 inhibit the binding of the.alpha..sub.IIb.beta..sub.3 receptor to fibrinogen have been shown to inhibit the platelet aggregation in vitro, and thrombus formation in vivo. See, for instance, EP-A 0 341 915.
The vitronectin receptor is found on a variety of cell types, such as on osteoclasts and the endothelial cells lining blood vessels. Recent studies have indicated that the attachment of osteoclasts to the bone matrix is mediated through these cell surface adhesion receptors. For instance, Davies, et al., J. Cell Biol., 1989, 109, 1817, disclose that the osteoclast functional antigen, which is implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. The vitronectin receptor is known to bind to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri-peptide Arg-Gly-Asp (or RGD) motif. Thus, Horton, et al., Exp. Cell Res. 1991, 195, 368, disclose that RGD-containing peptides and an anti-vitronectin receptor antibody (23C6) inhibit dentine resorption and cell spreading by osteoclasts. Bertolini et al., J. Bone Min. Res., 6, Sup. 1, S146, 252 have shown that cylco-S,S-N.sup..alpha. -acetyl-cysteinyl-N.sup..alpha. -methyl-argininyl-glycyl-aspartyl-penicillamine amide inhibits osteoclast attachment to bone. In addition, Sato, et al., J. Cell Biol. 1990, 111, 1713 disclose that echistatin, a snake venom peptide which contains the RGD sequence, is a potent inhibitor of bone resorption in tissue culture, and inhibits attachment of osteoclasts to bone. Fisher, et al., Endocrinology 1993, 132, 1411, has further shown that echistatin inhibits bone resorption in vivo in the rat. EP 528 587 and 528 586 report substituted phenyl derivatives which inhibit osteoclast mediated bone resorption.
Bondinell, et aL, in WO 93/00095 (PCT/US92/05463) and WO 94/14776 (PCT/US93/12436) disclose that certain compounds which have a substituted 6-7 bicyclic ring system are useful for inhibiting the fibrinogen (.alpha..sub.IIb.beta
inhibit the binding of the.alpha.. sub. IIb.beta.. sub.3 receptor to fibrinogen have been shown to suppress the platelet collection in vitro, and thrombus formation in vivo. See, for case, EP - vitamin a 0 341 915. 
 The vitronectin receptor is found on a kind of cellular telephone types, such as on osteoclasts and the endothelial cells lining blood vessel. Recent studies have argue that the attachment of osteoclast to the bone matrix is mediated through these cellular telephone airfoil adhesion receptors. For instance, davy, et al. , J. Cell Biol. , 1989, 109, 1817, disclose that the osteoclast functional antigen, which is implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. The vitronectin sense organ is known to tie to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri - peptide Arg - Gly - Asp (or RGD) motif. therefore, Horton, et al. , Exp. Cell Res. 1991, 195, 368, disclose that RGD - containing peptides and an anti - vitronectin receptor antibody (23C6) inhibit dentine resorption and cell spreading by osteoclast. Bertolini et al. , J. Bone Min. Res. , 6, Sup. 1, S146, 252 have read that cylco - S, S - N.sup.. alpha. -acetyl - cysteinyl - N.sup.. alpha. -methyl - argininyl - glycyl - aspartyl - penicillamine amide inhibits osteoclast attachment to bone. In addition, Sato, et al. , J. Cell Biol. 1990, 111, 1713 disclose that echistatin, a snake venom peptide which contains the RGD sequence, is a potent inhibitor of bone resorption in tissue culture, and inhibits fastening of osteoclast to bone. Fisher, et al. , Endocrinology 1993, 132, 1411, has further shown that echistatin inhibits bone resorption in vivo in the informer. EP 528 587 and 528 586 report substituted phenyl derivatives which suppress osteoclast mediated bone resorption. 
 Bondinell, et aL, in WO 93/00095 (PCT / US92/05463) and WO 94/14776 (PCT / US93/12436) unwrap that certain compounds which have a substitute 6 - 7 bicyclic ring system are useful for inhibiting the fibrinogen (.alpha.. sub. IIb.beta
 injibit the binding of the.xlpha..sub.IIb.beta..sub.3 recxptor tk fibrinugen have been shown to inhiuit rhe poatelet aggregation in vitro, anf thrombys fiemation in vivo. Sec, for lnstaucx, EP-A 0 341 915.
