising the step of administering to the mammal in need of such treatment an effective amount of a compound of formula I or pharmaceutical acceptable salts thereof wherein: G is R j is a) H, b) NH 2( c) NH-C alkyl, d) C Ϊ alkyl, e) -OC^ alkyl, f) -S C w alkyl, g ) C alkyl substituted with 1-3 F, 1-2 Cl, CN or -COOC lJ( alkyl, h) C M cycloalkyl, i) N(C lJ( alkyl) 2 or j) N CH^; A is d) a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom, wherein the 5-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three R S , e) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon at .om, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three R^, f) a β-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three Rs 5 , wherein Rj is a) H, b) F, 0 Cl, d) Br, e) Cu alkyl, f) NO 2 , or g) j and R, taken together are s is a) -S(=0), R<, b) -S(=O) 2 -N=S(O) J R 6 R 6 , c) -SC(=O)R 7 , d) -C(=O)R 8 , e) -C(=O)R,, f) -C(=O)NR 10 R llf g) -C(=NR 12 )R 8) h) -C RaXR^ORu, i) -C R^R^-OR,,, j) -C(R 8 )(R 1I )-OC(=O)R 13) k) -C(R,XR n )-OC(=O)R 13 , 1) -NR l0 R u , m) -N(R 10 )-C(=O)R 7 , n) -N(R 10 )-S(=O) i R 7) o) -C(OR )(OR 15 )R 8) p) -C(R 8 XR 16 )-NR 10 R 11 , or q) C w alkyl substituted with one or more =O other than at alpha position, -S(=O) j R 17 , -NR^R^ C M alkenyl, or C^ alkynyl; R 4 is a) C 1 alkyl optionally substituted with one or more halos, OH, CN, NRwRn, or -CO^, b) C^ alkenyl, c) -NR 16 R 18 , d) -N 3 , e) -NHCf^OJR,, f -NR 20 C(=O)R 7 , ε ) -N(R 19 ) 2 , h) -NR 16 R 19 , or i) -NRuR-o, Rs and Rg at each occurrence are the same or different and are a) C^ alkyl, or b) Rg and Rg taken together are -(CHΛ-; Ry is C alkyl optionally substituted with one or more halos; Re is a) H, or b) C w alkyl optionally substituted with one or more halos, or C M cycloalkyl; Rg is C alkyl substituted with one or more a) -S(=O)R 17> b ) "OR 13 , c) -OC(=O)R l3t d) -NR I0 R llf or e) C w alkenyl optionally substituted with CHO; R 10 and R n at each occurrence are the same or different and are a) H, b) G M alkyl, or c) C 3. g cycloalkyl; R 12 is a) -NR 10 R n , b) -OR 10 ; or c) -NHC(=O)R 10 ; R 13 is a) H, or b) C M alkyl; R 14 and R 15 at each occurrence are the same or different and are ) c ι-4 alkvl > or b) R 14 and R 16 taken together are -(CH),-; a) H, b) C w alkyl, or 0 C M cycloalkyl; R 17 is a) C l alkyl, or b) C j ^ cycloalkyl; R 18 is a) H, b) C M alkyl, c) C M alkenyl, d) Cs- 4 cycloalkyl, e) -ORu j Or Rι 9 is a) Cl, b) Br, or 0 I; R^o is a physiologically acceptable cation; R j , and R-^ at each occurrence are the same or different and are a) H, b) C alkyl, or 0 -N jj taken together are -(CH 2 ) m -; wherein R^ and R^ at each occurrence are the same or different and are a) H, b) F, c) Cl, d) C 1-2 alkyl, e) CN ) OH, g) 0^ 2 alkoxy, h) nitro, or i) amino; Q is a) - ' h) j) m x 1) ^ (CH 2 ) n ^ R C ^ (CH 2 Ji 38 ) p ^^- m) a diazinyl group optionally substituted with X and Y, n) a triazinyl group optionally substituted with X and Y, o) a quinolinyl group optionally substituted with X and Y, P ) a quinoxalinyl group optionally substituted with X and Y, q ) a naphthyridinyl group optionally substituted with X and Y, s) u) 1 07 v) y) Y I Q and R^ taken together are wherein Z 1 is a) -CH j -, b) -CH(R 1M )-CH 2 -, c) -C(O)-, or d) -CH 2 CH 2 CH 2 -; wherein Z 2 is a) -O 2 S-, b) -O-, c) -N(R 107 )-, d) -OS-, or e) -S-; wherein Z 3 is a) -o 2 s-, b) -O-, c) -OS-, or d) -S-; wherein A 1 is a) H-, or b) CH 3 ; wherein A 2 is a) H-, b) HO-, c) CH 3 -, d) CH 3 O-, e) R 102 O-CH 2 -C(O)-NH- f) R 103 O-C(O)-NH-, g) (C^alkyl-O-CXO)-, j ) (C 1 -C 3 )alkyl-O 2 C- k) CH 3 -C(O)-, 1) CH 3 -C(O)-CH 2 -, m) , or 0 0 V_7 A 1 and A 2 taken together are: a) "o < H- b) 0= or R 1 14 \ C) : wherein R 102 is a) H-, b) CH 3 -, c) phenyl-CHa-, or d) CH 3 C(O)-; wherein R 103 is a) (CrC^alkyl-, or b) phenyl-; wherein R 1M is a) H-, or b) HO-; wherein R 105 is a) H-, b) (C 1 -C 3 )alkyl-, c) CH 2 = CH-CH 2 -, or d) CH 3 -O-(CH 2 ) 2 -; wherein R 106 is a) CH 3 -C(O)-, b) H-C(O)-, c) Cl^CH-C O)-, d) HOCH -CKOK e) CH s SO 2 -, g ) F 2 CHC(O)-, h) N^N-C(O)- \=J i) H 3 C-C(O)-O-CH 2 -C(O)-, j) H-C(O)-O-CH 2 -C(O)-, k) ^-C(O)- 1) HC^-CH 2 O-CH 2 -C(O)-, or m) phenyl-CH 2 -O-CH 2 -C(O)-; wherein R 107 is a) R 102 O-C(R U0 XR 111 )-C(O)-, b) R 103 O-C(O)-, c) R 108 -C(O)-, o d) Q r~Λ :V f) H 3 C-C(O)-(CH 2 ) 2 -C(O)-, g) R 1M -SO 2 -, i) HO-CH 2 -C(O)-, j) ΕL∞-qCRJr, 1) (CH j ϊjN-CHj-CXOJ-NH-, n) F j -CH-CH 2 -, or o) R 160 R 161 NSO 2 wherein R 108 is a) H-, b) (C.-C alkyl, c) aryl -(CH 2 ) p , d) C1H 2 C-, e) C1 2 HC-, f) FH 2 C-, g) F 2 HC-, h) (C 3 -C 6 )cycloalkyl, or i) CNCH 2 -. wherein R 109 is a) alkylCi-C,, b) -CH^Cl c) -CH 2 CH=CH 2 , d) aryl, or e) -C^CN; wherein R llfl 1 and R 111 are independently a) H-, b) CH 3 -; or wherein R 1U ! is a) H-, b) CHaO-CH j O-CH*-, or c) HOCH 2 -; wherein R ιυ ' is a) CH 3 -, b) HOCH 2 -, c) (CH 3 ) 2 N-phenyl, or d) (CH^N-CH,-; wherein R is . a) HO-, b) CH 3 O-, 0 H.N-. d) CH 3 O-C(O)-O-, f) phenyl-CH 2 -O-CH 2 -C(O)-O-, g) HO-(CH 2 ) 2 -O-, h) CH 3 O-CH 2 -O-(CH 2 ) 2 -O-, or i) CH 3 O-CH 2 -O-;wherein R 113 is a) CH 3 -, b) HOCH 2 -, c) (CH 3 ) 2 N-phenyl, or d) (CH 3 ) 2 N-CH 2 -; wherein R llδ is a) H-, or b) C1-; wherein R 116 is a) HO- b) CH 3 O-, or c) F; wherein R 150 and R 161 are each H or alkyl C^ or R 150 and R lsl taken together with the nitrogen atom to which each is attached form a monocyclic heterocycHc ring having from 3 to 6 carbon atoms; B is an unsaturated 4-atom linker having one nitrogen and three carbons; M is a) H, b) Cu, alkyl, c) C M cycloalkyl, d) -(CH j ^ORu, or e) - CHΛ-NR^R ; is a) O, b) S, or 0 NM; W is a) CH, b) N, or c) S or O when Z is NM; Y is a) H, b) F, 0 Cl, d) Br, e) C, j a alkyl, or 0 NO 2 ; Y Λ X. i IiSs- a) H ( b) -CN, 0 OR^, d) halo, e) NO 2) f) tetrazoyl, g) -SH, h) Si^O)^, i) -S(=O) 2 -N=S(O) j R 5 R 6 , j) -SC(=O)R 7 , k) - ( X=0)R 25 , 1) -C(=O)NR 27 R 28) m) -C(=NR 29 )R 25 , n) -CO^XR^-OR^, o) - XR 25 XR 28 )-OC(=O)R 13 , p) -C(R 28 XOR 13 )-(CH 2 ) h -NR 27 R 28 , q) -NRA, r) -N(R 27 )C(=O)R 7 , s) -NCJ^^R,, t) -C(OR 14 XOR ιε )R 2β , ) -C(R 25 )(R 16 )-NR 27 R 26 , or v) C w alkyl substituted with one or more halos, OH, =O other than at alpha position, alkenyl, C M alkynyl, or cycloalkyl; R λ , Rg, Rg, Ry, R 13 , R M , R 15 , R 16 , and R 17 are the same as defined above; zs is a) H, b) C^ alkyl optionally substituted with one or more halos, C M cycloalkyl, C l alkyl substituted with one or more of -ORu, or OC^Ru, NRjγRaβ, or c) C M alkenyl optionally substituted with CHO, or CO,R ls ; R∞ is a) R jj g, or b) NRΛ; 2 and R 28 at each occurrence are the same or different and are a) H, b) C M alkyl, 0 C 3 _g cycloalkyl, d) -(CH 2 ) m OR 13 , e) - CHΛ-NR^R , or f) -(CH 2 ) h CH(COR 7 )- ) or -(CH 2 ) 2 N(CH 2 ) 2 (R 7 ); ∞ is b) -OR^ or 0 -NHC^O)^; wherein R∞ is a) H, b) C w alkyl optionally substituted with one or more halos, or c) C^ alkyl optionally substituted with one or more OH, or C 1-6 alkoxy, wherein E iε a) NR∞, 0 O; H, b) C M alkyl, c) -(CH 2 ) q -aryl, or d) halo; R 39 IS a) H, b) C j _ 6 alkyl optionally sub: 0 -(CH 2 ) q -aryl, d) -CO j R^o, e) -COR, ! , 0 - X=OMCH 2 ) q -C(=O)R w , g) -SO^-C^ alkyl, h) -S(=O) 2 -(CH 2 ) ς -aryl, or i) -(C=O) r Het; R<o is a) H, b) C,^ alkyl optionally substituted with one or more OH, halo, or -CN, c) -(CH 2 ) q -aryl, or d) -(CH 2 ) ς -OR <2 ; R <1 -S a) C,^ alkyl optionally substituted with one or more OH, halo, or -CN, b) -(CH 2 ) q -aryl, or c) -(CH 2 ) q -OR <2 ; R« is a) H, b) C^ alkyl, l; aryl is a) phenyl, b) pyridyl, or c) napthyl; a to c optionally substituted with one or more halo, -CN, OH, SH, C 1-6 alkyl, C M alkoxy, or C 1-6 alkylthio; wherein R^ is a) H, b) C x . 