CELL ADHESION INHIBITORS

Abstract: The present invention relates to novel compounds that are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. This invention also relates to pharmaceutical formulations comprising these compounds and methods of using them for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. The compounds and pharmaceutical composition of this inveniton can be used as therapeutic or prophylactic agents. They are particularly well-suited for treatment of many inflammatory and autoimmune diseases.

Description: CELL ADHESION INHIBITORS TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds that are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. This invention also relates to pharmaceutical formulations comprising these compounds and methods of using them for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies. The compounds and pharmaceutical compositions of this invention can be used as therapeutic or prophylactic agents. They are particularly well-suited for treatment of many inflammatory and autoimmune diseases. BACKGROUND OF THE INVENTION Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localize within the extra-cellular matrix. As such, cell adhesion constitutes one of the fundamental mechanisms underlying numerous biological phenomena. For example, cell adhesion is responsible for the adhesion of hematopoietic cells to endothelial cells and the subsequent migration of those hemopoietic cells out of blood vessels and to the site of injury. As such, cell adhesion plays a role in pathologies such as inflammation and immune reactions in mammals. Investigations into the molecular basis for cell adhesion have revealed that various cell-surface macromolecules — collectively known as cell adhesion molecules or receptors — mediate cell-cell and cell- matrix interactions. For example, proteins of the superfamily called "integrins" are key mediators in adhesive interactions between hematopoietic cells and their microenvironment (M.E. He ler, "VLA Proteins in the Integrin Family: Structures, Functions, and Their Role on Leukocytes.", Ann. Rev. Immunol.. 8, p. 365 (1990)) . Integrins are non-covalent heterodimenc complexes consisting of two subunits called α and β. There are at least 12 different α subunits (αl-o.6, α-L, -M, α-X, α- IIB, α-V and α-E) and at least 9 different β (βl-β9) subunits. Based on the type of ts and β subunit components, each integrin molecule is categorized into a subfamily. α4βl integrin, also known as very late antigen- 4 ("VLA- ") or CD49d/CD29, is a leukocyte cell surface receptor that participates in a wide variety of both cell-cell and cell-matrix adhesive interactions (M.E. Hemler, Ann. Rev. Immunol.- 8, p. 365 (1990) ) . It serves as a receptor for the cytokine-mducible endothelial cell surface protein, vascular ceil adhesion molecule-1 ("VCAM-1"), as well as to the extracellular matrix protein fibronectm ("FN") (Ruegg et al., J. Cell Biol .. 177, p. 179 (1991); ayner et al . , J. Cell Biol.. 105, p. 1873 (1987); Kramer et al., J. Biol. Chem.. 264, p. 4684 (1989); Gehlsen et al . Science, 24, p. 1228 (1988)) . Anti-VLA4 monoclonal antibodies ("mAb's") have been shown to inhibit VLA -dependent adhesive interactions both in vitro and in vivo (Ferguson et al. Proc. Natl. Acad. Sci.. 88, p. 8072 (1991); Ferguson et al., J. Immunol.. 150, p. 1172 (1993) ) . Results of in vivo experiments suggest that this inhibition of VLA- -dependent cell adhesion may prevent or inhibit several inflammatory and autoimmune pathologies (R. L. Lobb et al., "The Pathophysiologic Role of α4 Integrins In Vivo", J. Clin. Invest., 94, pp. 1722-28 (1994) ) . In order to identify the minimum active amino acid sequence necessary to bind VLA-4, Komoriya et al. ("The Minimal Essential Sequence for a Major Cell Type- Specific Adhesion Site (CS1) Within the Alternatively Spliced Type III Connecting Segment Domain of Fibronectir Is Leucine-Aspartic Acid-Valme", J. B ol . Chem. , 266 (23), pp. 15075-79 (1991) ) synthesized a variety of overlapping peptides based on the ammo acid sequence of the CS-1 region (the VLA-4 Dinding domain) of a particular species of fibronectm. They identified ar. ÷- ammo acid peptide, Glu-Ile-Leu-Asp-Val-Pro-Ser-Tnr fSE ID NO: 1], as well as two smaller overlapping pentapeptides, Glu-Ile-Leu-Asp-Val [SEQ ID NO: 2 ' an Leu-Asp-Val-Pro-Ser [SEQ ID NO: 3], that possesseα inhibitory activity against FN-dependent cell adhesicr.. These results suggested the tripeptide Leu-Asp-Val as a minimum sequence for cell-adhesion activity. It was later shown that Leu-Asp-Val binds only to lymphocytes that express an activated form of VLA-4, thus bringing into question the utility of such a peptide in vivo (E.A. Wayner et al . , "Activation-Dependent Recognition by Hematopoietic Cells of the LDV Sequence in the V Region of Fibronectm", J. Cell. Biol., 116(2), pp. 489-497 (1992)). However, certain larger peptides containing the LDV sequence were subsequently shown to be active m. vivo [T. A. Ferguson et al. , "Two Integrin Binding Peptides Abrogate T-cell-Mediated Immune Responses In Vivo", Proc. Natl. Acad. Sci. USA, 88, pp. 8072-76 (1991); and S. M. Wahl et al., "Synthetic Fibronectm Peptides Suppress Arthritis in Rats by Interrupting Leukocyte Adhesion and Recruitment", J. Clm. Invest.. 94, pp. 655-62 (1994)]. A cyclic pentapeptide, Arg-Cys-Asp-TPro-Cys I 1 (wherein TPro denotes 4-thιoprolιne) , which can inhibit both VLA-4 and VLA-5 adhesion to FN has also been describee (D.M. Nowlin et al . "A Novel Cyclic Pentapeptide Inhibits 4βl and c.531 Integr -mediateα Cell Adhesion", J. Biol. Chem., 268(27), pp. 20352-59 (1993); and PCT publication PCT/US91/04862) . This peptide as based on the tripeptiαe sequence Arg-Gly-Asp from FN Λ.iicr. had been known as a common motif m the recognition site for several extracellular-matrix proteins. Despite these advances, there remains a need for smal_, specific inhibitors of VLA-4-depenαent cell adnesior.. Ideally, such inhibitors would be semi- peptidic or non-peptidic so that tr.ey may be orally admmistereα. Such compounds wo ^ _a provide useful agents for treatment, prevention or suppression of various pathologies mediated by cell adhesion and VLA-4 binding. Co-pend g United States patent application 08/376,372 describes β-ammo aciα containing linear peptidyl compounαs with cell adhesion mhioitory activity. International patent applications WO 94/15958 and WO 92/00995 describe cyclic peptide ana peptidomimetic compounds with cell adhesion modulating activity. International patent applications WO 93/08823 and WO 92/08464 describe guanidinyl-, urea- and thiourea- containing cell adhesion modulating compounds. United States Patent 5,260,277 describes guanidinyl cell adhesion modulation compounds. SUMMARY OF THE INVENTION The present invention solves this problem by providing novel semi-peptidic compounds that inhibit the binding of ligands to VLA-4. These compounds are useful for inhibition, prevention and suppression of VLA-4- mediated cell adhesion and pathologies associated with that adhesion, such as inflammation and immune reactions. The compounds of this invention may be used alone or in combination with other therapeutic or prophylactic agents to inhibit, prevent or suppress cell adhesion. This invention also provides pharmaceutical formulations containing these VLA-4-mediated cell adhesion inhibitors and methods of using the compounds and compositions of the invention for inhibition of cell adhesion. According to one embodiment of this invention, these novel compounds, compositions and methods are advantageously used to treat inflammatory and immune diseases. The present invention also provides methods for preparing the compounds of this invention and intermediates useful in those methods. DETAILED DESCRIPTION OF THE INVENTION The following abbreviations are used in the description: Designa ion Reagent or Fragment Ac acetyl Bn benzyl Boc tert-butoxycarbonyl Bu butyl Cbz carbobenzyloxy Cy cyclohexyl CyM cyclohexylmethyl DIPEA diisopropylethylamine EDC 1- (3-diethylaminopropyl) -3- ethylcarbodiimide HOBT 1-hydroxybenzotriazole hydrate i-amyl isoamyl i-Pn isopentyl i-Pr isopropyl Me methyl 2-MPUBA 4- (N' - (2-methylphenyl) urea) - phenylmethy1ammo 2-MPUPA 4- (N' - (2-methylphenyl) urea) - phenylacetyl NMP N-methylpyrrolidinone NMM N-methylmorpholme Ph phenyl PUPA 4- (N' -phenylurea) phenylacetyl Su succ imidyl TBTU 2- (IH-benzo riazol-l-yl > - 1,1,3, 3-tetrametnyluronιum tetrafluoroborate TEA triethylamme TFA trifluoroacetic acid THAM tris (nydroxy)methylam omethane Definitions As used herein, the term "alkyl", alone or combination, refers to a straight-chain or branched-cham alkyl radical containing from 1 to 10, preferably from 1 to 6 and more preferably from 1 to 4, carbon atoms. Examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, decyl and the like. The term "alkenyl", alone or in combination, refers to a straight-chain or branched-chain alkenyl radical containing from 2 to 10, preferably from 2 to 6 and more preferably from 2 to 4, carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z- butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, decenyl and the like. The term "alkynyl", alone or in combination, refers to a straight-chain or branched-cham alkynyl radical containing from 2 to 10, preferably from 2 to c and more preferably from 2 to 4, carbon atoms. Examples of such radicals include, but are not limited to, etr.yr.l (acetylenyl ) , propynyl, propargyl, butynyl, hexynyl, decynyl and the like. The term "cycloalkyl", alone cr combinat on, refers to a cyclic alkyl radical containing from 3-1C, preferably from 3-8 and more preferably from 3-6, caroor. atoms and may be optionally ary -fused. Examples cf sucr radicals induce, but are not limited tc, cyclopropyl , cyclobutyl, cyciopentyi, cyclonexyi anc tne like. The term "cycloalkenyl", alone cr in combination, refers tc a cyclic carbocycle contaimnc from 4 to 8, preferably 5 or 6, caroon atoms and one :r more double bonds. Examples of such cycloalkenyl radicals induce, but are not limited tc, cyciopenteny_. , cyclohexenyl, cyclopentadienyl and the like. The term "aryl" refers to a caroocyclic aromatic group selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, azuienyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyly, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 3-triazolyl, 1,3,4- thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5- triazinyl, 1, 3, 5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b] furanyl, 2,3- dihydrobenzofuranyl, benzo[b] thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pterid yl, carbazolyl, acridmyl, phenazinyl, phenothiazinyl, phenoxazmyl, pyrazolo[1, 5-c]triazinyl and the like. "Aryl", "cycloalkyl" and "cycloalkenyl" groups, as defined this application may independently contain up to three substituents which are independently selected from the group consisting of halogen, hydroxyl, ammo, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, cyano, carboxy, carboalkoxy, Ar'-substituted alkyl, Ar'-substituted alkenyl or alkynyl, 1,2- dioxymethyiene, 1, 2-dιoxyethylene, alkoxy, alkenoxy or alkynoxy, Ar'-substituted alkoxy, A '-substituted alkenoxy or alkynoxy, alkylamino, alkenylammo or alkyr.ylammo, Ar'-substituted alkylamino, Ar'-substituted alkenylammo or alkynylamino, Ar'-substituted carbonyioxy, alkylcarbonyloxy, aliphatic or aromatic acyl, Ar'-substituted acyl, Ar'-substituted alkylcarbonyloxy, Ar'-substituted carbonylaminc, Ar'- substituted amino, Ar'-substituted oxy, Ar'-substituted carbonyi, alkylcarbonylamino, Ar'-substituted alkylcarbonvlammo, alkoxy-carbonylamino, Ar'-substituted alkoxycarbonyl-amino, Ar'-oxycarbonylamino. alkylsulfonylamino, mono- or bis- (Ar'-sulfonyl)amino, Ar'-substituted alkyl-sulfonylamino, morpholinocarbonylamino, thiomorpholinocarbonylamino, N- alkyl guanidino, N-Ar' guanidino, N-N- (Ar' ,alkyl) guanidino, N,N- (Ar' ,Ar' )guanidino, N,N-dialkyl guanidino, N,N,N-trialkyl guanidino, N-alkyl urea, N,N-dialkyl urea, N-Ar' urea, N,N- (Ar' ,alkyl) urea, N,N-(Ar') 2 urea, aralkyloxycarbonyl-substituted alkyl, aralkylaminocarbonyl, thioaryloxy and the like; wherein "Ar'" is defined similarly to aryl, but contains up to three substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylammo or alkynylamino, alkylcarbonyloxy, aliphatic or aromatic acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkyl urea. The term "aralkyl", alone or in combination, refers to an aryl substituted alkyl radical, wherein the term "alkyl" and "aryl" are as defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolylmethyl, furylmethyl, imidazolyl- methyl, indolylmethyl, thienylpropyl and the like. The term "alkoxy", alone or in combination, refers to an alkyl ether radical, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The term "alkenoxy", alone or in combination, refers to a radical of formula alkenyl-O-, wherein the term "alkenyl" is as defined above provided that the radical is not an enol ether. Examples of suitable alkenoxy radicals include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenoxy and the like. The term "alkynyloxy", alone or in combination, refers to a radical of formula alkynyl-0-, wherein the term "alkynyl" is as defined above provided that the radical is not an ynol ether. Examples of suitable alkynoxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy and the like. The term "thioalkoxy" refers to a thioetner radical of formula alkyl-S-, wherein alkyl is as defined above. The term "aikylammc", alone or combmaticr., refers to a mono- or di-alkyl-substituted ammo radical (i.e., a radical of formula al yl-NH- or (alkyl) 2 -N- , wherein the term "alkyl" is as defined above. Examples- of suitable alkylamino radicals mcluoe, but are net limited to, methylamino, ethylammo, propylam o, isopropylammo, t-butylammo, N,N-oiethylaminc and tr.v like. The term "alkenyla mc", a one or comomation, refers to a radical of formula a!