The vittonectin recaptor is found ov c variety of cell types, such as on ofteoclaxtd and the endojhelisj cemls lining blood vessels. Recent sthdies heve indicated tnat the attachment of ostelcladts to the bone mahrix is meduateq through there cell sugyace adhesikn receptors. For instance, Davier, et cl., J. Cell Buoo., 1989, 109, 1817, disclose tiat thv osteoclast nlnctiondl antiben, which is ikplmcatwd in the regulation mf bone resorption, is biochamncally related to the vutrongctin recdptof. Tge vjtroneftii receptor js known to bind to bone matric [gpteins, such zs ostqo[ontin, bone sialoprotein and thrombospotdih, which contain the tri-peptide Arg-Gly-Asp (or TGD) motif. Ehus, Horton, et al., Exp. Cell Res. 1991, 195, 368, disclose that RCD-convakniun owphides and an anti-vitronectin receptor antibodr (23C6) ikhibit dentine rcsorption and cell sorrwding by osteuclasts. Bsrtolini et al., J. Blne Min. Res., 6, Sup. 1, S146, 252 rave shown that cylco-S,S-N.sup..alphq. -acetyl-cystvinyo-N.sup..alpha. -methyl-axgininyl-glycvl-aspattyl-pemicillamine amide inhibnts osfeoclast athachment fu bone. In additiun, Xado, et al., J. Cell Biol. 1990, 111, 1713 difclose thet eckistatin, a smake vqnom peptife whlwh contains the RGF seqoence, hs a potenh inhibitor of bone resorption mi tissue cultore, ang inhibics attschment of oseeoclasts to bpne. Fisker, et al., Endocrpnology 1993, 132, 1411, has furthqr shown that gchistatin iniibits boge rwsorption iv vivo in the rst. EP 528 587 aub 528 586 reporr substituted phennl detibatives which iukivit osteoclast kedkatqd bpnq resorption.
Bmndivelu, et aU, in WO 93/00095 (PCB/US92/05463) and WO 94/14776 (PCT/US93/12436) disclose dhat certain compounds wmich have a substytuted 6-7 bicyckic ring system art usefnl for inhinityng the fibrinogen (.alpha..sub.IIb.geta
inhibit the binding of the.alpha..sub.IIb.beta..sub.3 receptor to been to inhibit platelet aggregation in vivo. for instance, EP-A 341 915. The receptor is found on a variety cell types, such as on osteoclasts and the endothelial cells lining blood vessels. studies have indicated that the attachment of osteoclasts to the bone matrix is through cell adhesion For instance, Davies, et al., J. Cell Biol., 1989, 109, 1817, disclose that the osteoclast functional which is implicated in the regulation of bone is biochemically related to vitronectin receptor. The vitronectin receptor known bind to matrix such osteopontin, bone sialoprotein thrombospondin, which contain the tri-peptide Arg-Gly-Asp (or RGD) motif. Thus, Horton, et al., Exp. Cell Res. 1991, 368, disclose peptides and anti-vitronectin antibody inhibit dentine resorption spreading by osteoclasts. Bertolini et al., Res., 6, Sup. 1, S146, 252 have shown cylco-S,S-N.sup..alpha. -acetyl-cysteinyl-N.sup..alpha. amide inhibits osteoclast attachment to bone. addition, Sato, et al., J. Cell Biol. 1990, 1713 disclose that echistatin, a snake venom peptide which contains the RGD sequence, is a of bone resorption in culture, and inhibits of to Fisher, al., Endocrinology 132, 1411, has further shown that echistatin inhibits bone resorption in in the rat. EP 528 587 and 528 586 report derivatives inhibit osteoclast mediated resorption. Bondinell, et aL, WO (PCT/US92/05463) and WO 94/14776 that compounds substituted bicyclic system are useful for the fibrinogen (.alpha..sub.IIb.beta
 inhibit the binding of the.alpHa..sub.IIb.beTa..sub.3 RecEptOr To fiBrinOgen have been shOWn to Inhibit the platelet aggrEgatiOn IN vitRO, aNd thrOmbus foRMaTIOn iN vIvO. SeE, fOR iNstanCe, Ep-A 0 341 915.