2 alkyl, C ) F ' θr d) OH; R^ is a) H, b) CF 3 , c) C^ alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R^ and R< 5 taken together are a 5-, 6-, or 7-membered ring of the formula, f) R << and R 45 taken together are -(CH 2 ) k -, when R 46 is an electron- withdrawing group; R <5 and R 6 at each occurrence are the same or different and are a) an electron-withdrawing group, b) H, c) CF 3) d) Cj. 3 alkyl optionally substituted with one halo, e) phenyl, provided at least one of R^ or R^ is an electron-withdrawing group, or f) R AS and R^ taken together are a 5-, 6-, 7-membered ring of the formula U is b) O, c) S, or d) NR 47 ; R 47 is a) H, or b) C« alkyl; wherein R <8 is a) carboxyl, b) halo, 0 -CN, d) mercapto, e) formyl, f> CF 3 , g) -NO 2 , h) C M alkoxy, i) C t< alkoxycarbonyl, j) C w alkythio, k) C^ acyl, 1) -NR <9 Rso, m) C,^ alkyl optionally substituted with OH, C 1 5 alkoxy, C ι 5 acyl, or n) C 2 ^ alkenyl phenyl optionally substituted with one or two R 51> o) phenyl optionally substituted with one or two R^, p) a 5-, or 6-membered (un)saturated heterocycHc moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R^, or ^ at each occurrence are the same or different and are a) H, b) C 1 alkyl, c) β. 6 cycloalkyl, or d) R 49 and R^, taken together with the nitrogen atom is a 5-, 6- membered saturated heterocycHc moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C l4 alkyL or C w acyl; a) carboxyl, b) halo, 0 -CN, d) mercapto, e) formyl, f) CF 3 , g ) -NO,, h) C 1-6 alkoxy, i) C^ alkoxycarbonyl, j ) C 1-6 alkythio, k) C w acyl, 1) C alkyl optionally substituted with OH, C l-β alkoxy, C^ acyl, or -NR^Reo, m) phenyl, n) -C^OJNRs, R^, o) -N 49 50 , p ) -N(R 52 )(-SO 2 R M ), q ) -SO 2 -NR 52 R 53 , or r) -S(=O) i R 54 ; Rsj and R∞ at each occurrence are the same or different and are a) H, b) C^ alkyl, or c) phenyl; Rs < is a) C l alkyl, or b) phenyl optionally substituted with C^ alkyl; wherein R^ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f CF 3 , g) -NO 2 , h) C 1-6 alkoxy, i) C t4 alkoxycarbonyl, j) C w alkythio k) C 1-6 acyl, 1) -NR∞ Rs,, m) C^ alkyl optionally substituted with OH, C^ alkoxy, C^ acyl, or -NR∞Rs,, n) C M alkenylphenyl optionally substituted with one or two Rgg, o) phenyl optionally substituted with one or two Rs 8 , p) a 5- or 6-membered (un)saturated heterocycHc moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R∞, or R^ g and ^ at each occurrence are the same or different and are a) H, b) formyl, 0 C alkyl, d) C acyl, e) phenyl, f) C^ cycloalkyl, or g) Rsg and R^ η taken membered saturated heterocycHc moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C^ alkyl, or C^ acyl; R∞ is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, 0 CF 3 , g) -NO 2 , h) C l4 alkoxy, i) C M alkoxycarbonyl, j) C w alkythio, k) C^ acyl, 1) phenyl, m) C, * alkyl optionally acyl, -NResR∞, -SR^, -O-SO^, or R, 69 " ^ -NH-CO-O- n) -C βONRa, Reo, o) -NR K R S ,, q) -SO j - R j jRβo, r) -S^R M , s) -CH=N-R €1 , or t) -CH(OH)-SO 3 Re,; R^ is the same as defined above; R jg and R^, at each occurrence are the same or different and are a) H, b) C^ alkyl, c) phenyl, or d) tolyl; Ώ . Re- is a) OH, b) benzyloxy, c) -NH-C(=O)-NH 2 , Re 2 and R & at each occurrence are the same or different and are a) H, or b) C 1 alkyl optionaUy substituted with phenyl or pyridyl; R^ is a) H, or b) a sodium ion; Res and R^ at each occurrence are the same or different and are a) H, b) formyl, c) Cn alkyl, d ) C^ acyl, e) phenyl, f) C^ cycloalkyl, g) Rg 5 and R^ taken together are a 5-, 6-membered saturated heterocycHc moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C w alkyl, or C^ acyl, h) -P(OXOR 70 XOR 71 ), or i) -SO j -R^; R^ is Reg is C M alkyl; Reg is a) C j ^ alkoxycarbonyl, or b) carboxyl; j 0 and R^ at each occurrence are the same or different and are a) H, or b) C M alkyl; Rγ j iS a) methyl, b) phenyl, or c) tolyl; wherein K is a) O, or b) S; Rγa, R^, Rγs, j6 , and R- 7 at each occurrence are the same or different and are a) H, b) carboxyl, c) halo, d) -CN, e) mercapto, f) formyl, g) CF 3 , h) -NO,, i) C t .β alkoxy, j ) C^ alkoxycarbonyl, k) C^ alkythio, » C,^ acyl, m) -NR jg R γg , n) CC,^ * aallkkyyll ooppttiioonnaallllyy substituted with OH, C^ alkoxy, C,^ acyl, -N ^R^, -N(phenyl)(CH 2 -CH 2 -OH), -O-CH(CH 3 )(OCH 2 CH 3 ), or -O-phenyl-[para-NHC(=O)CH 3 ] , o) C 2 _g alkenylphenyl optionally substituted with R^ p) phenyl optionally substituted with R^, or q) a 5-, or 6-membered (un)saturated heterocycHc moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with R^; Rg ! is the same as defined above; R-g and R-, at each occurrence are the same or different and are a) H, b) C M alkyl, c) phenyl, or d) Rγg and Rjg taken together with the nitrogen atom is a 5-, 6- membered saturated heterocycHc moiety which optionaUy has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C^ alkyl, or C^ acyl; wherein T is a) O, b) S, or c) SO 2 ; J S , Ryg, and R^ are the same as defined above; a) H, b) formyl, c) carboxyl, d) C w alkoxycarbonyl, e) C w alkyl, f) C M alkenyl, wherein the substituents (e) and (f) can be optionally substituted with OH, halo, C 1-β alkoxy, C M acyl, C,^ alkylthio or C,_s alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF 3 , -NO 2 , C,^ alkyl, C,^ alkoxy, C^ acyl, C^ alkylthio, or C,^ alkoxycarbonyl; h) -NRA, i) -OR,o, k) -SO 2 -N(R 92 )(R 93 ), or 1) a radical of the following formulas: Rg ! and R∞ at each occurrence are the same or different and are a) H, b) Cμg cycloalkyl, c) phenyl, d) C M acyl, e) C^ alkyl optionally substituted with OH, C w alkoxy which can be substituted with OH, a 5-, or 6-membered aromatic heterocycHc moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF 3 , halo, -NO 2 , C w alkoxy, -NR^R^, or < V is a) O, b) CH,, or 0 NR,,; R g3 and R^ at each occurrence are the same or different and are a) H, or b) C M alkyl; R 85 is a) OH, b) C, .4 alkoxy, or 0 -JN gg rtgg; a) H, or b) CC,^. 7 aallkkyyll ooppttiiconally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -CX=O)-NH 2) -CO 2 H, or -C(=NH)-NH 2 ; ^ is a) H, b) phenyl, or c) C w alkyl optionally substituted by OH; Rgg and Rgg at each occurrence are the same or different and are a) H, b) C^ alkyl c) cycloalky, or d) phenyl; R∞ is a) C^ alkyl optionally substituted with C 1-€ alkoxy or C^ hydroxy, C 3 ^ cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocycHc moiety having one to three nitrogen atoms, which can in turn be substituted with one or two -NO 2 , CF 3 , halo, -CN, OH, alkyl, C^ alkoxy, or C^ acyl; b) /— Λ ' K-(CH 2 - c) phenyl, or d) pyridyl; R^ is a) Cu, alkyl, b) C j . 