κenyl-.\"-- or (alkenyl) oN-, wherein the term "alkenyl" is as oe:_.:.£..: above, provided that the radical is not an enamme. Ar. example of such alkenylammo radicals is the allylamir.c radical. The term "alkynylamino", alone or in combination, refers to a radical of formula alkynyl-NK- or (alkynyl) 2 N-, wherein the term "alkynyl" is as defined above, provided that the radical is not an ynamine. An example of such alkynylammo radicals is the propargyl amino radical. The term "aryloxy", alone or in combination, refers to a radical of formula aryl-O-, wherein aryl is as defined above. Examples of aryloxy radicals include, but are not limited to, phenoxy, naphthoxy, pyridyloxy and the like. The term "arylamino", alone or m combination, refers to a radical of formula aryl-NH-, wherein aryl is as defined above. Examples of arylamino radicals include, but are not limited to, phenylam o (anilido) , naphthylamino, 2-, 3- and 4-pyrιdylamino and the like. The term "biaryl", alone or in combination, refers to a radical of formula aryl-aryl-, wherein the term "aryl" is as defined above. The term "thioaryl", alone or ir. combination, refers tc a radical of formula aryl-S-, wnere the term "aryl" is as defined above. An example c: a thioaryl radical is the thiophenyl radical. The term "aryl-fused cycloalkyl", alone or in combination, refers to a cycloalkyl radical which snares two adjacent atoms with an aryl radical, wherein the terms "cycloalkyl" and "aryl" are as defined above. An example of an aryl-fused cycloalkyl radical is the benzo- fused cyclobutyl radical. The term "aliphatic acyl", alone or in combination, refers tc radicals of formula alkyl-CO-, alkenyl-CO- and alkynyl-CO-derived from ar. alkane-, alkene- or alkyncarboxylic acid, wherein the terms "alkyl", "alkenyl" and "alkynyl" are as defined above. Examples of such aliphatic acyl radicals include, but are not limited to, acetyl, propionyl, butyryl, valeryl, 4- methylvaleryl, acryloyl, crotyl, propiolyl, methylpropiolyl and the like. The terms "aromatic acyl" or "aroyl", alone or in combination, refers to a radical of formula aryl-CO-, wherein the term "aryl" is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyi, pyridylcarbonyl and the like. The term "heterocycloyl", alone or m combination, refers to radicals of formula heterocycle- CO-, wherein the term "heterocycle" is as defined below. Examples cf suitable heterocycloyl radicals include but are not limited to, tetrahydrofuranylcarbonyl, piperidmyicarbonyl, tetrahydrothiophenecarbonyl and the like. The terms "morpholmocaroonyl" and "thiomorpπolmocarbonyl", alone cr m combination with other terms, refer to an N-carbonylated morpholmo and ar. N-carbonylated thiomorpholmo radical, respectively. The term "alkylcarbonylam o", alone or in combination, refers to a radical cf formula alkyl-CONK, wherein tr.e term "alkyl" is as defined above. The term "alkoxycarbonyiammo", alone or in combination, refers to a radical cf formula alkyl-OCONH-, wherein tr.e term "alkyl" is as defined above. The term "alkylsulfonylamino", alone or m combination, refers to a radical cf formula alkyl-S0 2 NH-, wherein the term "alkyl" is as defined above. The term "arylsulfonylammo", alone or in combination, refers to a radical of formula aryl-S0 2 NH-, wherein the term "aryl" is as defined above. The term "N-alkylurea", alone or in combination, refers to a radical of formula alkyl-NH-CO- NH-, wherein the term "alkyl" is as defined above. The term "N-arylurea", alone or in combination, refers to a radical of formula aryl-NH-CO-NH-, wherein the term "aryl" is as defined above. The term "halogen" means fluorine, chlorine, bromine and iodine. The terms "heterocycle" and "heterocyclic ring", alone or in combination, refer to a non-aromatic 3- to 10-membered ring containing at least one endocyclic N, 0 or S atom. The heterocycle may optionally be aryl- fused. The heterocycle may also be optionally substituted with one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, Ar'- substituted alkyl, Ar'-substituted alkenyl or alkynyl, 1, 2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy or alkynoxy, Ar'-substituted alkoxy, Ar'-substituted alkenoxy or alkynoxy, alkylamino, alkenylammo or alkynylamino, Ar'-substituted alkylamino, Ar'-substituted alkenylammo or alkynylamino, Ar'-substituted carbonyloxy, alkylcarbonyloxy, aliphatic or aromatic acyl, Ar'-substituted acyl, Ar'-substituted alkylcarbonyloxy, Ar'-substituted carbonylamino, Ar'- substituted amino, Ar'-substituted oxy, Ar'-substituted carbonyl, alkylcarbonylamino, Ar'-substituted alkylcarbonylamino, alkoxy-carbonylamino, Ar'-substituted alkoxycarbonyl-amino, Ar'-oxycarbonylamino, alkylsulfonylamino, mono- or bis- (Ar'-sulfonyl)amino. Ar'-substituted alkyl-sulfonylamino, morpholinocarbonylammo, thiomorpholinocarbonylamino, N- alkyl guanidino, N-Ar' guanidino, N-N- (Ar' ,alkyl) guanidino, N,N- (Ar' ,Ar' ) guanidino, N,N-dialkyl guanidino, N,N,N-trialkyl guanidino, N-alkyl urea, N,N-dialkyl urea, N-Ar' urea, N, - (Ar' ,alkyl) urea, N,N-(Ar') 2 urea, aralkoxycarbonyl-substituted alkyl, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl . The term "leaving group" generally refers to groups readily displaceable by a nucleophile, such as ar. amine, and alcohol or a thiol nucleophile. Such leaving groups are well known and include carboxylates, N- hydroxysuccmimide, N-hydroxybenzotnazole, halogen (halides), triflates, tosylates, mesylates, alkoxy, thioalkoxy and the like. The term "hydrophobic group" refers tc a grc r wr.ich is resistant to uniting witn cr absorbing water. Examples of such nydrophobic groups induce, but are r.ct liir.ited tc, methyl, ethyl, propy, utyl, pentyl, nexy., phenyl, benzyl, naphthyl, N-oenzyl midazolyl, methyl hioethyl and the lικe. The term "acidic functional group" refers :c _. group which has an acidic hyαroger. within it. Examples of such groups include, but are not limited tc, carboxylic acid, tetrazole, imidazoie, nydroxyl, mercapto, hydroxylaminocarbonyl, sulfonic acid, s lfir. c acid, phosphoric acid and phosphonic acid. The terms "activated derivative of a suιtah_y protected -amino acid" and "activated substituted- phenylacetic acid derivative" refer to derivatives of carboxylic acids wherein the -OH group is replaced by a superior leaving group. Examples of activated acid derivatives include, but are not limited to, the corresponding acyl halides (e.g. acid fluoride, acid chloride and acid bromide) , corresponding activated esters (e.g. nitrophenyl ester, the ester of 1- hydroxybenzotriazole, HOBT, or the ester of hydroxysuccinimide, HOSu) , and other conventional derivatives within the skill of the art. The terms "protected" or "protecting group" refer to a suitable chemical group which may be attached to a functional group of a molecule, then removed at a later stage to reveal the intact functional group and molecule. Examples of suitable protecting groups for various functional groups are described in T.W. Greene and P.G.M. Wuts, Protective Groups n Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser' s Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) . The compounds of this invention contain one or more asymmetric carbon atoms and tnus occur as racemates and racemic mixtures, single enantio ers, diastereomeric mixtures and individual diastereomers. All such isomeric forms cf these compounds are expressly included m tne present invention. Each stereogemc carbon may be of tne R or S configuration. Although the specific compounds exemplified m this application may be depicted in a particular stereocnemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned as part of the invention. Although amino acids and amino acid side chains may be depicted in a particular configuration, both natural and unnatural forms are envisioned as part of the invention. In view of the above definitions, other chemical terms used throughout this application can be easily understood by those of skill in the art. Terms may be used alone or in any combination thereof. The preferred and more preferred chain lengths of the radicals apply to all such combinations. This invention provides compounds which are capable cf inhibiting VLA-4-medιated cell adhesion by inhibiting the binding of ligands to that receptor. These ccmpounds are represented by formula (I) : Z-fY 1 )-^ 2 )-^ 3 )..^ (I) and pharmaceutically acceptable derivatives thereof; wherein: Z is selected from the group consisting of alkyl; aliphatic acyl optionally suostituted with N- alky - cr N-arylamido; aroyl; heterocycloyl; alkyl- or arylsuifcnyl; aralkylcarbonyl optionally substituted w tr. aryl; hεterocycloalkylcarbonyl; alκoxycarbonyl; araiKvlcxycarbonyl; cycloalkylcarbonyl optionally fused with aryl; heterocycloalkoxycarbonyl; alkylaminocarbonyi; arylami.c carbonyl and aralkylammocarbonyl optionally substituted with bis (alkylsulfonyl)amino, alkoxycarbonylamino or alkenyl; alkylsulfonyl; aralkylsuifonyl; arylsulfonyl; cycloalkylsulfonyl optionally fused with aryl; heterocyclylsulfonyl; heterocy lylalkylsulfonyl; aralkoxycarbonyl; aryloxycarbonyl; cycloalkyloxycarbonyl; heterocyclyloxycarbonyl; heterocyclylalkoxycarbonyl; mono- or di-alkyla inocarbonyl optionally substituted with aryl; (alkyl) (aralkyl) aminocarbonyl; mono- or di- aralkylaminocarbonyl; mono- or di-arylaminocarbonyl; (aryl) (alkyl) aminocarbonyl; mono- or di- cycloalkylaminocarbonyl; heterocyclylaminocarbonyl; heterocyclylalkylaminocarbonyl; (alkyl) (heterocyclyl) aminocarbonyl; (alkyl) (heterocyclylalkyl) aminocarbonyl; (aralkyl) (heterocyclyl)aminocarbonyl; (aralkyl) (heterocyclylalkyl) aminocarbonyl; alkenoyl optionally substituted with aryl; alkenylsulfonyl optionally substituted with aryl; alkynoyl optionally substituted with aryl; alkynylsulfonyl optionally substituted with aryl; cycloalkenylcarbonyl; cycloalkenylsulfonyl; cycloalkylalkanoyl; cycloalkylalkylsulfonyl; arylaroyl, biarylsulfonyl; alkoxysulfonyl; aralkoxysulfonyl; alkylaminosulfonyl; aryloxysulfonyl; arylaminosulfonyl; N-arylurea- substituted alkanoyl; N-arylurea-substituted alkylsulfonyl; cycloalkenyl-substituted carbonyl; cycloalkenyl-substituted sulfonyl; alkenoxycarbonyl optionally substituted with aryl; alkenoxysulfonyl optionally substituted with aryl; alkynoxycarbonyl optionally substituted with aryl; alkynoxysulfonyl optionally substituted with aryl; alkenyl- or alkynyl- aminocarbonyl optionally substituted with aryl; alkenyl- or alkynyl-aminosulfonyl optionally substituted with aryl; acylamino-substituted alkanoyl; acylamino- substituted alkylsulfonyl; aminocarbonyl-substituted alkanoyl; carba oyl-substituted alkanoyl; carbamoyl- substituted alkylsulfonyl; heterocyclylalkanoyl; heterocyclylaminosulfonyl; carboxyalkyl-substituted aralkoyl; carboxyalkyl-substituted aralkylsulfonyl; oxocarbocyclyl-fused aroyl; oxocarbocyclyl-fused arylsulfonyl; heterocyclylalkanoyl; N',N'-alkyl, arylhydrazinocarbonyl; aryloxy-substituted alkanoyl and heterocyclylalkylsulfonyl. Y '1 is -N(R : )-C(R 2 ) (A ' -)-C(O)-; Y 2 is -N(R " -)-C(R') (A : )-C(0)-; each Y 3 is represented by the formula -N(R : )- C(R ) (A 3 )-C(0)-; each R : is independently selected from the group consisting of hydrogen, alkyl, and aralkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkylalkyl; aryl; aminoalkyl; mono- or ci-alky -substituted ammoalkyl; mono- or di-aralkyl-substituted ammoalkyl; hydroxyalkyl; alkoxyalkyl; mercaptoaikyl; thioalkoxyalkyl A : is selected from tne group consisting of amino acid side chains and corresponding protected derivatives; cycloalkyl; and alκyl optionally substitutes with ammo, acylammo, ammo-substituted acyiam o, alkoxycarbonylamino, aryl, cycloalkyl, carboxy, aiκoxy, aralkyloxy, alkoxycarbonyl, aralkoxycarbonyl, aminocarbonyl, alkyiammocarbony , dialkylammocarconyl, (alkyl) (aralkyl) aminocaroonyl, arai ylammocarbor.yl, diaralkylammocarbonyl, hydroxyl, carboxyalkylaminocarbonyl, hydroxylammocarbony , mercapto, thioalkoxy or heterocycle; A 2 is selected from the group consisting of acidic functional groups and alkyl optionally substituted with an acidic functional group, protected acidic functional group or aryl; each A 3 is independently selected from the group consisting of amino acid side chains and corresponding protected derivatives; aryl; cycloalkyl; and alkyl optionally substituted with amino, acylamino, amino- substituted acylamino, aryl, cycloalkyl, carboxy, alkoxy, aralkyloxy, alkoxycarbonyl, aralkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (alkyl) (aralkyl) aminocarbonyl, aralkylammocarbonyl, diaralkylaminocarbonyl, hydroxy1, carboxyalkylammocarbonyl, hydroxylammocarbonyl, mercapto, thioalkoxy or heterocycle; or R and any A are taken together with the atoms to which they are attached form a 3- to 6-membered ring heterocycle; each R 2 is independently selected from the group consisting of hydrogen and alkyl; n is an integer from 0 to 8; and X is selected from tne group consisting of alkoxy; aryloxy; aralkyloxy; hydroxyl; ammo; alkylam c optionally substituted with hydroxy, aminocarbonyl, N- alkylammocarbonyl, carboxy or alkoxycarbonyl; dialkylammo; cycloalkylamino; dicycloalkylammo; cycloalkylalkylammo; (alkyl) (aryl) ammo; aralkylammc optionally substituted with carboxy; diaralkylammo; arylamino; heterocycle; and (mono- or bis-carboxylic