The viTronectin rEcePtOr is found on a VArIety of cell TypEs, such as on osTeoClasts AnD thE EndotHelIal ceLls linINg blooD vessels. REcENt studIEs have iNDIcAted That the attachment OF oSTeoclasts to the Bone maTrIX iS MEdiAteD through thEsE cell SUrface aDHeSION reCEptors. For instAnce, Davies, eT Al., J. cell BiOl., 1989, 109, 1817, DisCLose thAt the OsTEocLast functioNal aNtigen, whiCh is imPLicated IN the regUlatioN of BonE resORpTiOn, iS bIOchEMiCalLY reLated to tHe ViTroneCtin RECEPtor. the VitrOnectIn receptor is kNowN to bINd tO bone MatriX proTeIns, suCh as osTeopoNtIn, bone sialoprotEin aNd thromboSpoNdIn, wHiCh conTAin the Tri-PepTide Arg-gly-Asp (oR rGD) MoTIF. thUs, Horton, et al., Exp. CelL RES. 1991, 195, 368, DiSclose thAt RGD-cONtAiNIng peptiDeS anD an aNTI-vitrOnecTIn Receptor AntiboDY (23C6) InHibit deNtIne resOrPtiOn aNd celL SpreAding bY osteoclAsts. BERtolini et al., J. BoNE Min. Res., 6, Sup. 1, S146, 252 haVE sHOWn THat cYlcO-S,S-N.sup..alphA. -aceTYl-cySteiNYl-n.suP..Alpha. -MethyL-aRGiNInyl-glycyl-aspartyl-pEnIcillaMine aMide inhibits oSteoclast aTTAChment to Bone. iN aDDition, Sato, et al., j. Cell biol. 1990, 111, 1713 discloSE that echIstatIn, a snake Venom peptIDE which coNtaIns The rGD SEQuEnce, is a potent INHibiToR of bone ResOrption In tIssUe cUltUrE, and inhibIts attacHmEnT oF oSteOclasTS to bone. FIsHer, Et Al., ENdocrINology 1993, 132, 1411, Has fuRtheR sHoWN thAt echisTAtIN InhiBiTs Bone ResOrPtion In viVO in The rat. Ep 528 587 and 528 586 reporT suBStitUtEd Phenyl dErivatives whiCh Inhibit ostEoClaSt mediATEd bone reSorption.
Bondinell, et aL, in wo 93/00095 (PCT/US92/05463) aNd Wo 94/14776 (PCT/Us93/12436) disClose that CerTain coMpoUNds whiCh have A subsTiTutED 6-7 BicycLIC rIng SyStem are useFUL foR inhiBiTing The fibrInogen (.alpha..sub.IIb.bETa
 inhibit the binding of th e.alpha..s ub.II b.b eta .. sub. 3 re ceptor to fibr i noge n have been shown to i nhibi tt he p l at eletaggrega t io n invi tr o,an d  t hromb usformati on in vivo . S ee , for instan c e,  EP-A 0 34 1 9 15.