16 alkenyl, wherein the substituents (a) and (b) can be optionally substituted with C,^ alkoxycarbonyl, or a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or d) a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF 3 , -NO 2 , C^ alkyl, C^ alkoxy, C^ acyl, C 1-6 alkylthio, or C 1-6 alkoxycarbonyl; Rg 2 and Rg 3 at each occurrence are the same or different and are a) H, b) phenyl, c) C w alkyl, or d) benzyl; Rg 4 and Rg 5 at each occurrence are the same or different and are a) H, b) OH, c) C w alkyl optionally substituted with or d) R^ and R^ taken together are =O; R∞ is a) an aromatic moiety having 6 to 10 carbon atoms, b) a 5-, or 6-membered aromatic optionally benzo-fused heterocycHc moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (a) and (b) which can in turn be substituted with one or three -NO 2 , CF 3 , halo, -CN, OH, phenyl, C^ alkyl, C^ alkoxy, or C^ acyl, c) morpholinyl, d) OH, e) C 1-6 alkoxy, a) morpholinyl, b) OH, or c) C,_ 6 alkoxy; h is 1, 2, or 3; i is 0, 1, or 2; j is 0 or 1; k is 3, 4, or 5; 1 is 2 or 3; m is 4 or 5; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; with the proviso that n and P together are 1, 2, 3, 4, or 5; q is 1, 2, 3, or • 4; r is 2, 3, or 4; t is 0, 1, 2, 3, 4, 5, or 6; u is 1 or 2; w is 0, 1, 2, or 3. An object of the present invention is to provide a novel method for treating or preventing osteoporosis, bone resorption and other bone diseases. Still another object of the present invention is to prepare a medicament for treating or preventing osteoporosis, bone resorption and other bone diseases in a mammal These, and other objects, will readily be apparent to those skilled in the art as reference is made to the detailed description of the preferred embodiment. Detailed Description of the Preferred Embodiment In describing the preferred embodiment, certain terminology will be utilized for the sake of clarity. Such terminology is intended to encompass the recited embodiment, as well as all technical equivalents which operate in a similar manner for a similar purpose to achieve a similar result The present invention is directed to the use of the compounds ol formula I above to treat osteoporosis bone resorption or other bone diseases The compounds including their synthesis, arc described in greater detail in WO98/54161 and PCT/US98/25308 To the extent necessary for completion, the disclosure of these documents is expressly incorporated by reierence The compounds used in the invention can be prepared using known compounds and intermediates of oxazohdmones, lsoxazohnes and butyolactones as intermediates and synthetic methods known in the art Thioamides of the invention can typically be prepared by the reaction of the corresponding amide with Lawesson's reagent Compounds disclosed in the following pubhcations are suitable intermediates for preparation of the compounds used in this invention and are hereby incorporated by reference for their disclosure of suitable compounds that can be converted to the subject thiocarbonyl deπvatives U.S Patents 5,225,565; 5,182,403; 5,164,510; 5,247,090; 5,231,188; 5,565,571 , 5,547,950, and 5,523,403 PCT Application and pubhcations PCT/US93/04850, WO94/01110; PCT/US94/08904, WO95/07271 PCT US95/02972, WO95/25106, PCT US95/10992, WO96/13502 PCT/US96/05202, WO96/35691; PCT/US96/12766; PCT/TJS96/13726 PCT/US96/14135; PCT US96/17120; PCT US96/19149; PCT/US97/01970 PCT/US95/12751, WO96/15130; and PCT/US96/00718, WO96/23788 Chemical conversion techniques for converting various intermediates having a CH 2 NH 2 on the oxazokdinone ring to CH 2 NH-C(S)-CH 3 is disclosed by Hartke, K , Barrmeyer, S , J prakt Chem 1996, 338, 251-6 Similarly, conversion of CH 2 NHC(=0)CH 3 to CH 2 NHC(S)NHCH 3 is reported by Cava, M P ; Levinson, M I , Thionation Reactions of Lawesson's Reagents, Tetrahedron 1985, 41 , 5061-87 For the purpose of the present invention, the carbon content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix C, j defines the number ol carbon atoms present from the integer "1" to the integer "i", inclusive Thus, C alkyl refers to alkyl of 1-4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl and lsomeπc forms thereol The terms "Ci 2 alkyl", "Ci T alkyl", "Cμ alkyl", "C, <, alkyl '. "Cι 6 alkyl", "Ci 8 alkyl", and "Ci i 6 alkyl" reler to an alkyl group having one to two, one to three, one to lour, one to live, one to six, one to eight, or one to sixteen carbon atoms respectively such as, lor example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, dccyl, undecyl, dodecyl, tπdecyl, tetradecyl and their lsomeπc forms thereof The terms "C 2 ^ alkenyl", "C 2 5 alkenyl", "C 2 g alkenyl", "C 2 M alkenyl" and "C 2 , 6 alkenyl" refer to at least one double bond alkenyl group having two to four, two to five, two to eight, two to fourteen, or two to sixteen carbon atoms, respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl, pentdienyl, hexenyl, hexdienyl, heptenyl, heptdienyl, octenyl, octdienyl, octatπenyl, nonenyl, nonedienyl, nonatπenyl, undecenyl, undecdienyl, dodecenyl, tπdecenyl, tetradecenyl and their lsomeπc forms thereof. The terms "C 2-5 alkynyl", "C 2-8 alkynyl", and "C 2- ι 0 alkynyl" refer to at least one tπple bond alkynyl group having two to five, two to eight, or two to ten carbon atoms respectively such as, for example, ethynyl, propynyl, butynyL pentynyl, pentdiynyl, hexynyl, hexdiynyl, heptynyl, heptdiynyl, octynyl, octdiynyl, octatriynyl, nonynyl, nonediynyl, nonatriynyl and their isomeric forms thereof. The terms "C 3^t cycloalkyl", "C 3 _6 cycloalkyl", "C 5 -6 cycloalkyl", and "C 3 8 cycloalkyl" refer to a cycloalkyl having three to four, three to six, five to six, or three to eight carbon atoms respectively such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof. The terms "C alkoxy", alkoxy", and alkoxy" refer to an alkyl group having one to four, one to six, or one to eight carbon atoms respectively attached to an oxygen atom such as, for example, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric forms thereof. The terms "Ci 6 alkylamino", and "Ci 8 alkylamino" refer to an alkyl group having one to six, or one to eight carbon atoms respectively attached to an amino moiety such as, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino, hcxylamino, heptylamino, or octoylamino and their isomeric forms thereof The terms "Ci < , dialkylamino", and "Ci 8 dialkylamino" refer to two alkyl groups having one to six, or one to eight carbon atoms respectively attached to an ammo moiety such as, for example, dimethylamino, methylethylamino, diethylamino, dipropylamino, methypropylamino, ethylpropylamino, dibutylamino, dipentylamino, dihexylamino, methylhecylammo, diheptylamino, or dioctoylamino and their isomeric forms thereof The terms "C,. 3 acyl", "C acyl", "d. 5 acyl", "Q-β acyl", "C 1-8 acyl", and "C -8 acyl" refer to a carbonyl group having an alkyl group of one to three, one to four, one to five, one to six, one to eight, or two to eight carbon atoms. The terms "C M alkoxycarbonyl", "Cι-6 alkoxycarbonyl", and "Ci-s alkoxycarbonyl" refer to an ester group having an alkyl group of one to four, one to six, or one to eight carbon atoms. The term "Ci-g alkyl phenyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical. The term "C . 