acid) -substituted alkylamme; heterocyclylammo; heterocyclyi-substituted alkylamino and wherein the compound of formula I is expressly not N'-carboxymethyl-N- (phenylacetyl-L-leucyl-L-aspartyl-L- phenylalanyl-L-prolyl)piperazine (i.e., when Z=phenylacetyl, Y 1= L, Y 2 =D, Y 3 =F/P, n=2, and X=4- carboxymethylpiperazinyl) and expressly not phenylacetyl- L-leucyl-L-aspartyl-L-phenylalanyl-D-proline amide (i.e., when Z=phenylacetyl, Y X =L, Y 2 =D, Y 3 =F/p, n=2, and X=NH 2 ) . A "pharmaceutically acceptable derivative" denotes any pharmaceutically acceptable salt, ester, salt of such ester, amide or salt of such amide of a compound of this invention. The invention also includes any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention (e.g. a prodrug) . The invention also includes metabolites or residues of a compound of this invention characterized by the ability to inhibit, prevent cr suppress cell adhesion and cell adhesion- mediated pathologies. In a preferred embodiment of this invention, A is selected from the group consisting of cycloalkyl; heterocyclic ring (when A and R are taken together) ; and alkyl optionally substituted witn am o, acylam c, ammo-sucstituted acylamino, aryl, carboxy, cycloalkyl, hydroxy, alkoxy, aralkyloxy, a κoxycarbonyl, aralkoxycarbonyl, aminocarbonyl, alκyiammocarbonyl, dialkylamnocarbonyl, (alkyl) .aralky ) aminocarbonyl, aralkylaminocarbonyl, diarai ylammccaroonyi, alkoxycarconylammo, mercapto, thioalkoxy or heterocyc-e. More preferably, A is selected froir the gro_r consisting of ammocarbonyletnyi, benzyl, n-butyl, isobutyl, carboxyethyl, cyclonexyl, 1-hydroxyethyi, hydroxymethyl, mercaptomethyl, 1-methylpropyl, methylthioethyl, n-propyi, isopropyl, methoxycarbonylammobutyl, 6-aminohexanoylammobutyl and (when A : and R- are taken together) azetidine, aziridine, pyrrolid e, and piperidine. Even more preferably. A 1 is selected from the group consisting of benzyl, n-butyl, isobutyl, methylthioethyl, cyclohexyl, 1-methylpropyl, n-propyl and isopropyl. An alternate preferred A 1 is (when A : and R 1 are taken together) pyrrolidine. In an alternate preferred embodiment. A 2 is selected from the group consisting of alkyl optionally substituted with amino, aminocarbonyl, aryl, alkoxycarbonyl, aralkyloxycarbonyl, hydroxyla inocarbonyl, carboxy, NH-containing heterocycle, hydroxy, or mercapto; aralkyl optionally substituted with amino, aminocarbonyl, carboxy, NH- containing heterocycle, hydroxy, or mercapto; and heterocyclic ring (when A 2 and R 1 are taken together) . More preferably. A 2 is selected from the group consisting of carboxy ethyl, 2-carboxyethyl, 1- carboxyethyl, hydroxylaminocarbonylmethyl, hydroxymethyl, mercaptomethyl, imidazolylmethyl, N-Bn-imidazolylmethyl, phenyl, carbomethoxymethyl, carbobenzyloxymethyl, and (when A 2 and R 1 are taken together) azetidine, aziridine, pyrrolidine, and piperidine. Even more preferably. A 2 is selected from the group consisting of carboxymethyl, 2-carboxyethyl, 1- carboxyethyl, hydroxylaminocarbonylmethyl, hydroxymethyl, mercaptomethyl and imidazolylmethyl. According to another preferred embodiment, A 3 is independently selected from the group consisting of amino acid side chains and corresponding protected derivatives; cycloalkyl; and alkyl optionally substituted with aryl, cycloalkyl, carboxy, hydroxylaminocarbonyl, alkoxy, aralkyloxy, mercapto, N-containing heterocycle, carboxyalkylaminocarbonyl or amino-substituted acylamino. More preferably. A 3 is independently selected from the group consisting of amino acid side chains and corresponding protected derivatives; cyclohexyl; and alkyl optionally substituted with phenyl, cyclohexyl, carboxy, hydroxylaminocarbonyl, methoxy, benzyloxy, mercapto, N-benzylimidazolyl, biotinyl, tetrazolyl, valinyl-N-carbonyl or 6-aminohexanoylamino. According to another preferred embodiment, each Y 3 is independently selected from the group consisting of amino acids and corresponding protected derivatives. According to another preferred embodiment, Y- is leucinyl (R=H, R : =H, A : =ι-Bu) ; Y- is aspartyl (R : =H, R-=H, A : =carboxymethyl) ; n=2; and Y ' is valinylprolinyl (R : =H, R-=H, A 3 =i-Pr)/ (R : =H, R : with A ' =proline) . In another preferred embodiment, X is selected from the group consisting of alkoxy; aryloxy; aralkyloxy; hyαroxyl; ammo; mono- and d alkylammo optionally suostituted with hydroxy, aminocarbonyl, N- alkylam ocarbonyi, carbcxy cr alKoxycarbonyl; dialkylammo; cycloalkylam c; cycloalKylalkylam o; oicycloalkylammo; (alkyl) (aryl ) ammo; aralkylam c optionally substituted with carboxy; diaralkylam c; arylamino; N-contammg heterocycle; bis-carboxylic acid- suostituted alkylamme and (mono- or bis- carboxy)methylaminocarbonyl-substituted-N-contaming heterocycle. More preferably, X is selected from the group consisting of amino, methylammo, isopropylamino, isobutylammo, n-butylammo, t-butylamino, isoamylamino, isopentylamino, hexylamino, cyclohexylamino, cyclohexylmethylammo, methylphenylamino, phenylmethylamino, phenylamino, 4- methoxyphenylmethylamino, dimethylamino, diisopropylamino, diisobutylamino, hydroxy, methoxy, n- butoxy, t-butoxy, benzyloxy, 2-piperidinecarboxylιc acid, N'- ( , '-bis-carboxymethyl)-2-piperidinecarboxamide, N'- carboxymethyl-2-piperidinecarboxamide, l-hydroxymethyl-2- methylpropylamino, 1-N'-methylamido-l-methylethylammo, 3,3-dimethylbutylamino, 1-N'-methylamidobutylamino, 1- amido-2-methylbutylamino, l-carbomethoxy-2- methylbutylamino, l-N'-methylamιdo-2-methylbutylamino, 1- carboxy-1-phenylmethylamιno, morpholmo, piperidmyl, N- phenylpiperazinyi, pipecolmyl, and piperaz yl. According to another preferred embodiment, Z is selected from the group consisting of aliphatic acyl, aroyl, aralkylcarbonyl, heterocycloyl, alkoxycarbonyl, aralkyloxycarbonyl and heterocycloalkylcarbonyl. More preferably, Z is a (N-Ar'-urea) -para-substituted aralkylcarbonyl group and even more preferably, Z is a (N-A '-urea) -para-substituted phenylmethylcarbonyl group or (N-Ar'-urea) -para-substituted pyridylmethylcarbonyl group. Even more preferably, Z is a (N-crtho- substituted-Ar'urea) -para-substituted phenylmethylcarbonyl group or (N-meta-substituted- Ar'urea) -para-substituted phenylmethylcarbonyl group. Examples of some specific preferred compounds of this invention are provided in Table 1. Table 1. Z- (Y 1 ) - (Y z ) - (Y 3 ) D -X (I) wherein Y : is -N(R : )-C(R 2 ) (A : )-C(0)-; Y 2 is -N(R-)-C(R 2 ) (A 2 )-C(0)-; each Y 3 is represented by the formula -N(R : )-C(R 2 ) (A 3 )- C(O)-; For A : , A ; and A 3 , a single letter cooe refers to the side chain of the corresponding ammo ac d designated by that letter. A capital letter (e.g., A) indicates the L-a mo acid while a small letter (e.g., a) indicates the D-arr.mo acid. Botn capital and small letters (e.g., L(l)) indicates a mixture. Unless expressly noted to the contrary; compounds in :h s table have R and R : as hydrogen. - 3. where Het 1 , Het , Het J , Het 4 , and Het 3 in Table 1 are defined below: The more preferred compounds of formula (I) are selected from the group consisting of compound numbers 1, 2, 4, 144, 145, 146, 147, 148, 206, 315, 316, 317, 337, 338, 345, 346, 347, 357, 358 and 359 as identified in Table 1. Even more preferred compounds of formula (I) are selected from the group consisting of compound numbers 1, 206, 316, 358 and 359 as identified in Table 1. The most preferred compounds of formula (I) are selected from the group consisting of compound numbers 358 and 359 as identified in Table 1. Other compounds of this invention are compounds of formula II: κ-(γ 1 )-(y 2 )-(Y 3 ) n -j (ID and pharmaceutically acceptable derivatives thereof, wherein; K is selected from the group consisting of hydrogen, alkyl, aliphatic acyl, aroyl, aralkylcarbonyl, heterocycloyl, sulfonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, alkoxycarbonyl, aralkyloxycarbonyl, heterocycloalkoxycarbonyl, alkylam ocarbonyl and aralkylammocarbonyl; J is selected from the group consisting of alkoxy; aryloxy; aralkyloxy; hydroxyl; amino; alkylamino optionally substituted with hydroxy, aminocarbonyl, N- alkylammocarbonyl, carboxy or alkoxycarbonyl; dialkylammo; cycloalkylam o; dicycloalkylammo; (alkyl) (aryl)ammo; aralkylam o optionally substitutec with carboxy; diaralkylamino; arylamino; and (mono- or bis-carboxylic acid)-substituted alkylamine; and each Y 1 , Y 2 , Y 3 , R : , A , A~\ A 3 , R 2 , and n is independently as defined in formula I above. Compounds of this invention may be synthesized using any conventional technique. Preferably, these compounds are chemically synthesized from readily available starting materials, such as α-amino acids and their functional equivalents. Modular and convergent methods for the synthesis of these compounds are also preferred. In a convergent approach, for example, large sections of the final product are brought together in the last stages of the synthesis, rather than by incremental addition of small pieces to a growing molecular chain. According to one embodiment, compounds of the present invention may be synthesized in the following manner. A protected amino acid or functional equivalent is coupled to an appropriate activated ester moiety. The coupled product, if suitably functionalized, may be further reacted with yet another activated ester moiety. This material can be further manipulated to give the desired compounds of the invention. At each step of the above sequence, the ester can be hydrolyzed to the corresponding acid to give another compound of the invention. This acid may also be converted to a corresponding acid derivative by standard methods. Alternatively, the activated ester moieties mentioned above can be attached together first, tnen tne resulting compound can be attached to additional amine acids or their functional group equivalents. At this point the final manipulations and/or necessary deprotection steps can be performed. In another embodiment, under suitable conditions the desired functionalities can be incorporated (protected or unprotected) in one of the activated ester moieties. That ester is then coupled with an amino acid derivative or a moiety consisting of an ammo acid derivative previously coupled to an activated ester. The resulting product can then be subjected to any deprotection steps, if necessary, to give compounds of the invention. Alternatively, the compounds of this invention may be synthesized using solid support techniques. The core ammo acid or their functional equivalent groups are assembled using standard reiterative coupling methodology on a resin. When the desired core is complete, the resulting fragment can be coupled with an activated ester moiety and/or the tethered end of the fragment may be further deπvatized to give the desired product. Appropiate protection/deprotection methods may be used at any point during the synthetic sequence. The compounds of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous syster.. , increase oral availability, increase solubility to allow administration by injection, alter metabolism ana alter rate of excretion. Examples of these modifications include, but are not limited to, esterification with polyethylene glycols, deπvatization with pivolates or fatty acid substituents, conversion tc carbamates, hydroxylation of aromatic rings, and heteroatom-sucstitution in aromatic rings. As used throughout this application, the term "patient" refers to mammals, including humans. And the term "cell" refers to mammalian cells, including human cells. Once synthesized, the activities and VLA-4 specificities of the compounds according to this invention may be determined using in vitro and in vivo assays. For example, the cell adhesion inhibitory activity of these compounds may be measured by determining the concentration of inhibitor required to block the binding of VLA-4-expressing cells to fibronectin- or CSl-coated plates. In this assay microtiter wells are coated with either fibronectin (containing the CS-1 sequence) or CS-1. If CS-1 is used, it must be conjugated to a carrier protein, such as bovine serum albumin, in order to bind to the wells. Once the wells are coated, varying concentrations of the test compound are then added together with appropriately labelled, VLA-4-expressing cells. Alternatively, the test compound may be added first and allowed to incubate with the coated wells prior to the addition of the cells. The cells are allowed to incubate in the wells for at least 30 minutes. Following incubation, the wells are emptied and washed. Inhibition cf binding is measured by quantitating the fluorescence or radioactivity bound to the plate for each of the various concentrations of test compound, as well as for controls containing no test compound. VLA-4-expressing cells that may be utilized in this assay include Ramos cells, Jurkat cells, A375 melanoma cells, as well as human peripheral blood lymophocytes (PBLs) . The cells used m this assay may be fluorescently or radioactively labelled. A direct binding assay may also be employed to quantitate the inhibitory activity of the compounds of this invention. In this assay, a VCAM-IgG fusion protein containing the first two immunoglobulin domains of VCAM (D1D2) attached above the hinge region of an IgGl molecule ("VCAM 2D-IgG"), is conjugated to a marker enzyme, such as alkaline phosphatase ("AP") . The synthesis of this VCAM-IgG fusion is described in PCT publication WO 90/13300, the disclosure of which is herein incorporated by reference. The conjugation of that fusion to a marker enzyme is achieved by cross- linking methods well-known in the art. The VCAM-IgG enzyme conjugate