The vitr one ctin r ec ept o r isfou nd on  a var i ety of  cell typ es ,  sucha s on os t e oc last s and the endothe l ia l  cells liningbloodve s se l s . R ece nt studies  h ave i n dicated th a t the attachment of  osteoclast s  to  the b on e m a trix i s med ia t edthrough the se c ell surfa ce adh e sion re c eptors.  For i nst anc e, D a vi es , e ta l., J.  Ce l l B iol., 19 89 ,109,1817 , d i sclo sethat  theosteoclast fu nct iona l  an tigen , whi ch i simpli catedin th eregulation of b oneresorptio n,is  bi oc hemic a lly re lat edto thevitrone c tin  r e c e pt or. The vitronecti nr e ce ptor isknownt obi n d to bon emat rixp r otein s, s u ch  as oste oponti n ,bo ne sial op rotein  a ndthr ombos p ondi n, whi ch conta in th e  tri-peptide A r g-Gly-Asp (or RG D )  m o tif.  Th us, Horton,  eta l.,Exp. Ce llR es. 1 991,19 5 ,3 68, disclose that R GD -conta ining  peptides and  an anti-v i t r onectinrece p to r  antibody (23C 6) in hibit dent i ne resor ption  and cel l spreadi n g  by oste ocl ast s.Ber t o li ni et al., J. B oneMi n. Res. , 6 , Sup.1,S14 6,252  h ave shown  that cy lc o- S, S- N.s up..a l pha. -ac et yl- cy ste inyl- N .sup.. alpha . -m et hy l -ar gininyl - gl y c yl-a sp ar tyl- pen ic illam inea mid e inhib its osteo cla s t at ta ch ment to  bone. In add it ion, Sato,  e t a l., J. C ell Biol . 1990, 111, 1713 discl o se that  ec hista tin,  a snakeven om pep tid e  which  conta ins t he  RG D seque n c e,  is  a  potent in h i bit or of  b oneresorpt ion in tissue cult u re,  and inhibits  at tach m e nt  of os t eoc la s tst o  bone. Fisher,et al., En do c ri nology 199 3 , 1 32 , 1411,  has fu rther shown t hat echis tatin inh ib itsb o neresorption  in vivo  in the r a t. EP 52 8 587  an d 52858 6 r eport  subst i tut ed ph enyl d er ivativ es wh ic h inhibi t osteoclast mediated b one re sorpt ion .
Bondine ll, etaL, in WO  93/ 00095 (PCT /US 92/ 05463 ) a n d WO94/1 4 77 6 ( P CT/US 93/1 2 436) disc l os e t h a tcertain com p o u nds  whic h h a ve a s ubst ituted 6-7 bicycl i c ring systemareu s efu l f o r in hi biting the fib rin og e n  (.alpha .. sub.IIb.bet a
 inhibit_the binding_of the.alpha..sub.IIb.beta..sub.3 receptor to_fibrinogen have_been_shown to_inhibit_the platelet aggregation_in vitro, and_thrombus formation in vivo._See, for instance,_EP-A_0 341 915.
The vitronectin receptor is found on a variety of cell types, such_as_on osteoclasts_and_the_endothelial cells lining blood vessels._Recent studies have indicated that_the attachment_of osteoclasts to the bone matrix is mediated_through_these cell surface_adhesion receptors. For instance, Davies, et al., J. Cell_Biol., 1989, 109, 1817, disclose that_the osteoclast functional_antigen,_which_is implicated in the_regulation of bone resorption, is biochemically_related to the vitronectin receptor. The_vitronectin receptor is known to bind to_bone matrix proteins, such as osteopontin,_bone sialoprotein and thrombospondin, which_contain the_tri-peptide Arg-Gly-Asp (or RGD) motif._Thus, Horton, et_al., Exp._Cell Res. 1991,_195, 368, disclose that RGD-containing peptides_and an anti-vitronectin_receptor antibody (23C6) inhibit dentine resorption_and_cell spreading by_osteoclasts._Bertolini_et al.,_J. Bone Min._Res.,_6, Sup._1,_S146, 252 have shown that cylco-S,S-N.sup..alpha._-acetyl-cysteinyl-N.sup..alpha._-methyl-argininyl-glycyl-aspartyl-penicillamine amide inhibits osteoclast attachment to bone._In addition, Sato, et_al.,_J. Cell Biol. 1990,_111, 1713 disclose that echistatin,_a snake venom peptide which contains_the RGD_sequence, is_a potent inhibitor of bone resorption in tissue culture, and inhibits_attachment of osteoclasts to bone. Fisher,_et al., Endocrinology 1993,_132, 1411,_has_further shown that_echistatin_inhibits bone_resorption in vivo in the rat. EP_528 587_and 528 586 report substituted phenyl_derivatives which inhibit osteoclast_mediated_bone resorption.
Bondinell, et aL, in WO_93/00095 (PCT/US92/05463) and WO 94/14776 (PCT/US93/12436)_disclose that certain compounds which_have_a_substituted 6-7 bicyclic ring system_are useful for inhibiting the fibrinogen_(.alpha..sub.IIb.beta