8 alkenyl phenyl" refers to a at least one double bond alkenyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one phenyl radical. The term "Cι -8 alkyl pyridyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof which is substituted with at least one pyridyl radical. The term " -g hydroxyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a hydroxy group. The term "Cι_ 8 alkylsulfonyl" refers to an alkyl group having one to eight carbon atoms and isomeric forms thereof attached to a SO2 moiety. The term "Cι_ alkylthio" refers to an alkyl group having one to six carbon atoms and isomeric forms thereof attached to a sulfur atom. The term "Het" refers to 5 to 10 membered saturated, unsaturated or aromatic heterocyclic rings containing one or more oxygen, nitrogen, and sulfur forming such groups as, for example, pyridine, thiophene, furan, pyrazoline, pyrimidine, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4- pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4- isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1 -phthalazinyl, 4-oxo-2- imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5- oxazolyl, 4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2- benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole, benzisoxazole, 2-furanyl, 3-furanyL 2-thienyL 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3- isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazole-l -oxide, l,2,4-oxadiazol-3- yl, l,2,4-oxadiazol-5-yl, 5-oxo-l,2,4-oxadiazol-3-yl, l,2,4-thiadiazol-3-yl, 1,2,4- thiadiazol-5-yl, 3-oxo-l,2,4-thiadiazol-5-yl, l,3,4-thiadiazol-5-yl, 2-oxo- 1,3,4- thiadiazol-5-yl, l,2,4-triazol-3-yl, 1 ,2,4-triazol-5-yl, l,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-l-yl, 1,2,4-triazol-l-yl, 1-tetrazolyl, 1-indolyl, 1- indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl,l-purinyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolinyl, or 5-methyl-l,3,4-thiadiazol-2- yl, thiazoledione, 1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties may be substituted as appropriate. The term halo refers to fluoro, chloro, bromo, or iodo. When Q is the structure of the dotted line in the heterocyclic ring means that this bond can be either single or double In the case where the dotted line is a double bond, the R 19 group will not be present The compounds of Formula I of this invention contain a chiral center at C5 of the isoxazohne ring, and as such there exist two enantiomers or a racemic mixture of both This mvention relates to both the enantiomers, as well as mixtures contammg both the isomers In addition, depending on substituents, additional chiral centers and other isomeric forms may be present in any of A or Ri group, and this mvention embraces all possible stereoisomers and geometric forms in these groups In even more preferred embodiments, the compounds selected for use are of formula (II): wherem 7^ is -O 2 S-, -O-, -N(R 107 )-, -OS-, or -S-; w is 0, 1, 2, or 3; R 23 and R 24 are the same or different and can be H or F; and R 1 is H, NH 2 , NHalkylCrC; N(alkylC,-C 4 )2; ^ Hzfes alkylCi-d; OalkylC,-C 4 ; SalkylCι-C 4 ; alkyld-G, substituted with 1-3F, 1-2C1, CN, or -COOalkylC C 4 , or cycloalkyKVCβ, wherem in each occurrence of the alkyl group may be straight or branched; and R 107 is a) R 102 O-C(R I 10 )(R 111 )-C(O)-, b) R 103 O-C(O)-, c) R ,ϋ8 -C(O) , d) R 109 SO, , e) NC-CH, 0 FCHCH 2 -, or g) R , ) R 151 NSO 2 wherein R 102 is H, CH,-, phenyl-CH 2 -, or CH 3 C(O); each of R 110 and R 111 is selected from H or CH 3 , R 103 is alkyld- or phenyl; R 108 is H, alkyld-G,, aryl(CH 2 )o 5 , CNCH 2 -, C1CH 2 -, C1 2 HC-, FH 2 C-, F 2 HC-, or cycloalkylC 3 -C 6 ; R 150 and R 151 are the same or different and are selected from H, alkylCι-C , or R 150 and R 151 taken together with the mtrogen to which each is attached forms a monocychc heterocychc ring havmg from 3 to 6 carbon atoms Specifically preferred compounds for use mclude: (S)-trans-[[3-[3-Huoro-4-(tetrahydro-l-oxido-2H-thιopyran-4-yl)phenyl]-2-oxo-5- oxazohdmyl]methyl]thιourea; and (S)-N-[[3-[3-Fluoro-4-(4-thiomorphohnyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thio- acetamide, thiomorphokne S-oxide. The compounds used in the present mvention can be converted to their salts, where appropπate, according to conventional methods. The term "pharmaceutically acceptable salts" refers to acid addition salts useful for admmistenng the compounds used this mvention and mclude hydrochloπde, hydrobrormde, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citπc acid, 2-hydroxyethyl sulfonate, fumarate and the like. These salts may be in hydrated form. The compounds are useful for treatment of osteoporosis, bone resorption and other bone diseases in mammals The term "mammals" is intended to mclude both humans and non-human vertebrates, including, but not limited to companion animals and food animals In particularly prefeπed embodiments, the mamma! being treated is not concurrently sulfeπng from an antibacterial mfection The pharmaceutical compositions used in this invention may be prepared by combining the compounds of formula (I) with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques. Solid form compositions mclude powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be at least one substance which may also function as a diluent, flavormg agent, solubihzer, lubπcant, suspending agent, binder, tablet disintegrating agent, and encapsulatmg agent. Inert solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic mateπals, low melting wax, cocoa butter, and the like. Liquid form compositions include solutions, suspensions and emulsions. For example, there may be provided solutions of the compounds used in this invention dissolved in water and water-propylene glycol and water-polyethylene glycol systems, optionally containing suitable conventional coloring agents, flavormg agents, stabilizers and thickening agents. Preferably, the pharmaceutical composition is provided employing conventional techniques in unit dosage form containing effective or appropriate amounts of the active component. The quantity of active component, that is the compound used accord g to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application, the potency of the particular compound, the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition. In therapeutic use for treating or preventing osteoporosis, bone resorption or other bone diseases in vertebrate animals, the compounds or pharmaceutical compositions thereof will be administered orally, nasally, parenterally, topically, transdermally, or rectally at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level ol active component in the animal undergoing treatment which will be effective Generally, such cflective amount of dosage ol active component will be in the range of about 0. 1 to about 100, more prclerably about 3.0 to about 50 mg/kg of patient body weight/day. It is to be understood that the dosages may vary depending upon the requirements of the patient, the severity of the condition being treated, and the particular compound being used. Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., 2-4 four times per day. Once a day dehvery of the compound using osmotic dehvery technology such as the OROS system developed by Alza Corp. is also contemplated as falling within the scope of the invention. When the compounds according to this invention are administered parenterally, i.e., by injection, for example, by intravenous injection or by other parenteral routes of administration, they will generally contain a pharmaceutically acceptable amount of the compound or a soluble salt (acid addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for example, water-for-injection and a buffer to provide a suitably buffered isotonic solution, for example, having a pH of about 3.5-6. Suitable buffering agents include, for example, trisodium orthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine, L(+)-lysine and L(+)-arginine to name but a few representative buffering agents. The compound of this invention generally will be dissolved in the caπier in an amount sufficient to provide a pharmaceutically acceptable injectable concentration in the range of about 1 mg/mL to about 400 mg/mL of solution. The resulting liquid pharmaceutical composition will be administered so as to obtain the above-mentioned effective amount of dosage. The compounds according to this invention are advantageously administered orally in solid and liquid dosage forms. The mvention is descπbed