is then placed in the wells of a multi-well filtration plate, such as that contained in the Millipore Multiscreen Assay System (Millipore Corp., Bedford, MA) . Varying concentrations cf the test inhibitory compound are then added to the wells followed by addition of VLA-4-expressιng cells. The cells, compound and VCAM-IgG enzyme conjugate are rr.ixed together and allowed to incubate at room temperature. Following incubation, tne wells are vacuum aramed, leaving behind tne cells and any bound VCAM. jantitation of bound VCAM is determined by aαding an appropriate colorimetπc substrate for the enzyme conjugated to VCAM-IgG and αetermming the amount of reaction product. Decreased reaction product indicates increased binding inhibitory activity. In order to assess the VLA-4 inhibitory specificity of the compounds of this invention, assays for other major groups of mtegrms, i.e., β2 and β3, as well as other βl integrins, such as VLA-5, VLA-6 and α4β7 are performed. These assays may be similar to the adhesion inhibition and direct binding assays described above, substituting the appropriate mtegrin-expressmg cell and corresponding ligand. For example, polymorphonuclear cells (PMNs) express β2 integrins on their surface and bind to ICAM. β3 integrins are involved in platelet aggregation and inhibition may be measured in a standard platelet aggregation assay. VLA-5 binds specifically to Arg-Gly-Asp sequences, while VLA-6 binds to laminin. α4β7 is a recently discovered homologue of VLA-4, which also binds fibronectm and VCAM. Specificity with respect to α4β7 is determined in a binding assay that utilizes the above-described VCAM- IgG-enzyme marker conjugate and a cell line that expresses α4β7, but not VLA-4, such as RPMI-8866 cells. Once VLA-4-specιf c inhibitors are identified, they may be further characterized in in v vo assays. One such assay tests the inhibition of contact hypersensitivity in an animal, such as described by P.L. Chisholm et al . , "Monoclonal Antibodies to the Integrin α-4 Subunit Inhibit the Murme Contact Hypersensitivity Response", Eur. J. Immunol.. 23, pp. 682-688 (1993) and m "Current Protocols m Immunology", J. E. Coligan, et al., Eds., John Wiley & Sons, New York, 1, pp. 4.2.1- 4.2.5 (1991), the disclosures of which is herein incorporated by reference. In th s assay, the skin of the animal is sensitized by exposure to an irritant, such as dmitrofluorobenzene, followed by light physical irritation, such as scratching the skin lightly with a sharp edge. Following a recovery period, the animals are re-sensitized following the same procedure. Several days after sensitization, one ear of the animal is exposed tc the chemical irritant, while the other ear is treated with a non-irritant control solution. Shortly after treating the ears, the animals are given various doses of the VLA-4 inhibitor by subcutaneous injection. I_n vivo inhibition of cell adhesion-associated inflammation is assessed by measuring the ear swelling response of the animal in the treated versus untreated ear. Swelling is measured using calipers or other suitable instrument to measure ear thickness. In this manner, one may identify those inhibitors of this invention which are best suited for inhibiting inflammation. Another in vivo assay that may be employed to test the inhibitors of this invention is the sheep asthma assay. This assay is performed essentially as described m W. M. Abraham et al., "α-Integrms Mediate Antigen- mduced Late 3ronchιal Responses and Prolonged Airway Hyperresponsiveness in Sheep", J. Cl . Invest. , 93, pp. 776-87 (1994), the disclosure of which is herein incorporated by reference. This assay measures inhibition of Ascaris antigen-induced late phase airway responses and airway hyperresponsiveness in asthmatic sheep. The compounds of the present invention may be used m the form of pharmaceutically acceptable salts derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alg ate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, ca phorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl- propionate, picrate, pivalate, propionate, succinate. tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamme salts, N-methyl-D- glucam e, tris (hydroxymethyl)methylamme and salts with ammo acids such as argmme, lysme, and so forth. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. The compounds of the present invention may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vagmally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, mtra-articular, mtra-synovial, mtrasternal, mtrathecal, mtrahepatic, mtralesional and mtracranial injection or infusion techniques. The pharmaceutical compositions of this invention comprise any of the compounds of the present invention, or pharmaceutically acceptable derivatives thereof, together with any pharmaceutically acceptable carrier. The term "carrier" as used herein includes acceptable adjuvants and vehicles. Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glyc e, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protam e sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyv yl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. According to this invention, the pharmaceutical compositions may be in the form of a sterile mjectable preparation, for example a sterile mjectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile mjectable preparation may also be a sterile mjectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution m 1, 3-butanedιol. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution and lsotomc sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol. The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. Fcr oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions cf this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non- irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation 5 (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in 1.0 one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying 15 wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not liiritec 20 to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecano , benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensicr.: 25 m lsotomc, pH adjusted sterile saline, or, , as solutions in lsotomc, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulatec 30 in an ointment such as petrolatum. The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a etered dose inhaler. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which the ingredient is co- administered. The dosage and dose rate of the compounds of this invention effective to prevent, suppress or inhibit cell adhesion will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the judgment of the treating physician. Dosage levels of between about 0.001 and about 100 mg/kg body weight per day, preferably between about 0.1 and about 10 mg/kg body weight per day of the active ingredient compound are useful. According to another embodiment compositions containing a compound of this invention may also comprise an additional agent selected from the group consisting of corticosteroids, bronchodilators, antiasthmatics (mast cell stabilizers) , antnnflammatories, antirheumatics, immunosuppressants, antimetabolites, immunonodulators, antipsoπatics and antidiabetics. Specific compounds within each of these classes may be selected from any of tnose listed under the appropriate group headings m "Comprehensive Medicinal Chemistry", Pergamon Press, Oxford, England, pp. 970-986 (1990), the disclosure of which is herein incorporated by reference. Also included within this group are compounds such as theophylline, s lfasalazme and ammosalicylates (antnnflammatories) ; cyclosporm, FK-506, and rapa ycin (immunosuppressants); cyclophosphamide and methotrexate (antimetabolites) ; and ir.terferons (immunomodulators) . According to other embodiments, the invention provides methods for preventing, inhibiting or suppressing cell adhesion-associated inflammation and cell adhesion-associated immune or autoimmune responses. VlA4-assocιated cell adhesion plays a central role m a variety of inflammation, immune and autoimmune diseases. Tnus, inhibition of cell adhesion by the compounds of tnis invention may be utilized m methods of treating or preventing inflammatory, immune and autoimmune diseases. Preferably the diseases to be treated with the methods of this invention are selected from asthma, arthritis, psoriasis, transplantation rejection, multiple sclerosis, diabetes and inflammatory bowel disease. These methods may employ the compounds of this invention in a monotherapy or in combination with an anti-inflammatory or immunosuppressive agent. Such combination therapies include administration of the agents in a single dosage form or in multiple dosage forms administered at the same time or at different times. In order that this invention may be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way. EXAMPLES GENERAL PROCEDURES FOR AMIDE BOND FORMATION IN SOLUTION: PROCEDURE A: coupling with EDC/HOBt A solution of carboxylic acid (1.2 eq.) m DKF at 0°C was treated with HOBT (1.8 eq.) and EDC (1.4 eq. . The mixture was stirred at 0 C C for 1 to 2 h and then tne free amine (1.0 eq., neutralized with TEA or DIPEA) was added. After stirring at RT for more than 3 h, the reaction mixture was diluted with ethyl acetate, washeα with water (IX), 5% aqueous citric acid (2X) , sat. NaHCO (2X), and brine (IX), dried (Na,SO, or MgSO , and concentrated m vacuo . PROCEDURE B : coupling using activated ester (N- hydroxysuccinate or chloride) A solution of free amine (1-1.2 eq. ,neutralized with TEA or DIPEA) in CH 2 C1 2 was treated with activated ester or acyl halide (1 eq.) at 0 °C or RT. After stirring at RT for over 1 h, the reaction mixture was washed with 51 aqueous citric acid (2X), sat. NaHCO, (2X) , and brine (IX), dried (Na 2 S0 4 or MgSO , and concentrated in vacuo. GENERAL PROCEDURE FOR UREA FORMATION IN SOLUTION: PROCEDURE C: formation of urea with isocyanate and amine. A solution of amme (1 eq.) and TEA (1 eq.) CH 2 C1 was treated with an isocyanate (1 eq.) and was stirred at RT for over 0.5 h. After concentration m vacuo, the product was either used as is or purified by- chromatography. GENERAL PROCEDURES FOR DEPROTECTION IN SOLUTION: PROCEDURE D : removal of BOC with TFA A solution of tBuOC(0)NH-R (where R is alkyl optionally substituted with any number of suitable functional groups) in CH 2 C1- at 0 °C was treated with trifluoroacetic acid. The reaction was allowed to warm to RT and stirred for 1 to 2 h. After concentration i n vacuo the resulting amine/TFA salt was stored and neutralized with TEA or DIPEA prior to use. PROCEDURE E : removal of BOC with HCl A solution of tBuOC(0)NH-R (where R is alkyl optionally substituted with any number of suitable functional groups) in dioxane at 0 °C was treated with 4N HC1 in dioxane. The reaction was allowed to warm to RT and stirred for 1 to 2 h. After concentration in vacuo the resulting amine/HCl salt was stored and neutralized with TEA or DIPEA prior to use. PROCEDURE F: hydrogenation A mixture of starting material and 10% Pd/C in methanol, water, ethyl acetate, and/or DMF was vigorously stirrec under hydrogen (40 to 50 psi) for more than 2 h at RT. The resulting mixture was filtered through a plug of Celite and the filtrate concentrated in vacuo . GENERAL PROCEDURES FOR AMIDE BOND FORMATION ON SOLID SUPPORT: PROCEDURE G: coupling with DCC/HOBt A mixture of resin (see below for preparation of resin MCB1), tBuOC (0)NH-AA,-C0 H (where AA is an ammo acid cr functional equivalent) or R -CO H (10 eq.), HOBt (10 eq. , DCC (10 eq) and N-methylmorpholine (3 eq) in NMP was snaken for over 0.5 h at RT. The resin was then washed w th NMP (2X) and CH,Ci (3X) . PROCEDURE H: displacement from resin with amine A mixture of resin and amine (xs) in DMF was shaken for 6 h at RT. The resin was then washed with methanol (3X) and the combined solutions concentrated in vacuo . GENERAL PROCEDURES FOR DEPROTECTION ON SOLID SUPPORT: PROCEDURE I: removal of BOC with TFA/CH 2 C1 2 A mixture of resin and 50% TFA/CH 2 C1 2 was shaken for over 0.5 h at RT. The resin was then washed with CH 2 C1 2 (2X), isopropanol (IX), and CH 2 C1 2 (3X) . PROCEDURE J: HF with scavengers The protected product was treated with HF at -10 to 0 °C for over 1.5 h in the presence of anisole or thioamsole as scavenger. The HF was removed with a stream of N 2 at 0 °C. Example 1 SYNTHESIS OF COMMON INTERMEDIATES Succinimidyl 3-Isoquinolιnecarboxylate (iOn-OSu) : A solution of 3-ιsoqumolmecarboxylιc acid (1.2 eq.) in DMF at 0 °C was treated with EDC (1.4 eq.) . The mixture was stirred at 0 °C for 1 to 2 h and then N- hyαroxysuccinimide (1.0 eq.) was added. After stirring at RT for more than 3 h, the reaction mixture was poured into 6C . sat. NaHCO, and the product filtered: -H NMR (CDC1., 300 MHz, ppm) 9.35 (s, IH) , 8.67 (s, IH) , 8.09 ( , IH; , 7.96 ( , IH) , 7.82 ( , 2H) , 2.94 (s, 4H) . Succinimidyl 2-Ouιnolιnecarboxylate (On-OSu) : A solution of 2-quιnolιne carboxylic acid (1.2 eq.) in DMF at 0 °C was treated with EDC (1.4 eq.) . The mixture was stirred at 0 °C for 1 to 2 h and then N- hydroxysuccinimide (1.0 eq.) was added. After stirring at RT for more than 3 h, the reaction mixture was poured into 60% sat. NaHC0 3 and the product filtered: l E NMR (CDC1 3 , 300 MHz, ppm) 8.35 (d, IH) , 8.27 (d, IH) , 8.19 (d. IH) , 7 . 87 (d, IH) , 7 . 80 (m, IH) , 7 . 68 (m, IH) , 2 . 