in greater detail by the following non-limiting examples. Example 1 (S)-trans-[ [ 3-[3-Fluoro-4-(tctrahydro- l -oxιdo-2H-thιopyran-4-yl)phenyl]-2-oxo-5- oxa/ohdmyl] methyl] thiourea Step 1 : A solution of 1,1 -thιocarbonyldi-2(lH)-pyridone (192 mg, 0.827 mmol) in anhydrous methylene chloride (8.3 mL) at 0°C under a nitrogen atmosphere was treated with a solution of (S)-trans-3-[3-fluoro-4-(tetrahydro-l-oxido-2H-thιopyran-4- yl)phenyl]-5-aminomethyl-2-oxazolidinone, as prepared in Example 9 of WO98/54161, Step 1, (225 mg, 0.689 mmol) in anhydrous methylene chloride (28 mL) over 30 mmutes. The resulting mixture was stirred at 0°C for 30 minutes and at ambient temperature for 40 minutes and was then diluted with methylene chloride (20 mL), washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel (32 - 63 mm, 40 g), eluting with a gradient of acetonitrile/methylene chloride (30/70 - 60/40) under 15 psi N 2 , and those fractions with an R f = 0.12 by TLC (acetonitrile/methylene chloride, 30/70) were pooled and concentrated to give (S)- trans-3-[3-Fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4- yl)phenyl]-5- isothiocyanatomethyl-2-oxazolidinone, mp 165 - 167°C. Step 2: A solution of (S)-trans-3-[3-fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4- yl)phenyl]-5-isothiocyanatomethyl-2-oxazolidinone (Step 1, 230 mg, 0.624 mmol) in anhydrous tetrahydrofuran (31.2 mL) at 0°C under a nitrogen atmosphere was treated (bubbled) with a stream of ammonia gas for 5 minutes. The reaction pot was sealed, and the resultmg mixture was stirred at 0°C for 1 hour The excess ammonia was then removed under a stream of nitrogen, and the reaction mixture was concentrated in vacuo to give the crude product Tπturation with methanol/mcthylenc chloπde/diethyl ether gave the title compound, mp 209 - 210°C (dec ) Example 2 (5)-N-[[3-[3-Fluoro-4-(4-thιomorphohnyl)phenyl]-2-oxo-5-oxa/ohdιnyl]methyl|thιo- acetamide, thiomorphohne S-oxide (34) 1. 62 63 An ice cold, stirred mixture of sodium metapeπodate (1.08 g, 5.05 mmol) and water (12 mL), under mtrogen, was treated with 62 (1.5 g, 4.8 mmol) and MeOH (17 mL) and kept at 6 °C for 18 h and at 4 °C for 3 h. It was then treated with additional sodium metaperiodate (0.1 g), kept at 4°C for 3 h and extracted with CHC1 3 The extract was dried (MgSO ) and concntrated to give 1.4 g of 63: 1H NMR [300 MHz, (CD 3 ) 2 SO] d 2.84 (m, 2H), 3.01 (m, 2H), 3.16 (m, 2H), 3.50 (m, 3H), 3.65 (m, 1H), 3.77 (d,d, 1H), 4.03 (t, 1H), 4.66 (m, 1H), 5.18 (t, 1H), 7.16 (m, 2H), 7.52 (m, 1H); MS(ES) m/z 329 (M+FT), 351 (M+Na * ). An ice cold, stirred mixture of 63 (1.27 g, 3.87 mmol) and tnethylamine (0.732 L, 5.25 mmol) in CH 2 C1 2 (130 mL), under nitrogen, was treated with m- mtrobenzenesulfonyl chloride (1.15 g, 5.19 mmol) and kept at ambient temperature for about 24 h. It was diluted with CH2CI2, washed with water and brine, dπed (Na 2 SO 4 ) and concentrated to give 78 which was used m the next reaction without purification 78 33 A stirred mixture of the product (78) from the previous reaction, acetonitrde (70 mL) and isopropanol (70 L) was treated with concentrated ammonium hydroxide (70 mL, 29 9% NH 3 ) and kept at 40 °C for 2 h, at ambient temperature for 18 h and at 40-45 °C for 4 h; it was concentrated to about 50 mL, diluted with water and extracted with CH 2 C1 2 The extracts were washed with water and brine, dried (MgSO 4 ) and concentrated Chromatography of the residue on sihca gel with 5% MeOH-CHC gave 0.58 g of 33: MS(ES) m/z 328 (M+H + ), 350 (M+Na + ); Η NMR [300 MHz, (CD 3 ) 2 SO] d 2.81 (m, 4H), 3.01 (m, 2H), 3.16 (m, 2H), 3.30 (broad s), 3.49 (m, 2H), 3.80 (d,d, 1H), 4.01 (t, 1H), 4 58 (m, 1H), 7.19 (m, 2H), 7.51 (m, 1H). 33 34 A stirred suspension of 33 (3.7 g, 0.011 mol) and tπethylamine (3.5 mL, 0.025 mol) m THF (120 mL) was cooled, an ice bath, under nitrogen, treated, dropwise durmg 2 mm, with a solution of ethyl dithioacetate (1.47 mL, 0.0128 mol) m THF (2 mL) and kept at ambient temperature for 22 h The resultmg solution was concentrated and the residue crystallized from acetonitπle to give 3.61 g of 34: mp 176-177 °C ; Η NMR [300 MHz, (CD 3 ) 2 SO] d 2.42 (s, 3H), 2.85 (m, 2H), 3.01 (m, 2H), 3.18 (m, 3H), 3.50 (m, 2H), 3.78 (d,d, 1H), 3.89 (broad s, 2H), 4.12 (t, 1H), 4.92 (m, 1H), 7.18 (m, 2H), 7.49 (m, 1H), 10.33 (s, 1H); IR (DRIFT) 3186, 3102, 1741 cm "1 ; MS(ES) m/z 386 (M+H + ), 408 (M+Na + ). Anal, calcd for C, 6 H 20 FN 3 O 3 S 2 o 0.5 H 2 O: C, 48.71 ; H, 5.37; N, 10.65; S, 16.26; H 2 O, 2.38. Found: C, 48.75; H, 5.17; N, 10.72; S, 16.07; H 2 O, 1 72 Use of the Compounds The toxicity of the compound of Example 2 was evaluated in rats treated orally with 30, 60, 120, or 200 mg/kg/day of the compound of Example 2, water, or vehicle (contammg 80% propylene glycol, 5% cremophor, and 30-mg/ml povidone) for 4 weeks given 2 divided doses at 8 hours apart Reversibility of drug-induced changes was determmed 4 and 8 weeks followmg drug withdrawal The pathogenesis ol the bone changes was evaluated in a study in rats treated with 200 mg/kg/day for 3 or 7 days TGF-betal pro tern levels m bone marrow supernatants and serum were determmed using ELISA at the end of each of the dosing peπod Toxicity was evaluated usmg clinical, hematological, biochemical, and pathologic end pomts All doses, but 200 mg/kg day, were well tolerated clinically. In addition to anorexia, weight loss, GI effects, hematopoietic suppression and lymphoid depletion, administration of the compound of Example 2, at 120 and 200 mg kg/day, caused an increase m bone mass and density (hyperostosis) of the trabecular (spongy) bone of the sternum, femur/tibia, vertebrae, and basal cranium. Endosteal cortical bone formation occurred rarely. Hyperostosis, which became evident by Day 7 was characterized by proliferation of osteoblasts and deposition of osteoid within the marrow cavity in a trabecular configuration and/or as deposits of new bone over the existing trabeculae. At Day 28, marrow cavities were traversed by abundant normal looking trabecular bone that was lined by some peri-trabecular osteoblast proliferation and osteoid deposition. There were no significant osseous changes on Day 3 except for some subtle focal proliferation/activation of osteoblasts. The newly formed bone spicules, still present after 4 and 8 weeks of drug withdrawal, were qualitatively indistinguishable from the pre-existing bone. In relatively severe cases, osteoblast proliferation and osteoid accumulation on Day 7 and newly formed trabecular bones on Day 28 or after the recovery periods compromised or obliterated the marrow spaces. However, the bone marrow did not show changes other than hypocellularity related to hematopoietic suppression. TGF-betal was modestly but significantly increased in marrow supernatants on Day 3 but not on Day 7 or 28 Serum TGF-betal was slightly but significantly decreased on Day 3 Increased levels of TGF-betal in marrow supernatant preceded hyperostosis suggestmg a possible mechanistic relationship The compound of Example 2 increased bone mass and density within a short period of time in an orderly manner at a well-tolerated doses Newly formed bone that persisted for up to 8 weeks alter drug withdrawal (the longest penod evaluated) was morphologically indistinguishable lrom normal trabecular bones Having descπbed the invention in detail and by relercnce to the prclerred embodiments thereof, it will be apparent that modifications and vaπations are possible without departing from the scope of the appended claims.

Claims: WHAT IS CLAIMED IS: 1. A method of treating or preventing osteoporosis, bone resorption or other bone disease in a vertebrate mammal, comprising the step ol admmistermg to a mammal in need ol such treatment, an eflectivc amount ol a compound ol lor ula I I or pharmaceutical acceptable salts thereof wherein: i is a) H, b) NH,, c) NH-Cn alkyl, d) C M alkyl, e) -OC lJt alkyl, f) -S C 1 alkyl, g) C l alkyl substituted with 1-3 F, 1-2 Cl, CN or -COOC^ alkyl, b) C^ cycloalkyl, i) N(C M alkyl) 2 or j) NtCH^; A is d) a 5-membered heteroaromatic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom, wherein the 5-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three R^, e) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three R^, f) a β-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three R^, wherein ^ is a) H, b) F, c) Cl, d) Br, e) C w alkyl, f) NO 2 , or g ) Rj and R 3 taken together are -O- Cf ^-O-; Ra is a) -S(=O), R„ b) -S(=O) 2 -N=S(O) j R s R 6 , c) -SC(=O)R 7 , d) -C(=O)R 8 , e) -C^)!^, ϋ -C ^N ^, g ) -C(=NR 12 )R 8 , . i) -Cd^XRa)-©^, j) -C(R e KR 11 )-OC(=O)R 13 , 1) -NR 10 R U , m) -N(R 10 )-C(=O)R 7 , n) -N(R 10 )-S(=O) i R 7 , P) -C(R 8 XR 16 )-NR l0 R n , or q) C w alkyl substituted with one or more =O other than at alpha position, -S(=O) j R 17 , -NR JQ R H , C^ alkenyl, or C M alkynyl; R< is a) C l alkyl optionally substituted with one or more halos, OH, CN, NRwRu, or -CO 2 R 13 , b) C M alkenyl, c) -NR 16 R lg , ) -N„ e) -NHC(=O)R 7 , f) -NR 20 C(=O)R 7) g) -N(R lβ ) 2 , h) -NR 16 R 19 , or i) -NR W R JO , Rs and R^ at each occurrence are the same or different and are a) C 2 alkyl, or b) Rj and Rg taken together are - CH^-; 7 is C alkyl optionally substituted with one or more halos; a) H, or b) C^ alkyl optionally substituted with one or more halos, or C M cycloalkyl; Rg is C^ alkyl substituted with one or more a) -S(=O)R 17 , b) -OR 13 , c) -OC(=O)R 13 , d) -NR 10 R U , or e) C w alkenyl optionally substituted with CHO; R 10 and R u at each occurrence are the same or different and are a) H, b) C w alkyl, or c) C M cycloalkyl; R k „12 is a) -NR 10 R U , b) -OR 10 ; or c) -NHC(=O)R 10 ; R 13 is a) H, or b) C w alkyl; R M and R 15 at each occurrence are the same or different and are a) C w alkyl, or b) R M and R 16 taken together are -(CH),-; a) H, b) C M alkyl, or 0 Cj-β cycloalkyl; R 17 is a> C l alkyl, or b) C M cycloalkyl; R 18 is a) H, b) C^ alkyl, c) C 2 alkenyl, d) C j ^ cycloalkyl, e) -OR 13 or f) -NR^R∞; R 19 is a) Cl, b) Br, or c) I; Rao is a physiologically acceptable cation; Rj ! and R^ at each occurrence are the same or different and are a) H, b) C w alkyl, or c) -N jj R j a taken together are -(CHa),.,-; wherein R 23 and R 2 at each occurrence are the same or different and are a) H, b) F, 0 Cl, d) C x . 2 alkyl, e) CN f) OH, g) C^ alkoxy, h) nitro, or i) amino; Q is a) :»- h) j ) OT x 1) m) a diazinyl group optionally substituted with X and Y, n) a triazinyl group optionally substituted with X and Y, o) a quinolinyl group optionally substituted with X and Y, P) a quinoxalinyl group optionally substituted with X and Y, q ) a naphthyridinyl group optionally substituted with X and Y, s) U) v) y) Y I Q and R^ taken together are wherein Z 1 is a) -CH 2 -, b) -CH(R 1(H )-CH 2 -, c) -C(O)-, or d) -CH 2 CH 2 CH 2 -; wherein Z 2 is a) -o 2 s-, b) -O-, c) -N(R 107 )-, d) -OS-, or e) -S-; wherein Z 3 is a) -O 2 S-, b) -O-, c) -OS-, or d) -S-; wherein A 1 is a) H-, or b) CH 3 ; wherein A 2 is a) H-, b) HO-, c) CH 3 -, d) CH 3 O-, e) R l02 O-CH 2 -C(O)-NH- ) R 103 O-C(O)-NH-, g) (C 1 -C 2 )alkyl-O-(XO)-, h) HO-CH j -, i) CH 3 O-NH-, j) (C 1 -C 3 )alkyl-O 2 C- k) CH j -C(O)-, 1) CH,-C(O)-CH j -, m) or o o n) A 1 and A 2 taken together are: a) ,112 "o *+ b) o= , or R 1 14 \ c) N = wherein R 102 is a) H-, c) phenyl-CH jj -, or d) CH 3 C(O)-; wherein R 103 is a) (C 1 -C 3 )alkyl-, or b) phenyl-; wherein R lw is a) H-, or b) HO-; wherein R 105 is a) H-, b) (C 1 -C 3 )alkyl-, c) CH, = CH-CIV, or d) CH 8 -O-(CH 2 ) 2 -; wherein R 106 is a) CH 3 -C(O)-, b) H-C(O)-, c) Cl 2 CH-C(O)-, d) HOCH 2 -C(O)-, e) CH 3 SO 2 -, D' 15 f ) u C(0)- g) F 2 CHC(O)-, Q ) N^N-C(O)- i) H 3 C-C(O)-O-CH 2 -C(O)-, j) H-C(O)-O-CH 2 -C(O)-, k ) ^~ C(0)" 1) HC-^)-CH 2 O-CH 2 -C(O)-, or m) phenyl-CH 2 -O-CH 2 -C(O)-; wherein R 107 is a) R 102 O-C(R 110 XR 111 )-C(O)-, b) R 103 O-C(O)-, c) R 108 -C(O)-, ϋ H 3 C-C(O)-(CH 2 ) 2 -C(O)-, g) R 109 -SO 2 -, i) HO-CH 2 -C(O)-, j) R - CH j )^, 1) (CH 3 ) 2 N-CH 2 -C(O)-NH-, m) NC-CH 2 -, n) F 2 -CH-CH 2 -, or o) R I6O R IBI NS Q 2 wherein R 108 is a) H-, b) (C.-C alkyl, c) aryl -(CH 2 ) p , d) C1H 2 C-, e) C1 2 HC-, f) FH j C-, g) F 2 HC-, h) (C 3 -C 6 )cycloalkyl, or i) CNCH 2 -. wherein R 109 is a) alkylC 1 -C 4 , b) -CH j Cl c) -CH^CH^K j , d) aryl, or e) -CHjCN; wherein R llc 1 and R m are independently a) H-, b) CH 3 -; or wherein R is a) H-, b) CHaO-CH^O-CH j -, or c) HOCH 2 -; wherein R 113 is a) CH 3 -, b) HOCH 2 -, 0 (CH 3 ) 2 N-phenyl, or d) (CH 3 ) 2 N-CH 2 -; wherein R 1W is a) HO-, b) CH j O-, d) CH,O-C(O)-O-. e) CH 3 -C(O)-O-CH 2 -C(O)-O-, f) phenyl-CH 2 -O-CH 2 -C(O)-O- ( g) HO-(CH 2 ) 2 -O-, h) CH 3 O-CH 2 -O-(CH 2 ) 2 -O-, or i) CH 3 O-CH 2 -O-;wherein R 113 is a) CH 3 -, b) HOCH 2 -, c) (CH 3 ) 2 N-phenyl, or d) (CH 3 ) 2 N-CH 2 -; wherein R 115 is a) H-, or b) C1-; wherein R 116 is a) HO- b) CH 3 O-, or c) F; wherein R 150 and R 151 are each H or alkyl C C 4 or R 150 and R 151 taken together with the nitrogen atom to which each is attached form a monocyclic heterocychc ring having from 3 to 6 carbon atoms; B is an unsaturated -atom linker having one nitrogen and three carbons; M is a) H, b) C 14 alkyl, 0 Cs. 8 cycloalkyl, e) -(CH 2 ) h -NR 21 R 22 ; Z is a) O, b) S, or 0 NM; W is a) CH, b) N, or c) S or O when Z is NM; Y is a) H, b) F, c) Cl, d) Br, e) C 1 3 alkyl, or 0 NO 2 ; X is a) H, b) -CN, c) OR d) halo, e) NO 2> f) tetrazoyl, g) -SH, i) -S(=O) 2 -N=S(O) j R 5 R 5( j) -SC(=O)R 7 , k) -CX^ a, 1) - ^im^, m) -C(=NR 29 )R 25I n) -( JS XR^ OR,,, o) -(XR 25 XR 28 -O(X=0)R 13 , P) -C(R 28 XOR 13 )-(CH 2 ) h -NR 27 R 28 , q) -N ^R∞, r) -N(R 27 )C(=0)R 1 , s) -N(R 27 )-S(=O) i R 7( t) -CXOR M XOR^R,,, u) -C(R 25 )(R 16 )-NR 27 R 26 , or v) C. . alkyl substituted with or alpha position, alkynyl, or C M cycloalkyl; R < , Rg, Rg, R,, R 13 , R M , R 15 , R 16 , and R 17 are the same as