91 ( s , 4H) . Methyl 4-Isocγanatophenvlacetate (KCl): A well-stirred cold solution of methyl p- aminophenylacetate (9.8 g, 59.4 mmol) in CH 2 C1 2 (200 L) and TEA (25 mL, 18 g, 178.2 mmol) was treated with C0C1 2 (96 L of 1.9 M solution in toluene) over 1 h. The reaction mixture was stirred at 0 °C for an additional 1 h. The reaction mixture was concentrated and 3:1 ether/pet ether (125mL) was added. The mixture was filtered and the filtrate concentrated to give KCl as a brown liquid. The crude product was purified by distillation (118-120 °C/1.0mm) to afford pure KCl (8.5 g, 75%) as a colorless liquid: : H NMR (CDC1 3 , 300 MHz, ppm) 7.20 (d, J = 8.4 Hz), 7.02 (d, J = 8.4 Hz), 3.69 (s, 3H) , 3.48 (s, 2H) . 4-PhenylureidQphenylacetic acid: 4-Phenylureidophenylacetic acid was prepared using procedure C with 4-amino-phenylacetic acid and phenyl isocyanate: *H NMR (CD.SOCD,, 300 MHz, ppm) 8.72- 8.64 (m, 2H) , 7.44 (d, 2H) , 7.36 (d, 2H), 7.28 (d, 2H) , 7.16 (d, 2H) , 6.96 (t, IH) , 3.52 (s, 2H); m/z 272. 4-o-Tolγlureidophenvlacetic acid: 4-o-Tolylureidophenylacetic acid was prepared using procedure C with 4-amino-phenylacetic acid and o- tolyl isocyanate: H NMR (CD^SOCD,, 300 MHz, ppm) 8.97 (s, IH), 7.88 (s, IH) , 7.83 (d, IH) , 7.38 (d, 2H) , 7.17- 7 . 09 (m, 4H) , 6 . 92 ( t , IH) , 3 . 48 ( s , 2H ) , 2 . 23 ( s , 3H) ; m/z 285. 4- (2-Fluorophenγl)ureidophenylacetic acid: 4- (2-Fluorophenyl)ureidophenylacetic acid was prepared using procedure C with 2-fluoroaniline and KCl: l H NMR (CD 3 SOCD 3 , 300 MHz, ppm) 9.00 (s, 1H),8.51 (d, 2.4 Hz, IH), 8.14 (dd, 8.3 Hz, 1.5 Hz, IH) , 7.37 (d, 8.5 Hz, 2H) , 7.07-7.25 ( , 4H) , 6.99 ( , IH) , 3.48 (s, 2H) . 4- (2-Hvdroχyphenylureιdo)phenylacetιc acid: 4- (2-Hydroxyphenylureιdo)phenylacetic acid was prepared using procedure C with 2-hydroxyanιlme and KCl: Ε NMR (CD J SOCD,, 300 MHZ, ppm) 9.90 (s, 1H),9.25 (s, IH) , 8.12 (S,1H), 8.02 (bd, IH) , 7.37 (d, 2H) , 7.13 (d, 2H) , 6.70-6.97 (in, 3H) , 3.48 (s, 2H) . N-Succmimidyl 4- (2- (3-methylPvndylure do)phenylacetate: Prepared in three steps as follows: Procedure C with 2-ammo-3-methylpyrιdme and KCl to give methyl 4- (2- (3-methylpyrιdyl- ureido)phenylacetate. A solution of methyl 4- (2- (3- methylpyridylureido)phenylacetate (1 eq.) in methanol was treated with 1 N NaOH (2 eq.). The reaction was stirred for 16 h, then acidified carefully with 1 N HC1 to pH 7 then with acetic acid to pH 3. The product was filtered and washed with methanol then ether to give 4- (2- (3-methylpyrιdylureido)phenylacetic acid: : H NMR (CD,SOCD 3 , 300 MHz, ppm) 11.97 (s, IH) , 8.64 (brs, IH) , 8.31 (s, IH), 7.69 (m, IH) , 7.62 (d, 8.4 Hz, 2H) , 7.33 (d, 8 . 4 Hz, 2H) , 7 . 09 (m, IH) , 3 . 62 ( s , 2H) , 2 . 38 ( s , 3H) ; m/z 286 . A solution of 4- (2- (3- methylpyridylureido)phenylacetιc acid (1 eq.), N- hydroxysuccinimide (1.2 eq.) and EDC (1.2 eq.) m DMF was made basic (pH 10) with TEA. After stirring at RT for over 12 h, the reaction was poured into 60% sat. NaHC0 3 and the product filtered: : H NMR (CD,S0CD 3 , 300 MHz, ppm) 12.04 (s, IH) , 8.84 (s, IH) , 8.31 (s, IH) , 7.72 (m, 3H) , 7.42 (m, 2H), 7.10 ( m, IH) , 4.18 (s, 2H) , 2.98 (3, 4H) , 2.38 (s, 3H) ; m/z 383. N-Succmimidyl 4- (2-pyrιdylureιdo) phenylacetate: Prepared in three steps as follows: Procedure C with 2-amιnopyrιdme and KCl to give methyl 4- (2-pyrιdylureιdo)phenylacetate: : H NMR (CDC1 3 , 300 MHz, ppm) 8.20 (s, 2H) , 7.62-7.51 (m, 3H) , 7.33 (d, 2H) , 7.01 (d, 2H) , 6.89-6.85 ( , IH) , 3.70 (s, 3H) , 3.59 (s, 2H) . A solution of methyl 4- (2- pyridylureido)phenylacetate (5.7 g, 20.0 mmol) in methanol :20 mL) was treated with 1 N NaOH (40 mL) . The reaction was stirred for 16 h, then acidified carefully with 1 N HC1 to pH 7 then with acetic acid to pH 3. The product was filtered and washed with methanol then ether to give 4- (2-pyrιdyl) ureidophenylacetic acid (4.7 g, 87%) as a white powder: : H NMR (CD 3 SOCD 3 , 300 MHz, ppm) 10.62 (bs, IH), 9.53 (bs, IH) , 8.39 (d, IH) , 7.82 (t, IH) , 7.63-7.55 (m, IH) , 7.33-7.27 (d, 2H) , 7.14-7.08 (m, IH) , 3.62 (s, 3H) . A solution of 4- (2-pyrιdyl)ureidophenylacetic acid (1 eq.), N-hydroxysuccmimide (1.2 eq.) and EDC (1.2 eq.) in DMF was made basic (pH 10) with TEA. After stirring at RT for over 12 h, the reaction was poured into 60% sat. NaHC0 3 and the product filtered: H NMR (CD 3 SOCD 3 , 300 MHz, ppm) 10.08 (s, IH) , 9.57 (s, IH) , 8.39 (m, IH), 7.86 (m, IH) , 7.62 (m, 3H) , 7.38 (d, 2H) , 7.12 (m, IH) , 4.15 (s, 2H) , 2.91 (s, 4H) ; m/z 369. 3-Methoxy-4-phenylureidophenylacetic acid: Prepared in six steps from 3-methoxy-4-nitrobenzoic acid as follows: A mixture of 3-methoxy-4-nitrobenzoic acid (2.01 g, 10.2 mmol) and thionyl chloride (2.3 mL, 31.5 mmol) was stirred at 80-90 °C for 1.5 h. The reaction was concentrated and the residue diluted with ether. The organic solution was washed with sat. aq. NaHCO, (2 X), H ; 0, then sat. aq. NaCl, dried (MgS0 ) and concentrated tc afford 3-methoxy-4-nitrobenzoyl chloride (1.92 g, 87?) as a white solid: : H NMR (CDC13, 300 MHz, ppm) 7.95-7.70 (rn, 3K) , 4.06 (s, 3H) . A cold (0 °C) solution of TMSCHN 2 (2 M in hexane, 1.5 mL, 3.0 mmol) and triethylamine (420 μL, 3.0 mir.cl) was treated with a solution of 3-methoxy-4- nitrobenzoyl chloride (0.52 g, 2.4 mmol) in acetonitrile (8.5 mL) . The reaction was stirred at 0 °C for 24 h and then concentrated. The residue was slurried with sat. aq. NaHCO, and the mixture extracted with ether (3X) . The combined ether washes were washed with water, then sat. aq. NaCl, dried (MgSO„) and concentrated to afford fo- diazo-3-methoxy-4-nitroacetophenone (0.53 g, 100%) as a yellow foam: 2 H NMR (CDC1 3 , 300 MHz, ppm) 7.88 (d, 10 Hz, IH) , 7 . 61 ( s, IH) , 7 .27 (d, 10 Hz, IH) , 5 . 97 ( s , IH) , 4 . 02 ( s , 3H) . A refluxing solution of fo-diazo-3-methoxy-4- nitroacetophenone (7.95 g, 35.9 mmol) in t-BuOH (100 mL) was treated with a filtered solution of silver benzoate (2.50 g, 10.9 mmol) in triethylamine (15 mL) dropwise over 1 h. After refluxing for 45 min, decolorizing carbon was added and the hot mixture filtered through a pad of Celite. The filtrate was concentrated and the residue diluted with ethyl acetate. The organic solution was washed with 5% aq. NaHC0 3 (2 X), H-O, 5% aq. citric acid, H 2 0, then sat. aq. NaCl, dried (MgSO < ) and concentrated to afford t-butyl 3-methoxy-4- nitrophenylacetate (8.92 g, 93%) as a brown oil: α H NMR (CDC1 3 , 300 MHz, ppm) 7.83 (d, 8.3 Hz, IH) , 7.03 (s, IH) , 6.93 (d, 8.3 Hz, IH) , 3.97 (s, 3H) , 3.58 (s, 2H) , 1.45 (s, 9H) . A mixture of t-butyl 3-methoxy-4- nitrophenylacetate (0.144 g, 0.539 mmol) and 10% Pd on carbon (0.155 g) in ethyl acetate (8 mL) and methanol (2 mL) was stirred under H 2 (40-60 psi) for 2 h. The mixture was filtered through Celite and the filtrate concentrated to afford t-butyl 4-amino-3-methoxyphenylacetate (0.123 g, 96%) as a light yellow oil: > H NMR (CDC1 3; 300 MHz, ppm) 6.70 (m, 3H) , 4.04 (bs, 2H) , 3.84 (s, 3H) , 3.42 (s, 2H) , 1.43 (s, 9H) . Procedure C with t-butyl 4-amino-3- methoxyphenylacetate and phenyl isocyanate gave t-butyl 3-methoxy-4-phenylureidophenylacetate: l H NMR (CDC1 3 , 300 MHz, ppm) 8.00 (d,ll Hz, IH) 7.65-6.94 (m, 7H) , 6.80 (d, 9.0 Hz, IH), 6.74 (s, IH) , 3.68 (s, 3H) , 3.45 (s, 2H) , 1.44 (s, 9H) . A solution of t-butyl 3-methoxy-4- phenylureidophenylacetate (0.108 g, 0.303 mmol) in trifluoroacetic acid (5.0 mL) was stirred for 30 min. The reaction was concentrated and the residue coevaporated with methylene chloride (2X) then ether to afford 3-methoxy-4-phenylureidophenylacetic acid (0.090 g, 99%) as a white foam: '' E NMR (CD,SOCD 3 , 300 MHz, ppm) 9.28 (s,lH), 8.18 (s, IH) , 8.02 (d, 7.5 Hz, IH) , 7.58- 7.15 (m, 5H) , 6.91 (bm, 2H) , 6.77 (d, 7.5 Hz, IH) , 3.85 (s, 3H) , 3.49 (s, 2H) . N-Succinimidvl 3-methoxv-4-phenylureidophenylacetate: A solution of 3-methoxy-4- phenylureidophenylacetic acid (1 eq.) in DMF at 0 C C was treated with EDC (1.1 eq.) . The mixture was stirred at 0 °C for 1 to 2 h and then N-hydroxysuccinimide (1.1 eq.) was added. After stirring at RT for more than 3 h, the reaction mixture was poured into 60?_ sat. NaHC0 3 and the N-succinimidyl 3-methoxy-4-phenylureidophenylacetate filtered. N-Succinimidy 6- (2-methoxy-3-o- tolylureido)pvridylacetate: Prepared in six steps from 2, 6-dichloro-3-nitropyridine as follows: A slurry of 2, 6-dichloro-3-nitropyridine (92%, 9.9 g, 47 mmol) and K 2 C0 3 powder (6.5 g, 47 mmol) in methanol (100 mL) was stirred for a week at RT. The reaction was filtered and concentrated. The residue was partitioned in ethyl acetate and 60% sat. aq. NaHC0 3 . The organic solution was washed with 60% sat. aq. NaHCO, (2X) , H 2 0, then sat. aq. NaCl, dried (MgS0 4 ) and concentrated to afford 2-chloro-6-methoxy-5-nitropyridine and 2-chloro-6- methoxy-3-nitropyridine (8.9 g, 100%) as a light yellow solid: H NMR (CDC1 3 , 300 MHz, ppm) 8.31 (d, 8.3 Hz, IH) , 8.28 (d, 8.9 Hz, IH) , 7.10 (d, 8.3 Hz, IH) , 6.82 (d, 8.9 Hz, IH) , 4.15 (s, 3H) , 4.06 (s, 3H) . A mixture of 2-chloro-6-methoxy-5-nitropyridine and 2-chloro-6-methoxy-3-nitropyridine (8.9 g, 47 mmol), t-butyl methyl alonate (10 mL, 60 mmol), and NaH (95%, 3.1 g, 120 mmol) in THF (250 mL) was stirred at RT for 24 h. The reaction was concentrated and the residue treated with trifluoroacetic acid (200 mL) for 2 h. The reaction was concentrated and the product separated by flash chromatography (silica gel, 95:5 hexane-ethyl acetate) to afford methyl 6- (2-methoxy-3-nitro)pyridylacetate (3.3 g, 62%) as a yellow oil: 2 H NMR (CDC1 3 , 300 MHz, ppm) 8.27 (d, 8.0 Hz, IH), 7.04 (d, 8.0 Hz, IH) , 4.09 (s, 3H) , 3.85 (s, 2H) , 3.75 (s, 3H) . A mixture of methyl 6- (2-methoxy-3- nitro)pyridylacetate (0.047 g, 0.21 mmol) and 10% Pd on carbon (C.063 g) in ethyl acetate (2 mL) and ethanol (1 L) was stirred under H ; (40-50 psi) for 6 h. The mixture was filtered through Celite and the filtrate concentrated to afford methyl 6- (2-methoxy-3-amino)pyridylacetate (0.041 g, 100Ϊ-) as a light yellow oil: ; H NMR (CDClj, 300 MHz, ppm) 6.82 (d, 7.6 Hz, IH) , 6.65 (d, 7.6 Hz, IH) , 3.94 (s, 3H), 3.70 (s, 3H) , 3.65 (s, 2H) . Procedure C with methyl 6- (2-methoxy-3- amino)pyridylacetate and o-tolyl isocyanate to give methyl 6- ,'2-methoxy-3-o-tolylureido)pyridylacetate: : H NMR (CDC1 . ., 300 MHz, ppm) 8.33 (d, 7.9 Hz, IH) , 7.51 (d, 7.8 Hz, IH) , 7.41 (s, IH) , 7.17 (m, 2H) , 7.08 (m, 2H) , 6 . 77 ( d, 7 . 9 Hz , IH) , 3 . 81 ( s , 3H) , 3 . 71 ( s , 3H) , 3 . 67 ( s , 2H) , 2 . 20 ( s , 3H) . A solution of methyl 6- (2-methoxy-3-o- tolylureido)pyridylacetate (0.023 g, 0.070 mmol) in 5 methanol (1.0 mL) was treated with 2 M LiOH (90 μL, 0.18 mmol) . The reaction was stirred for 18 h, diluted with H 2 0 (5.0 mL) and washed with ether (2X) . The aqueous solution was then acidified with 5% aq. citric acid. The product was filtered and washed with H,0 then ether to 10.- give 6- (2-methoxy-3-o-tolylureido)pyridylacetic acid (0.C14 g, 64%) as a white solid: H NMR (CD 3 0D, 300 MHz, ppm! 8.50-8.25 (m, 3H) , 7.60 (bd, IH) , 7.28-7.00 ( , 3H), 4.01 (s, 3H), 3.69 (s, 2H) , 2.30 (s, 3H) ; MS, m/z 316. A solution of 6- (2-methoxy-3-o- 15 tolylureido)pyridylacetic acid (1.61 g, 5.10 mmol) in DMF at C °C was treated with EDC (1.00 g, 5.2 mmol) . The mixture was stirred at 0 °C for 1 to 2 h and then N- hydroxysuccinimide (0.60 g, 5.2 mmol) was added. After stirring at RT for more than 3 h, the reaction mixture 0 was poured into 60% sat. NaHCO, and the N-succinimidyl 6- (2-r.ethoxy-3-o-tolylureido)pyridylacetate filtered. H-Lr QBn)V-NHCH,: H-LD (OBn)V-NHCH, was prepared by sequentially using procedure B with BOC-Val-OSu and methylamine, 5 procedure D, procedure B with BOC-Asp (OBn) -OSu, procedure D, procedure B with BOC-Leu-OSu, then procedure D. H-LD 'OBn)V-OCH ? : H-L (OBn)V-OCH 3 was prepared by sequentially using procedure B with BOC-Asp (OBn) -OSu and H-Val-OMe, procedure D, procedure B with BOC-Leu-OSu, then procedure D. H-LD (OBn)V-OBn: H-LD(OBn)V-OBn was prepared by sequentially using procedure B with BOC-Asp(OBn)-OSu and H-Val-OBn, procedure D, procedure B with BOC-Leu-OSu, then procedure D. H-LPfQBn)vp-QBn: H-LD(OBn)VP-OBn was prepared by sequentially using procedure B with BOC-Val-OSu and H-Pro-OBn, procedure D, procedure B with BOC-Asp(OBn)-OSu, procedure D, procedure B with BOC-Leu-OSu, then procedure D. H-LD(OBn)VP-OMe: H-LD(OBn)VP-OMe was prepareα by sequentially using procedure A with BOC-Val-OH and H-Pro-OMe, procedure D, procedure B with BOC-Asp (OBn) -OSu, procedure D, procedure B with BOC-Leu-OSu, then procedure D. H-LDVP-OH: H-LDVP-OH was prepared by sequentially using procedure B with BOC-Val-OSu and H-Pro-OBn, procedure D, procedure B with BOC-Asp (OBn)-OSu, procedure D, procedure B with BOC-Leu-OSu, procedure F, then procedure D. H-MD(OBn)VP-OBn: H-MD(OBn)VP-OBn was prepared by sequentially using procedure B with BOC-Val-OSu and H-Pro-OBn, procedure D, procedure B with BOC-Asp(OBn)-OSu, procedure D, procedure B with BOC-Met-OSu, then procedure D. H-LD ( OBn ) VP-NH, : H-LD(OBn)VP-NH 2 was prepared by sequentially using procedure B with BOC-Val-OSu and H-Pro—NH 2 , procedure D, procedure B with BOC-Asp (OBn) -OSu, procedure D, procedure B with BOC-Leu-OSu, then procedure D. Resin (MBC1) : Modified resin MBC1 (0.437 mmol/g) was synthesized according to the literature procedure (see: Richter, L.S., et al . , Tetrahedron Lett. 35, p. 5547 (1994)) . MBC1 was treated with 50 TFA/CH Cl . and triethylsilane for 2 h at RT then washed with CH^Cl ^ (2X) , isopropanol (IX), and CH,C1 ; (3X) before use. MBC2: MBC2 was prepared by sequentially using procedure G with BOC-Asp (OBn) -OH, procedure I, procedure G with BOC-Leu-OH, procedure I, tneπ procedure G with 4- phenylureidophenylacetic acid. MBC3: MBC3 was prepared by sequentially using procedure G with BOC-Val-OK, procedure I, procedure G with BOC-Asp (OBn) -OH, procedure I, procedure G with BOC- Leu-OH, procedure I, then procedure G with 4- phenylureidophenylacetic acid. MBC4 : MBC4 was prepared by sequentially using procedure G with BOC-Pro-OH, procedure I, procedure G with BOC-Val-OH, procedure I, procedure G with BOC- Asp (OBn) -OH, procedure I, procedure G with BOC-Leu-OH, procedure I, then procedure G with 4- phenylureidophenylacetic acid. Example 2 Compound 77: Compound 77 was prepared by using procedure A with picolinic acid and H-LD(OBn)V-OBn then procedure F. Purification by HPLC gave the title compound: m/z 451. Example 3 Compound 6 : Compound 64 was prepared by using procedure A with hydrocmnamic acid and H-LD (OBn)V-OBn then procedure F. Purification by HPLC gave the title compound: m/z 478. Example 4 Compound 155: Compound 155 was prepared by using procedure B witn chloro 4-pr.enylbutyrate and H-LD (OBn) V-OBn then procedure F. Purification by HPLC gave the title compound: m/z 492. Example 5 Compound 15 "7 : Compound 1Ξ "7 was prepared oy using procedure B witn BOC- Asp (OBn) -OS and lsobutylamme, procedure D, procedure B with BOC-Leu-OSu, procedure D, procedure B with iQn-OSu, then proceaure F. Purification by HPLC gave the title compound: m/z 457. Example 6 Compound 164: Compound 164 was prepared by using procedure B with Qn- OSu and H-LD(OBn)V-NHCH 3 then procedure F. Purification by HPLC gave the title compound: m/z 514. Example 7 Compound 174: Compound 174 was prepared by using procedure B with BOC- Asp (OBn) -OSu and valmol, procedure D, procedure B witr. BOC-Leu-OSu, procedure D, procedure B with Qn-OSu, then proceaure F. Purification by HPLC gave the title compound: m/z 487. Example 8 Compound 177: Compound 177 was prepared by using procedure B with BOC- Asp 05r.'