defined above; a) H, b) C,^ alkyl optionally substituted with one or more halos, C M cycloalkyl, C M alkyl substituted with one or more of -S(=O),R„, -OR,., or OC(=O)R,,, NR^ *,, or c) C 2 ^ alkenyl optionally substituted with CHO, or CO 2 R 13 ; a) R jg , or b) NR,,^; R^ and R 2g at each occurrence are the same or different and are a) H, b) C,^ alkyl, c) C 3 .g cycloalkyl, d) -(CH 2 ) m OR 13> e) -(CH 2 ) h -NR 21 R 22 , or f) Rz, and R∞ taken together are -(CH OTCOR,)-, or -(CH 2 ) 2 N(CH 2 ) 2 (R 7 ); R is c) -NHC(=O)R 28 ; in R j o is a) H, b) Cj. 8 alkyl optionally substituted with one or more halos, or c) C M alkyl optionally substituted with one or more OH, or C w alkoxy, wherein E is b) S(=0 , or 0 O; R is a) H, b) C^ alkyl, 0 -(CH 2 ) q -aryl, or d) halo; a) H, b) C^ alkyl optionally substituted with one or more OH, halo, or -CN, 0 -(CH^-aryl, d) -CO 2 R„, e) -COR< lf f) -C(=OMCH 1 ) q -C(=O)R 40 , g) -S(=O) 2 -C lJβ alkyl, h) -S(=O) 2 -(CH 2 ) q -aryl, or i) -(C=O) r Het; R«o is a) H, b) C,^ alkyl optionally substituted with one or more OH, halo, or -CN, c) -(CH 2 ) q -aryl, or d) -(CH 2 ) q -OR <2 ; R is a) C,^ alkyl optionally substituted with one or more OH, halo, or -CN, b) -(CH^-aryl, or c) -(CH^-OR^; R <2 is a) H, b) C M alkyl, c) -(CHa aryl, or d) -C(=O)-C w alkyl; aryl is a) phenyl, b) pyridyl, or c) napthyl; a to c optionally substituted with one or more halo, -CN, OH, SH, C M alkyl C t< alkoxy, or C M alkylthio; wherein R M is a) H, b) C,, alkyl, 0 F, or d) OH; R u is a) H, b) CF 3 , c) C M alkyl optionally substituted with one or more halo, d) phenyl optionally substituted with one or more halo, e) R u and R^ taken together are a 5-, 6-, or 7-membered ring of the formula, 0 R << and R <5 taken together are -(CH 2 ) k -, when R <6 is an electron- withdrawing group; R <5 and R <6 at each occurrence are the same or different and are a) an electron-withdrawing group, b) H, c) CF 3 , d) C^ alkyl optionally substituted with one halo, e) phenyl, provided at least one of R^ or R^ is an electron-withdrawing group, or f) R <5 and R +6 taken together are a 5-, 6-, 7-membered ring of the formula U is b) O, c) S, or d) NR 47 ; R< 7 is a) H, or b) C w alkyl; wherein R 8 is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g ) -NO 2 , h) C M alkoxy, i) C w alkoxycarbonyl, j) Cι. 6 alkythio, k) C^ acyl, m) C^ alkyl optionally substituted with OH, C,. 5 alkoxy, C 1 5 acyl, or -NR 49 R S0 , n) C 2 _ g alkenylphenyl optionally substituted with one or two Rg,, o) phenyl optionally substituted with one or two Rg,, p) a 5-, or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R^, or d R^, at each occurrence are the same or different and are a) H, b) C M alkyl, c) O M cycloalkyl, or d) R 49 and R^ taken together with the nitrogen atom is a 5-, 6- membered saturated heterocychc moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C w alkyl, or C M acyl; a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f> CF 3 , g ) -NO 2 , h) C j . 6 alkoxy, i) C t4 alkoxycarbonyl, j ) C w alkythio, k) C. * acyl, 1) C M alkyl optionally substituted with OH, C w alkoxy, C w acyl, or -NRURM, m) phenyl, q) -SO 2 -NR 52 R g3 , or r) -S^O),^; Rg 2 and Rg 3 at each occurrence are the same or different and are a) H, b) C j ^ alkyl, or c) phenyl; R S4 is a) C 1-4 alkyl, or b) phenyl optionally substituted with C^ alkyl; wherein Rgg is a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, ) CF S , g) -NO 2 , h) C M alkoxy, i) C w alkoxycarbonyl, j) C 1-6 alkythio k) C 1-6 acyl, acyl, or n) C 2 ^ alkenylphenyl optionally substituted with one or two Rg 8 , o) phenyl optionally substituted with one or two Rgg, p) a 5- or 6-membered (un)saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two Rgj, or Rg 5 and Rg 7 at each occurrence i H, a ) b) formyl, c) C M alkyl, d) C acyl, e) phenyl, f) C 3-6 cycloalkyl, or g) Rgg and Rg 7 taken membered saturated heterocychc moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C w alkyl, or C w acyl; a) carboxyl, b) halo, c) -CN, d) mercapto, e) formyl, f) CF 3 , g) -NO 2 , h) C M alkoxy, i) C w alkoxycarbonyl, j) C 1-6 alkythio, k) C 1-6 acyl, 1) phenyl, m) C w alkyl optionally substituted with OH, azido, C^ alkoxy, C^ acyl, -NRggR∞, -SR^, -O-SO^, or q ) -SO j -N β j Rβo, 8) -CH=N-R 61 , or t) -CH(OH)-SO 3 R 64 ; R S4 is the same as defined above; R g9 and R^ at each occurrence are the same or different and are a) H, b) C^ alkyl, c) phenyl, or d) tolyl; a) OH, b) benzyloxy, c) -NH-C(=O)-NH 2 , d) -NH-CHS^NH* or R^ and R^ at each occurrence are the same or different and are a) H, or b) C l alkyl optionally substituted with phenyl or pyridyl; R^ j is a) H, or b) a sodium ion; Rgg and ^ at each occurrence are the same or different and are a) H, b) formyL c) C w alkyl, d) C M acyl, e) phenyl, ft C« cycloalkyl, g) Reg and R^ taken together are a 5-, 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C M alkyl, or C M acyl, h) -P(OXOR 70 XOR 71 ), or R^is N -N N -N u" V N (CH j l j C^S ^ I C H Rgg is C w a Ikyl; ∞i a) C^ alkoxycarbonyl, or b) carboxyl; Rγo and R, ! at each occurrence are the same or different and are a) H, or b) C 1-s alkyl; R jj is a) methyl, b) phenyL or c) tolyl; wherein K is a) O, or b) S; R73» R74» 7 5 , Rγg, and R^ at each occurrence are the same or different and are a) H, b) carboxyl, c) halo, d) -CN, e) mercapto, f) formyl, g) CF a , h) -NO lf i) C,.β alkoxy. j) C,^ alkoxycarbonyl, k) C,. 