-OSu and H-Tnr-OCH , proceaure D, proceaure B with BCC-Leu-OSu, procedure D, proceaure B with 4- metncxybenzenesulfonyl chloriae, then procedure F. Purification by HPLC gave the title compound: m/z 532. Example 9 Corpcund 180: Compound 180 was prepared by using proceaure B with BC7- Val-C5u and methylamme, procedure D, procedure B with BOC-Asp (OBn) -OSu, procedure D, procedure B with BOC-N- MeLe--OSu, procedure D, procedure B with phenylacetyl chloride, then procedure F. Purification by HPLC gave the title compound: m/z 491. Example 10 Compound 189: Compound 189 was prepared by using procedure B with BOC- Val-OSu and ethylamine, procedure D, procedure B with BOC-Asp(OBn)-OSu, procedure D, procedure B with BOC-Leu- OSu, procedure D, procedure B with phenylsulfonyl chloride, then procedure F. Purification by HPLC gave the title compound: m/z 499. Example Compound 345: Compound 345 was prepared by using procedure A with 4-o- tolylureidophenylacetic acid and H-LD(OBn)V-OBn then procedure F. Purification by HPLC gave the title compound: m/z 606. Example 12 Compound 206: Compound 206 was prepared by using procedure A with 4-o- tolylureidophenylacetic acid and H-LD(OBn)VP-OBn then procedure F. Purification by HPLC gave the title compound: m/z 709. Example 13 Compound 144: Compoound 144 was prepared by using procedure A with 4- (2-hydroxyphenylureido)phenylacetic acid and H-LD(OBn)VP- OBn then procedure F. Purification by HPLC gave the title compound: m/z 711, 24.6 min (gradient 8). Example 14 Compound 145: Compound 145 was prepared by using procedure A with 4- phenylureidophenylacetic acid and H-LD(OBn)VP-OBn then procedure F. Purification by HPLC gave the title compound: m/z 695, 26.8 mm (gradient 8). Example 15 Compound 146: Compound 146 was prepared by using procedure A with 4- (2- hydroxyphenylureidojphenylacetic acid and H-MD(OBn)VP-OB: then procedure F. Purification by HPLC gave the title compound: m/z 729, 22.4 mm (gradient 8) . Example 16 Compound 1 : Compound 1 was prepared by using procedure A with 3- methoxy-4-phenylureιdophenylacetιc acid and H-LD(OBn/VP- OBn then procedure F. Purification by HPLC gave the title compound: m/z 725, 28.5 mm (gradient 8) . Example 17 Compound 2: Compound 2 was prepared by using procedure A with 3- methoxy-4-phenylureιdophenylacetιc acid ana H-MD(OBn)VP- OBn then procedure F. Purification by HPLC gave the title compound: m/z 743, 27.0 mm (gradient 8). Example 18 Compound 315: Compound 315 was prepared by using procedure A with 4-o- tolylureidophenylacetic acid and H-MD (OBn)VP-OBn then procedure F. Purification by HPLC gave the title compound: m/z 727. Example 19 Compound 346: Compound 346 was prepared by using procedure B with N- Hydroxysuccinimidyl 4- (2- (3-methylpyrιdyl- ureido) phenylacetate and H-LDVP-OH. Purification by HP! gave Compound 346: m/z 710. Example 20 Compound 3 6: Compound 316 was prepared by using procedure B with N- hydroxysuccinyimidyl 4- (2-pyrιdylureιdo) phenylacetate ar H-LDVP-OH. Purification by HPLC gave the title compounc m/z 696. Example 21 Compound 4: Compound -_ was prepared by using proceaure B with N- hydroxysuccinimidyl 6- (2-methoxy-3-o- tolylureiao) pyridylacetate and H-LDVP-OH. Purification by HPLC gave the title compound: m/z 740, 30.7 mm (gradient 6) . Example 22 Compound 147: Compound 147 was prepared by using procedure B with N- hydroxysuccinimidyl 3-methoxy-4-phenylureidophenylacetate and H-LD(OBn)VP-NH z then procedure F. Purification by HPLC gave the title compound: m/z 724, 26.7 mm (gradient 8) . Example 23 Compound 148: Compound 148 was prepared by using procedure A with 4-c- tolyiureiαophenylacetic acid and H-LD(OBn)VP-NH then procedure F. Purification by HPLC gave the title compound: m/z 708, 26.0 mm (gradient 8). Example 24 Compound 317: Compcunα 317 was prepared by using procedure B with N- hyαroxysuccinimidyl 6- (2-methoxy-3-c- tolyiureiαo)pyridylacetate and H-LD(OBn)VP-NH then proceaure F. Purification py HPLC gave the title compounc: m/z 739, 28.0 mm .gradient 8) . Example 25 Compound 336: Compound 336 was prepared by using procedure A with 4- (2- fluorophenyl)ureidophenylacetic acid and H-LD(OBn)VP-OBn then procedure F. Purification by HPLC gave the title compound: m/z 713. Example 2$ Compound 32: Compound 32 was prepared by using procedure B with iQn- OSu and H-LD(OBn)VP-OBn then procedure F. Purification by HPLC gave the title compound: m/z 598, 24.7 in (gradient 8) . Example 27 Compound 34: Compound 34 was prepared by using procedure B with phenylacetyl chloride and H-LD(OBn:VP-OBn then procedure F. Purification by HPLC gave the title compound: m/z 561, 23.7 min (gradient 8) . Example 28 Compound 39: Compound 39 was prepared by using procedure A with 3- (-4- hydroxyphenyDpropionic acid and H-LD(OBn)VP-OMe then procedure F. Purification by HPLC gave Compound 39: m/z 591, 21.5 min (gradient 8). Example 29 Compound 42: Crude compound 42 was prepared by sequentially using procedure A with BOC-Val-OH and H-homoPro-OBn, procedure D, procedure B with BOC-Asp(OBn)-OSu, procedure D, procedure B with BOC-Leu-OSu, procedure D, procedure B with phenyl acetyl chloride then procedure F. Purification by HPLC gave the title compound: m/z 575, 26.4 min (gradient 8). Example 30 Compound 52: Compound 52 was prepared by sequentially using procedure A with BOC-norVal-OH and methylamine, procedure D, procedure B with BOC-Asp(OBn) -OSu, procedure D, procedure B with BOC-Leu-OSu, procedure D, procedure B with Qn-OSu then procedure F. Purification by HPLC gave the title compound: m/z 518, 30.2 mm (gradient 8). Examp e 1 Compound 46: Compound 46 was prepared by sequentially using proceaure A with BOC-Val-OH and methylamme, procedure D, proceaure B with BOC-Asp(OBn) -OSu, procedure D, procedure A with BOC-N-MeLeu-OH, procedure D, procedure A with 3- (4- hydroxyphenyl)propionic acid then procedure F. Purification by HPLC gave the title compound: m/z 521, 18.7 mm (gradient 8). Example 32 Compound 61: Compound 61 was prepared by sequentially using proceaure B with BOC-Thr-OSu and morpholine, procedure D, proceaure B with BOC-Asp (OBn) -OSu, procedure D, procedure B with BOC-Leu-OSu, procedure D, procedure B with Qn-OSu tne procedure F. Purification by HPLC gave the title compound: m/z 572, 24.0 mm (gradient 8). Example 33 Compound 213: Compound 213 was prepared by using procedure H with MBC2 and benzyamine then procedure J: m/z 588. Example 34 Compound 214: Compound 214 was prepared by using procedure H with MBC2 and morpholine then procedure J: m/z 568. Example 35 Compound 215: Compound 215 was prepared by using procedure H with MBC2 and isopropylamine then procedure J: m/z 540. Example 36 Compound 21c: Compound 216 was prepared by using procedure H with MBC2 and cyciohexylamine then procedure J: m/z 580. Example 37 Compound 21 " : Compound 21 " was prepared by using procedure H witn MB 2 and isobutylamine then procedure J: m/z 554. Example 38 Compound 218: Compound 218 was prepared by using procedure H with MBC2 and piperdme then procedure J: m/z 566. Example 39 Compound 318: Compound 318 was prepared by using procedure H with MBC3 and morpholine then procedure J: m/z 667. Example 40 Compound 319: Compound 319 was prepared by using procedure H with MBC3 and isopropylamine then procedure J: m/z 640. Example 41 Compound 320: Compound 320 was prepared by using procedure H with MBC3 and cyclohexylamme then proceaure J: m/z 679. Example 42 Compound 321: Compound 321 was prepared by using procedure H with MBC3 ana oenzylamine then procedure J: m/z 687. Example 43 Compound 322: Compound 322 was prepared by using procedure H with MBC3 ana piper d e then procedure J: m/z 665. Example 44 Compound 323: Compound 323 was ' prepared by using procedure H with MBC3 and isobutylamine then procedure J: m/z 653. Example 45 Compound 324: Compound 324 was prepared by using procedure H with MBC4 and cyclohexylamme then procedure J: m/z 777. Example 46 Compound 325: Compound 325 was prepared by using procedure H with MBC4 and piperdme then procedure J: m/z 763. Example 47 Compound 326: Compound 326 was prepared by using procedure H with MBC4 and benzylamme then procedure J: m/z 785. Example 48 Compound 327: Compound 327 was prepared by using procedure H with MBC4 and lsopropylamme then procedure J: m/z 736. Example 49 Compound 328: Compound 328 was prepared by using procedure H with MBC4 and lsobutylamme then procedure J: m/z 750. Example 50 Compound 363 A. A mixture of o-tolylureidophenylacetic acid (3.53 g, 12.4 mmol), H-Leu-OtBu » HCl (2.78 g, 12.4 mmol), TBTU (3.98 g, 12.4 mmol), and iPr 2 NEt (4.32 mL, 24.8 mmmol) in DMF (25 mL) was stirred overnight at RT. The product was precipitated by addition of H 2 0 (10 mL) . The solids were collected by filtration on a medium frit, washing with 2:1 DMF/H 2 0 (35 mL) , H 2 0 (25 mL) , and Et 2 0 (2 x 25 mL) , and dried on the filter (4.18 g, 74%). All of this product was suspended in CH 2 C1 2 (16 mL) and treated with TFA (16 mL) and stirred at RT 2 hr. The reaction was concentrated to a syrup which was evaporated from CH 2 Cl t (2 x 20 mL) . The residue was triturated with Et 2 0 (lOOmL) at RT for 2 hr. The solids were collected by filtration _ on a medium frit, washing with Et ? 0 (50 mL) , and dried on the filter (3.40 g, 93%): MS (FAB) 398. B. A mixture of DCC (0.206 g, 1.0 mmol) and HOBT (0.135 g, 1.0 mmol) in EtOAc (6 mL) was stirred at RT 20 min until homogeneous. Fmoc-Asp-OtBu (0.411 g, 1.0 mmol), piperonylamine (0.12 mL, 1.0 mmol), and N- methylmorpholine (0.22 mL, 2.0 mmol) were added. After stirring overnight, the reaction was filtered to remove solids and the cake washed with fresh EtOAc (10 mL) . The filtrate was washed with H 2 0 (2x) , 5% citric acid (lx), 5- NaHC0 3 (lx), and brine (lx), and dried (MgSO . Flash column chromatography on Si0 2 eluting with 1001 CHC1-. to 2% MeOH/CHCl 3 provided 0.54 g (100%) of pure product as a solid: mp = 128-130°C; TLC (2% MeOH/CHCl 3 ) R,=0.10; MS (FAB) 545; ] H NMR (CDC1 3 , 300 MHz, ppm) 7.75-7.72 (m, 2H. , 7.59-7.56 (m, 2H) , 7.40-7.34 ( m, 2H) , 7.30-7.25 (m, 2H) , 6.71-6.66 ( m, 3H) , 6.13-6.10 (m, 2H) , 5.84 (s, 2H) , 4.46 (m, IH) , 4.38-4.16 (m, 5H) , 2.86 (dd, IH, J=4.7, 15.6 Hz), 2.72 (dd, IH, J=4.16, 15.6 Hz), 1.45 (s, 9H) . C. The product from Example 50B (0.25 g, 0.46 mmol), piperidine (0.45 L, 4.6 mmol), and CH 2 C1 2 (0.45 mL) were stirred at RT for 90 min. The reaction was evaporated to a solid residue. Flash column chromatography on Si0 2 using a MeOH/EtOAc gradient provided product (0.138 g, 93%) as a colorless oil: MS (FAB) 323; TLC(10% MeOH/EtOAc) R f =0.15; α H NMR (CDC1 3 , 300 MHz, ppm) 7.63 (br s, IH) , 6.75-6.68 (m, 3H) , 5.90 (s, 2H) , 4.34 (dd, IH, J=5.7, 14.7 Hz), 4.28 (dd, IH, J=5.7, 14.7 Hz), 3.65 (dd, IH, J=3.4, 9.3 Hz), 2.62 (dd, IH, J=3.4, 15.7 Hz), 2.38 (dd, IH, J=9.3, 15.7 Hz), 1.74 (s, 2H) , 1.42 (s, 9H) . D. The product from Example 50C (2.55 g, 7.91 mmol) and Eschenmoser' s salt (1.61 g, 8.70 mmol) were refluxed in MeCN (80 mL) under an inert atmosphere for 42 hr. The reaction was cooled to RT and evaporated to dryness. The residue was diluted with 5% NaHC0 3 and extracted with EtOAc (3x) . The combined organic extracts were washed with 5% NaHC0 3 (lx) , H 2 0 (lx), and brine (lx), and dried (MgSO < ) . The crude product was dissolved in Et 2 0 (250 mL) and passed through a short pad of Si0 , eluting with Et,0 followed by EtOAc. The slightly impure product thus obtained was further purified by trituration with ice cold Et 2 0 (30 mL) and collected by filtration to give a white solid (0.904 g, 34%): mp=121-123°C; TLC (10% MeOH/CHCl 3 ) R f =0.59; H NMR (CDC1 3 , 300 MHz, ppm) 6.75-6.66 (m, 3H), 5.92 (s, 2H) , 4.66 (A of AB, IH, J=14.7 Hz), 4.23 (B of AB, IH, J=14.7 Hz), 4.15 (ABq, 2H, J=11.9 Hz), 3.68 (dd, dd, IH, J=5.2, 10.9 Hz), 2.72 (dd, IH, J=5.2, 17.3 Hz), 2.41 (dd, IH, J=10.9, 17.3 Hz), 1.45 (s, 9H) ; C,H,N for C : -H 22 N 2 0 5 , theory— C:61.07, H:6.63, N:8.38, found— C:60.80, H:6.59, N:8.22. E. The product from Example 50D (0.50 g, 1.5 mmol), the product from Example 50A (0.596 g, 1.5 mmol), and EDC (0.314 g, 1.64 mmol) were stirred in NMP (3 mL) at RT for 48 hr. The reaction was poured into EtOAc (60 mL) , washed with H 2 0 (8 x 6 mL) , brine (lx), and dried (MgS0 4 ) . Flash column chromatography on Si0 2 eluting with 100% CHCl, to 30% EtOAc/CHCl 3 provided product (0.94 g, 88%) as a pale yellow oil: MS (FAB) 714; TLC (10% MeOH/CHCl 3 ) R f =0.40; : H NMR (CDC1 3 , 300 MHz, ppm) consistent wi th structure and indicative of diastereomers. F. The product from Example 50E (0.94 g, 1.32 mmol) was stirred in TFA (10 L) at RT for 3 hr. The reaction was concentrated to dryness and the residue evaporated from CH 2 C1 ; (3 x 10 mL) . The crude product was triturated with Et 2 0 at RT, collected by filtration and dried on the filter (0.733g, 84%): MS (FAB) 658 (M+H), 680 (M+Na); TLC (5% HOAc/EtOAc) R f =0.15; l NMR (d 6 -DMSO, 300 MHz, ppm) consistent wi th structure and indicative of diastereomers. Example 51 Compound 364: A. In the same manner as described in Example 50B, Fmoc- Asp-OtBu (8.23 g, 20.0 mmol) was reacted with H-Gly- OBn»HCl (4.03 g, 20.0 mmol). Flash column chromatography on SiC : , using an EtOAc/hexane gradient provided product (9.8 g, 88%) as a waxy solid: MS (FAB) 559; TLC (10% MeOH/CHClj) R f =0.71; > H NMR (CDC1 3 , 300 MHz, ppm) 7.73 (d, 2H, J=7.5 Hz), 7.59 (d, 2H, J=7.4 Hz), 7.40-7.26 (m, 9H) , 6.44 (br s, IH) , 6.09 (d, IH, J=8.3 Hz), 5.13 (s, 2H) , 4.52-4.49 ( , IH) , 4.41-4.29 ( , 2H) , 4.21 (t, IH, J=7.1 Hz), 4.04 (d, 2H, J=5.2 Hz), 2.95 (dd, IH, J=4.6, 15.7 Hz), 2.79 (dd, IH, J=4.3, 15.7 Hz), 1.46 (s, 9H) . B. The product of Example 51A (9.8 g, 17.54 mmol) was deprotected in the manner described in Example 50C. Filtration through a pad of SiO : with 100% EtOAc followed by 5% MeOH/CHCl 3 provided product (4.24 g, 72%) as an oil: MS (FAB) 337; TLC (3% MeOH/EtOAc) R=0.15; : H NMR (CDC1 3 , ' 300 MHz, ppm) 8.00 (t, IH, J=5.4 Hz.-, 7.30-7.21 (m, 5H) , 5.07 (s, 2H) , 3.98 (AB of ABX, 2H, J=5.4, 18.1 Hz), 3.60 (dd, IH, J=3.4, 9.2 Hz), 2.60 (dd, IH, J=3.4, 5.4 Hz), 2.38 (dd, IH, J=9.2, 15.4 Hz), 1.79 (br s, 2H) , 1.36 (s, 9H) . C. The product of Example 51B (4.24 g, 12.60 mmol) was cyclized in the manner described in Example 50D. Flash column chromatography using an EtOAc/CHCl, gradient provided product as a syrup (1.4 g, 32 ) : MS (FAB) 349; TLC (1:1 EtOAc/CHCl 3 ) R f =0.53; H NMR (CDC1„ 300 MHz, ppm) 7.35-7.25 (m, 5H) , 5.11 (s, 2H) , 4.21 (A of AB, IH, J=17.5 Hz), 3.95 (B of AB, IH, J=17.5 Hz), 3.71 (dd, IH, J=5.1, 11.2 Hz), 2.68 (dd, IH, J=5.1, 17.2 Hz), 2.36 (dd, IH, J=11.2, 17.2 Hz), 1.43 (s, 9H) . D. The product of Example 51C (1.40 g, 4.02 mmol) was coupled with the product of Example 50A using the procedure of Example 50E. Flash column chromatography using a CHCl 3 /EtOAc gradient provided product as a brittle, pale yellow foam (2.21 g, 76%): MS (FAB) 728; TLC (1:1 CHCl 3 /EtOAc) R f =0.28; ] H NMR (CDC1 3 , 300 MHz, ppm) consistent with structure and indicative of diastereomers . E. The product of Example 51D (0.15 g, 0.21 mmol) was deprotected and purified as described in Example 50F. The product was obtained as an off-white solid (0.127 g, 90%): MS (FAB) 672 (M+H), 695 (M+Na); TLC (9:1:0.1 CHCl 3 /MeOH/AcOH) Rf=0.54; *H NMR (d'-DMSO, 300 MHz, ppm) consistent wi th structure and indica ti ve of diastereomers . Exampl 52 Compound 365 A. The product from Example 51E (0.100 g, 0.15 mmol;, 4- methoxybenzyla ine (20 μL, 0.15 mmol), and TBTU (0.0482 g, 0.15 mmol) NMP (0.3 L) were treated with iPr NEt (78 μL, 0.45 mmol). After stirring overnight at RT, the reaction was diluted with EtOAc (10 mL' , washed with HC (5 x 2 mL) , 5'- citric acid (2 x 2 mL) , 5 NaHCO. (2 x 2 L) and brine (1 x 2 mL) and dried (MgSO ; ) . Filtration through a short pad of SiO , eluting with 2. MeOH/CHCi followed by 4 MeOH/CHCl., provided product as a foar. (0.087 g, 73'.): MS (FAB) 792; TLC (9:1 CHCl./MeOH) R r =0.41; -H NMR (CDC1., 300 MHz, ppm, consi stent wi tr. structure and indicative of diastereomers . B. A suspension of the product of Example 52A (0.087 g, 0.11 mmol) and Degussa type ElOl NE/W 10% Pd/C (0.017 g) in MeOH (10 mL) was hydrogenated under 25 psi H 2 for 18 hr. The reaction was filtered through Celite, rinsing with MeOH. The filtrate was evaporated to dryness. The residue was triturated with Et 2 0 and the resultant beige solids collected by filtration (36.1 mg, 47%) : MS (F7AB) 701 (M+H), 723 (M+Na); α H NMR (d 6 -DMS0, 300 MHz, ppm) consistent wi th structure and indicative of diastereomers . Example 53 Inhibition of VLA4-Dependent Adhesion to BSA-CS1 This assay was used to assess the potency of VLA4-dιrected inhibitory compounds cf this invention. 1. Conjugation of CS1 to BSA We dissolved BSA-SMCC (Pierce Chemical, Rockford, IL; Catalog # 77115) in H 2 0 at a concentration of 10 mg/mL. [SEQ ID N0:4] : Cys-Tyr-Asp-Glu-Leu-Pro-Gln- Leu-Val-Thr-Leu-Pro-His-Pro-Asn-Leu-His-Gly-Pro-Glu-Ile- Leu-Asp-Val-?ro-Ser-Thr ("Cys-Tyr-CSl peptide"), which we synthesized cy conventional solid phase chemistry and purified by HPLC, was dissolved in 1O M HEPES pH 5, 50 mM NaCl and 0. mM EDTA also at a concentration of 10 mg/mL. We then mixeα 500 L of BSA-SMCC, 250 uL of Cys-Tyr-CSl peptide and " 5 μL of 1 mM HEPES pH ~ > .5 and allowed the conjugation, reaction to proceed for 30 minutes. We stopped the reaction by adding 1 μL cf beta- mercaptoethanol . Samples were analyzed for cross-linking by SDS-PAGE. This reaction produced multiple molecules of the Cys-Tyr-CSl peptide conjugate to each BSA molecule. 2. Preparation of Plates for Adhesion Assay We coated the wells of a Linbro titertek polystyrene 96-well flat bottom plate (Flow Laboratories, Maclean, VA; catalog #76-231-05) with 100 μL of the above-described BSA-CS1 solution diluted to 1 μg/mL in 0.05 M NaHC0 3 (15mM NaHC0 3 , 35mM Na 2 C0 3 ) pH 9.2. Some wells were not coated with CS1 in order to assess non¬ specific cell binding (NSB) . The plate was then incubated overnight at 4°C. Following this incubation, the contents of the wells were removed by inverting and blotting the plate. All of the wells were then blocked with 100 μL of 1% BSA in PBS, 0.02% NaN 3 , for a minimum of one hour at room temperature. 3. Preparation of Fluorescently Labelled Ramos Cells Ramos cells are grown, maintained and labelled in RPMI 1640 culture medium containing 1% BSA. Just prior to running the assay, we added 2 ' , 7 ' -bis- (2- carboxyethyl) -5 (and -6) carboxyfluorescein acetoxvmethyl ester ("BCECF-AM"; Molecular Probes Inc., Eugene, Oregon; catalog #3-1150) to a final concentration of 2uM to a culture cf Ramos cells (4 x 10 cells/mL) . We incubated the cells for 20 minutes at 37°c Following labelling, the cells were washed twice assay buffer (24 mM TRIS, 137 mM NaCl, 2.7 mM KCl, pH 7.4, containing 0.1% BSA and 2mM glucose) to remove any cations originating from the culture medium. The cells were then resuspended assay buffer to 4 x 10 cells/mL and 2mM MnCl 2 was added to upregulate VLA4 on the surface of the cells. 4. Running the Assay Immediately prior to running the assay, we removed the BSA blocking solution from the 96-well plates and washed the wells with 100 μL of assay buffer. We then added to each well 25 μL of test cell adhesion inhibitory compound at 2x the final concentration and 25 μL of the labelled Ramos cells. Final concentrations were selected across a range of anticipated IC50s, usually between 0.01 nM - 10 μM. Each concentration of compound was tested in triplicate. The compound and cells are allowed to incubate for 30 minutes at room temperature. We then emptied the contents of the plate and washed the wells 4 times with assay buffer. Using a light microscope, we examined the NSB wells. If more than a few cells are bound to those wells, we washed the plate once more to remove the excess non-specifically bound cells. Binding of the Ramos cells to the CS1 peptide- coated wells was measured by adding 100 μL of assay buffer to each well and quantitating fluorescence in a Millipore Cytofluor 2300 System plate reader set at 485 nm excitation and 530 nm emission. Binding was expressed as an IC50 — the concentration of inhibitor at which 50% of control binding occurs. Percent binding is calculated by the formula: [(F TB - F NS ) - (Fj - F NS )]/[(F TE - F..) x 100 = % binding, where F TB is total fluorescence bound to CSl-contaming wells without added inhibitor; F is fluorescence bound in wells lacking CS1; and F, is fluorescence bound in wells containing an inhibitor of this invention. Other compounds according to this invention were similarly assayed. The IC50 range for each of these compounds is indicated in the table below: T compounds tested in this table demonstrated an IC, < 1 mM Example : Direct Binding Of VLA4-Presentmg e..s To VCAM-IgG We next examined tne aci it;, cf tne compouncs of this invention to inhibit VCA /VLA4 omding, utiiizir.: a VCAM-IgG-alkaline phosphatase ccrr._gate. To carry cut this assay, we used the Millipore Multiscreen Assay System (Millipore Corp., Bedforα, MA) to wash the cells efficiently. 1. Preparation of VCAM-IσG-AP coniuσates The construction of VCAM 2D-IgG expression vectors, transfection of CHO cells with those constructs and purification of the resulting expression product is described in PCT publication WO 90/13300, the disclosure of which is herein incorporated by reference. 1.2 ml of purified VCAM 2D-IgG (5 mg/ l in 10 mM HEPES, pH 7.5) was reacted with 44 μl of Traut's reagent (2-iminothiolane, 20 mg/ml in water; Pierce Chemical, Rockford, IL.) at room temperature for 30 minutes. The sameple was desalted on a 15 ml Sephadex G- 25 column equilibrated with 100 mM NaCl, 10 mM MES, pH 5.0. One ml fractions were collected and absorbance at 280 nm was determined. The two peak fractions were pooled. One ml of calf intestinal alkaline phosphatase (19 mg/ml; Pierce Chemical, Rockford, IL) was reacted with 100 μl of sulfo-SMCC (30 mg/ml m water) and 100 μl 1 M HEPES, pH 7.5 for 35 minutes at room temperature. The reaction mix was desalted on a 12 ml Sephadex G-25 column equilibrated with 150 mM NaCl, 10 mM HEPES, pH 6.0. One ml fractions were collected and absorbance at 280 nm was determined. The two peak fractions were pooled and stored on ice. The alkaline phosphatase-SMCC and VCAM 2D-IgG- lmmothilane adducts were cross-linked at a molar ratio of 2:1m Tris-HCL, pH 7.5 by incubation at room temperature for 30 minutes. Extent of cross-linking was determined by SDS-PAGE. The cross-linked products were stabilized by the addition of 2 mM MgCl and 0.25 mM ZnCl_ and stored at 4°C. 2. Bindmσ Assay We first blocked a 96-well filtration plate for by adding 275 μL of PBS containing 0.1% Tween 20 and 2% BSA ("blocking buffer") to each well and incubating for 1 hour at room temperature. The plate was then placed onto a vacuum manifold and the blocking buffer was drained through the bottom of the filtration wells into a waste collection tray. Then we washed the wells three times with 200-250 μL of Tris-buffered saline, containing 0.1% BSA, 2 mM glucose and 1 mM HEPES, pH 7.5 ("assay buffer") to wash out any remaining blocking buffer. We then drained the plates and blotted them on paper towels to remove buffer on the underside of the plate. We then prepared a stock solution of VCAM-IgG- AP (4 μg/mL m assay bμffer) and filtered it throμgh a 0.2 μ low protein binding syringe filter (Gelman Sciences, Ann Arbor, MI # 4454) . This solution was then diluted 1:10 in assay buffer and 25 μL was added to every well of the washed plate. We diluted the cell adhesion inhibitor being tested to 2x final concentration in assay buffer and added 25 μL of each dilution to triplicate wells in the plate. Final concentrations used ranged from 0.01 nM - 10 μM. Control wells for total binding and non-specific binding received 25 μL of assay buffer, instead of inhibitor. Total binding wells contained cells and VCAM- IgG-AP m assay buffer. Non-specific binding wells contained only VCAM-IgG-AP m assay buffer. Jurkat cells were washed once in assay buffer to remove growth medium and resuspended at 8 x 10 /mL m assay buffer containing 2 mM MnCl 2 . We added 50 μl of Jurkat cells to every well, except the non-specific binding wells, which received 50 μL of assay buffer to maintain a final assay volume of 100 μL per well. We gently mixed the contents of the wells by tapping the sides of the plate. The plate was then allowed to incubate undisturbed for 60 minutes at room temperature. At the end of the 60 minute incubation, we placed the plate on the vacuum manifold to drain the wells. We carefully added 100 μL of assay buffer containing ImM MnCl 2 (wash buffer) to each well so as not to disturb the cells on the bottom. The wash buffer was removed by vacuum and the plate was washed again with 150 μL of wash buffer. After draining the wash buffer again, the underside of the plate was blotted on paper towels. Next, we prepared a 10 mg/mL solution of 4- nitrophenylphosphate in 0.1 M glycine, 1 mM ZnCl 2 , pH 10.5 (substrate buffer) and added 100 μL immediately added to each well. The plate was incubated for 30 minutes at room temperature to allow the colorimetric reaction to proceed. We stopped the reaction by adding 100 μl of 3 N NaOH to each well. The contents of the 96-well filtration plate was then transferred directly into a 96-well flat bottom plate using the vacuum manifold. The plate was read at a wavelength of 405 nm to determine the amount of VCAM conjugate bound to the