6 alkythio, 1) C 1-6 acyl, m) -NR. 8 R 79 , n) CC,^ aallkkyyll ooppttiioonnaallllyy substituted with OH, C,^ alkoxy, C,_g acyl, -NR 78 R 79 , -N(phenylXCH 2 -CH 2 -OH), -O-CH(CH 3 )(OCH 2 CH 3 ), or -O-phenyl-[para-NHC(=O)CH 3 ], o) C 2 _g alkenylphenyl optionally substituted with Rg,, p) phenyl optionally substituted with Rg j , or q) a 5-, or 6-membered (un)satuτated heterocychc moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with R^; Rg ! is the same as defined above; jβ and R^ at each occurrence are the same or different and are a) H, b) C M alkyl, c) phenyl, or d) Rγg and R^ taken together with the nitrogen atom is a 5-, 6- membered saturated heterocychc moiety which optionally has a further hetero atom selected from the group consisting of S, N, and O, and can in turn be optionally substituted with, including on the further nitrogen atom, C w alkyl, or C M acyl wherein T is a) O, b) S, or c) SO 2 ; Rγ , Rγg, and -γ are the same as defined above; R β o is a) H, b) formyl, c) carboxyl, d) C,^ alkoxycarbonyl, e) C M alkyl, f C M alkenyl, wherein the substituents (e) and (0 can be optionally substituted with OH, halo, C l-6 alkoxy, C w acyl, C M alkylthio or C,^ alkoxycarbonyl, or phenyl optionally substituted with halo, g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, -CN, formyl, CF 3 , -NO 2 , C,^ alkyl, C,^ alkoxy, 0,-s acyl, C,^ alkylthio, or C,^ alkoxycarbonyl; i) -OR*, j) -S^ R, ! , 1) a radical of the following formulas: Rg ! and R at each occurrence are the same or different and are a) H, b) O M cycloalkyl, c) phenyl, d) C w acyl, e) C M alkyl optionally substituted with OH, C ι alkoxy which can be substituted with OH, a 5-, or 6-membered aromatic heterocychc moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF 3 , halo, -NO 2 , C w alkoxy, -NR^R^, or 03- V is a) O, b) CH j , or Rg j and R^ at each occurrence are the same or different and are a) H, or b) C alkyl; Res is a) OH, b) C alkoxy, or 0 -X rt gg rt gg , a) H, or b) CC,,.. 77 aallkkyyll ooppttiiconally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, -C ^-NIL j , -CO 2 H, or - X=NH NH 2 ; a) H, b) phenyl, or 0 C j . 6 alkyl optionally substituted by OH; Rgg and R^ at each occurrence are the same or different and are a) H, b) C w alkyl c) Cj-s cycloalky, or d) phenyl; *> is a) C, . alkyl optionally substituted with C. * alkoxy or C M cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two -NO 2 , CF 3 , halo, -CN, OH, C^ alkyl, C w alkoxy, or C^ acyl; c) phenyl, or d) pyridyl; Re, is a) Cue alkyl, b) C 2 . 16 alkenyl, wherein the substituents (a) and (b) can be optionally substituted with C,^ alkoxycarbonyl, or a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, c) an aromatic moiety having 6 to 10 carbon atoms, or d) a 5-, 6-, 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, -CN, formyl, CF a , -NO 2 , C 1 alkyl, C w alkoxy, C^ acyl, C w alkylthio, or C w alkoxycarbonyl; Rgj and Rg 3 at each occurrence are the same or different and are a) H, b) phenyl, c) C M alkyl, or d) benzyl; R^ and Rg 5 at each occurrence are the same or different and are a) H, b) OH, c) C 1-6 alkyl optionally substituted with -NRga R^, or d) R^ and R^ taken together are =O; R∞ is a) an aromatic moiety having 6 to 10 carbon atoms, b) a 6-, or 6-membered aromatic optionally benzo-fused heterocychc moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (a) and (b) which can in turn be substituted with one or three -NO 2 , CF S , halo, -CN, OH, phenyl, C w alkyl, C w alkoxy, or C x ^ acyl, c) morpholinyl, d) OH, e) C w alkoxy, f) -N βj R,,, g) -Cf^O^ ,,, or h) gv -S Cθ- a) morpholinyl b) OH, or c) C^ alkoxy; h is 1, 2, or 3; i is 0, 1, or 2; j is 0 or 1; k is 3, 4, or 5; 1 is 2 or 3; m is 4 or 5; n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, 4, or 5; with the proviso that n and p together are 1, 2, 3, 4, or 5; q is 1, 2, 3, or 4; r is 2, 3, or 4; t is 0, 1, 2, 3, 4, 5, or 6; u is 1 or 2; w is 0, 1, 2, or 3. 2. The method according to claim 1 wherein said mammal is a human. 3. The method according to claim 1 wherein the compound is administered in the range of about 0.1 to about 100 mg/kg of mammal body weight/day. 4. The method according to claim 1 wherein the compound is administered orally, nasally, parenterally, topically, transdermally, or rectally. 5. The method according to claim 1 wherein said compound is selected from the group consisting of : (S)-trans-[[3-[3-Fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]thiourea; and (S)-N-[[3-[3-Ruoro-4-(4-thιomo holιnyl)phenyl]-2-oxo-5-oxazohdιnyl]methyl]thιo- acetarrude, thiomorpholine S-oxide; and pharmaceutically acceptable salts thereof The method according to claim 1 wherein said mammal is not suffeπng from an antibacterial infection A method ol treating or preventing osteoporosis, bone resorption or other bone disease in a vertebrate mammal, comprising the step of administering to a mammal in need of such treatment, an effective amount of a compound of formula II wherem Zj is -O 2 S-, -O-, -N(R 107 )-, -OS-, or -S-; w is O, 1, 2, or 3; R 23 and R 24 are the same or different and can be H or F; and R 1 is H, NH 2 , NHalkylC,-C 4 ; N(alkyld-C 4 ) 2 ; -NCCH-O K alkylCι-C 4 ; OalkylC,-C 4 ; SalkylCι-C 4 ; alkylCι-C 4 substituted with 1-3F, 1-2C1, CN, or -COOalkylCi-O, or cycloalkylC 3 -C 6 , wherem m each occurrence of the alkyl group may be straight or branched; and R 107 ιs a) R 102 O-C(R 110 )(R m )-C(O)-, b) R 103 O-C(O)-, c) R 108 -C(O)-, d) R 109 -SO 2 -, e) NC-CH 2 -, f) FCHCH 2 -, or g) R 150 R 151 NSO 2 .; wherem R 102 is H, CH 3 -, phenyl-CH 2 -, or CH 3 C(O); each of R 110 and R 1 " is selected from H or aryl(CH 2 ) 0 , CNCH 2 -, C1CH 2 -, C1 2 HC-, FH 2 C-, F 2 HC-, or cycloalkylO-C R^ 0 and R^ 1 are the same or dillcrent and are selected from H, alkylCι-C 4 , or R no and R 151 taken together with the nitrogen to which each is attached lorms a monocychc heterocychc ring having from 3 to 6 carbon atoms 8 The method according to claim 7 wherem said mammal is a human 9. The method according to claim 7 wherein the compound is administered in the range of about 0.1 to about 100 mg/kg of mammal body weight/day. 10. The method according to claim 7 wherem the compound is administered orally, nasally, parenterally, topically, transdermally, or rectalfy. 11. The method according to claim 7 wherein said compound is selected from the group consisting of : (S)-trans-[[3-[3-Fluoro-4-(tetrahydro-l-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]thiourea; and (S)-N-[[3-[3-Huoro-4-(4-thiomoφholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]thio- acetamide, thiomorpholine S-oxide; and pharmaceutically acceptable salts thereof. 12. The method according to claim 7 wherein said mammal is not suffering from an antibacterial infection. The use of a compound of formula (I) or formula (II) to prepare a medicament lor treatmg or preventmg osteoporosis, bone resoφtion or other bone disease in a mammal

Inventors: JENSEN RICHARD K, MESFIN GEBRE-MARIAM, JENSEN, RICHARD, K., MESFIN, GEBRE-MARIAM
Applicants: JENSEN RICHARD K, MESFIN GEBRE MARIAM, UPJOHN CO, JENSEN, RICHARD, K., MESFIN, GEBRE-MARIAM, PHARMACIA & UPJOHN COMPANY
Application year: 2001
Main classification: A61K31
IPC codes: A61K31, A61P19, C07D263, C07D413