cells. Percent binding is calculated by the formula: [ (A τ: . - A NS ) - (Aj - A NS ) ]/[ (A T5 - A=) x 100 = % binding, where A TB is the absorbance at 405 nm of CSl-containing wells without added inhibitor; A., is the absorbance at 405 nr. in wells lacking CS1; and A x is absorbance at 405 n in wells containing an inhibitor of this invention We assayed other compounds of this invention in the same assay. The IC50 values are comparable to those derived from the CS1 binding assay described in the previous example, although certain compounds demonstrated up to 10-fold greater binding in this assay than in the previous assay. Example 55 Inhibition Of Mouse Contact Hypersensitivity We anesthetized 20-g female Balb/c mice (Jackson Laboratories, Bar Harbor, ME) with sodium 2 pentobarbital (90 mg/kg, ι.p.). A 3 cm patch of abdominal skm was then exposed by closely shaving the fur. The skin was then scrubbed with 70 c ~ ethanol, followed by application of 25 μL of 0.5 " DNFB in 4 :1 v/v acetone:olive oil onto the bare abdominal skm. We then lightly scratched the skm with the applying pipet tip to encoμrage mild inflammation. Twenty four hours after the initial sensitization we again sensitized the mouse with 25 ]iL of 0.5% DNFB at same abdominal skm location, again followed by light scratching with the pipet tip. The second sensitization was performed while restraining the unanesthetized mouse. On Day 5 (120 hours after the initial sensitization), we anesthetized the mice with 90:10 mg/kg ketamine:xylazme, l.p. and applied a sub-irritant dose of 10 L of 0.2% DNFB to the dorsal surface of the left ear. The right ear received a similar application of the 4:1 v/v acetone:olive oil vehicle. Four hours after challenging the immune response, we administered various concentrations of the inhibitors of this invention to the mice in 100 μL 0.5% sodium phosphate buffer, pH 8.8, and 3% v/v DMSO by subcutaneous (s.c.) injection. Less soluble inhibitors occasionally required up to 30% DMSO addition the highest concentrations tested. Groups of 8 mice were used for each treatment tested. Positive (PS2 anti-mouse VLA-4 antibody, 8 mg/kg, i.v.), and negative control (phosphate-buffered physiological saline, PBS, 100 μL i.v.; DMSO in PBS, 100 μL s.c.) groups were routinely tested for comparison as part of the assay of test compounds. Twenty four hours after challenge mice were again anesthetized with ketamme:xylazme and the ear thickness of both ears measured with an engineer's micrometer to an accuracy of 10 -4 inches. The ear swelling response for each mouse was the difference between its control- and DNF3-cnallenged ear thickness. Typical unmhibiteα ear swelling responses were 65- ~ 5 x 10 -4 in. Inhibition of the ear swelling response was judged by comparison of treated groups with their negative control group. Percent inhibition was calculated as: r I ! (mean negative control group - (mear. test group ear | ! ear swelling} swel. r.c x 00 | I mean negative control group ear swelling | Statistical significance of tne difference among treatment groups was evaluated using one-way analysis c: variance followed ry computation cf the Tu ey-Kramer Honestly Significant Difference (JMP, SAS Institute using p<0.05. The inhibitors of this invention cause a statistically significant reduction in the ear swelling response of DNFB-treated mice as compared to uninhibited control animals. Example 56 Inhibition Of Ascaris Antigen-Induced Late Phase Airway Sensitivity In Allergic Sheep Sheep which had previously been shown to develop both early and late bronchial responses to Ascari s suum antigen were used in this study. The protocol used for the experiment was that described in W. M. Abraham et al., J. Clin. Invest. , 93, pp. 776-87 (1994), except that the VLA-4 inhibitors of this invention were administered to the animals was dissolved in 3-4 ml cf 50% aqueous ethanol and delivered by aerosol spray. The results showed that all cf the VLA-4 inhibitors of this invention inhibited the airway responses associated with administration of Ascari s suurr. antigen. While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide ether compounds and methods which utilize the compounds cf th s invention. Therefore, it will be appreciated that the scope of th s invention is to be defined by the claims appended hereto rather than the specific embodiments which nave oeen presented hereinbefore oy way of example. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: (A: NAME: Biogen, Inc. (except US) B: STREET: 14 Cambridge Center c* CITY: Cambridge STATE: Massachusetts E COUNTRY: United States of America POSTAL CODE (ZIP) : 02142 G TELEPHONE: 617-679-2200 TELEFAX: 617-679-2838 NAME: Ko-Chung Lin (US only STREET: 253 Lincoln Street CITY: Lexington STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP) : 02173 NAKΞ: Steven P. Adams (US only) STREET: 12 Berkley Lane CITY: Andover STATE: Massachusetts COUNTRY: United States cf America POSTAL CODE (ZIP) : C1810 NAME: Alfreαc C. Castrc S only STREET: 21 Gienwood Avenue CITY: oDur STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP) : 01801 NAME: Craig N. Zimmerman 'US only STREET: 134 Highland Aveπ-e fct CITY: Somerville STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP) : 02143 NAKΞ: Julio Hernan Cuervo (US only) STREET: 16 Elmer Street #303 CITY: Cambridge STATE: Massachusetts COUNTRY: United States of America POSTAL CODE (ZIP) : 02138 NAME: Wen-Cherng Lee (US only) STREET: 192 Spring Street CITY: Lexington STATE: Massachusetts COUNTRY: United States of America (F) POSTAL CODE (ZIP) : 02173 (A NAME: Charles E. Hammond (US only) (B STREET: 4 Chester Avenue (C CITY: Burlington (D STATE: Massachusetts (E COUNTRY: United States of America (F POSTAL CODE (ZIP) : 01803 (A NAME: Mary Beth Carter (US only) (B STREET: 106 Sycamore Street (C CITY: Bel ont (D STATE: Massachusetts (E COUNTRY: United States of America (F POSTAL CODE (ZIP) : 02178 (A NAME: Ronald G. Almqu st (B STREET: 50 Solomon Pierce oa: (C CITY: Lexington (D STATE: Massachusetts (E COUNTRY: United States cf America (F POSTAL CODE (ZIP) : C2173 (A NAME: Carol Lee Ensmger (US only (B STREET: 732 Princeton Blvd. Apt #20 (C CITY: Lowell (D STATE: Massachusetts (E COUNTRY: United States cf America POSTAL CODE (ZIP) : 01851 : ι) TITLE OF INVENTION: CELL ADHESI: :K:Ξ:TORS .11) NUMBER OF SEQUENCES: 4 (ιv) COMPUTER READABLE FORK: ', ?. ■ MEDIUM TYPE: Floppy dιs (3, COMPUTER: IBM PC compat Dle ,C) OPERATING SYSTEM: PC-DOS/KS-DC, (0) SOFTWARE: Patentln Release #1. Version #1.33 (EPO (v ) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: US 03/498, (B) FILING DATE: ll-JUL-1995 INFORMATION FOR SEQ ID NO: 1: (1) SEQUENCE CHARACTERISTICS: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1: Glu lie Leu Asp Val Pro Ser Thr 1 5 (2) INFORMATION FOR SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ill) HYPOTHETICAL: NC (lv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: Glu lie Leu Asp Val 1 5 (2) INFORMATION FOR SEQ ID NO: 3: (l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5 ammo acids (B) TYPE: ammc acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ml HYPOTHETICAL: NC (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Leu Asp Val Pro Ser 1 5 ( 2 i INFORMATION FOR SEQ ID NO: 4: (l) SEQUENCE CHARACTERISTICS: (A) LENGTH: 27 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO: : Cys Tyr Asp Glu Leu Pro Gin Leu Val Thr Leu Pro His Pro Asn Leu 1 5 10 15 His Gly Pro Glu lie Leu Asp Val Pro Ser Thr 20 25

Claims: CLAIMS We claim: 1. A cell adhesion inhibitory compound of formula (I) , Z-(Y 1 )-(Y 2 )-(Y 3 ) n -X (I) and pharmaceutically acceptable derivatives thereof; wherein: Z is selected from the group consisting of alkyl; aliphatic acyl optionally substituted with N- alky - or N-arylamido; aroyl; heterocycloyl; alkyl- or arylsulfonyl; aralkylcarbonyl optionally substituted with aryl; heterocycloalkylcarbonyi; a oxycarbonyl; aralkylcxycarbonyl; cycloalkylcarconyl optionally fused with aryl; heterocycloalkoxycarbc yl; alkylammocarbonyl; arylar.mc carbonyl and aralkyla r.ocarbonyl optionally substituted with bis (alkylsulfony , ammo, alkcxycaroonylammo or alkenyl; alκylsuifonyl; aral.-:ylsulfonyl; arylsulfonyl; cycloalkylsulfonyi opt cr.ally fused with aryl; heterccyclylsulfonyl; heterccyciylalkylsulfonyl; aralkoxyc rbonyl; arylcxycarbonyl; cycloalkyloxycarccnyl; heterccyclyloxycarbonyl; heterocyclylalkoxycaroonyl; mono- or di-alkylaminocarbonyl optionally substituted with aryl; (alkyl) (aralkyl) aminocarbonyl; mono- or di- aralkylammocarbonyl; mono- or di-aryiaminocarbonyl; (aryl (alkyl)aminocarbonyl; mono- or di- cycloalkylaminocarbonyl; heterocyciylaminocarbonyl; heterocyclylalkylaminocarbonyl; (alkyl) (heterocyclyl) aminocarbonyl; (alkyl) (heterocyclylalkyl)aminocarbonyl; (aralkyl) (heterocyclyl)aminocarbonyl; (aralkyl) (heterocyclylalkyl)aminocarbonyl; alkenoyl optionally substituted with aryl; alkenylsulfonyl optionally substituted with aryl; alkynoyl optionally substituted with aryl; alkynylsulfonyl optionally substituted with aryl; cycloalkenylcarbonyl; cycloalkenylsulfonyl; cycloalkylalkanoyl; cycloalkylalkylsulfonyl; arylaroyi, biarylsulfonyl; alkoxysulfonyl; aralkoxysulfonyl; alkylaminosulfonyl; aryloxysulfonyl; arylaminosulfonyi; N-arylurea- substituted alkanoyl; N-arylurea-substituted alkylsulfonyl; cycloalkenyl-substituted carbonyl; cycloalkenyl-substituted sulfonyl; alkenoxycarbonyl optionally substituted with aryl; alkenoxysulfonyl optionally substituted with aryl; alkynoxycarbonyl optionally substituted with aryl; alkynoxysulfonyl optionally substituted with aryl; alkenyl- or alkynyl- aminocarbonyl optionally substituted with aryl; alkenyl- or alkynyl-aminosulfonyl optionally substituted with aryl; acylamino-substituted alkanoyl; acylamino- substituted alkylsulfonyl; aminocarbonyl-substituted alkanoyl; carbamoyl-substituted alkanoyl; carba oyl- substituted alkylsulfonyl; heterocyclylalkanoyl; heterocyclylaminosulfonyl; carboxyalkyl-substituted aralkoyl; carboxyalkyl-substituted aralkylsulfonyl; oxocarbocyclyl-fused aroyl; oxocarbocyclyl-fused arylsulfonyl; heterocyclylalkanoyl; N',N'-alkyl, arylhydrazinocarbonyl; aryloxy-substituted alkanoyl and heterocyclylalkylsulfonyl. Y 1 is -N(R α )-C(R 2 ) (A : )-C(0)-; Y ; is -N(R -C(R ) (A : )-C(0)-; each Y 3 is represented by the formula -N(R : )- C(R 2 ) (A 3 )-C(0)-; each R : is independently selected from the group consisting of hydrogen, alkyl, and aralkyl; alkenyl; alkynyl; cycloalkyl; cycloalkenyl; cycloalkylalkyl; aryl; ammoalkyl; mono- or di-alkyl-substituted ammoalkyl; mono- or di-aralkyl-substituted ammoalkyl; hydroxyalkyl; alkoxyalkyl; mercaptoalkyl; thioalkoxyalkyl A : is selected from the group consisting of ammo acid side chains and corresponding protected derivatives; cycloalkyl; and alkyl optionally substituted with ammo, acylamino, ammo-substituted acylamino, alkoxycarbonylammo, aryl, cycloalkyl, carboxy, aiκoxy, aralkyloxy, alkoxycarbonyl, aralkoxycarbonyl, aminocarbonyl, alkylammocarbonyl, dialkylaminocarbonyl, (alkyl) (aralkyl) aminocarbonyl, araikyiammocaroonyl, diaralkylammocarboπyl, r.yαroxyl, carooxyaikylammocarbonyl, r.yαroxyiammccaroonyi, mercapto, thioalkoxy or heterocycle; A is selected from the group consisting cf acidic functional groups a a alkyl optionally substitutes with an acidic functional group, prctecteα aciα c functional group or aryl; each A ' is independently selected from the grcu consisting of amino acid side chains and corresponding protected derivatives; aryl; cycloalkyl; and alkyl optionally substituted witn ammo, acylamino, amino- suostituted acylamino, aryl, cycloalkyl, carboxy, alkoxy, aralkyloxy, alkoxycarbonyl, aral oxycarbonyi, aminocarbonyl, alkylammocarbonyl, dialkylaminocarbonyl, (alkyl) (aralkyl) aminocarbonyl, aralkylaminocarbonyl, diaralkylaminocarbonyl, hydroxyl, carboxyalkylaminocarbonyl, hydroxylaminocarbonyl, mercapto, thioalkoxy or heterocycle; or R : and any A are taken together with the atoms to which they are attached form a 3- to 6-membered ring heterocycle; each R 2 is independently selected from the group consisting of hydrogen and alkyl; n is an integer from 0 to 8; and X is selected from the group consisting of alkoxy; aryloxy; aralkyloxy; hydroxyl; amino; alkyiam r.i optionally substituted with hydroxy, aminocarbonyl, N- alkylammocaroonyl, carboxy or alkoxycarbonyl; dialkylammc; cycloalkylammo; d cycioaikylammo; cycloalkylai ylamino; (alkyl ) (aryl ) amino; aralkylammc optionally substituted with carboxy; diaralkyiamino; arylamino; heterocycle; and (mono- or bis-carboxylic ac d) -substituted alkylamine; heterocyclylamino; heterocycly -substituted al ylamino. and wherein tne compound of formula I s expressly net N' -carboxymethyl-N- (phenylacetyl-L-leucyi-L-asparty - - phenyiaiany -L-prolyl) piperazine ( .e., when Z=pnenylacetyl, Y-=L, Y =D, Y =F/F, n=2, and X=4- carboxymethylpiperazmyl ) and expressly not phenylace * ./. - L-ieucyl-L-aspartyl-L-phenylalanyl-D-prciine amide :. ' .., when Z=phenylacetyl, Y : =L, Y-=D, Y ' =F/p, n=2, and X=NH 2. The cell adhesion inhibitory compound according tc claim 1, wherein: Z s selected from the group consisting of alkyl; aliphatic acyl optionally substituted with N- alkyl- or N-arylamido; aroyl; heterocycloyl; alkyl- and arylsulfonyl; aralkylcarbonyl optionally substituted with aryl; heterocycloalkylcarbonyl; alkoxycarbonyl; aralkyloxycarbonyl; cycloalkylcarbonyl optionally fused with aryl; heterocycloalkoxycarbonyl; alkylammocarbonyl; arylaminocarbonyl and aralkylaminocarbonyl optionally substituted with bis- (alkylsulfonyl) amino, alkoxycarbonylamino or alkenyl; each R 1 is independently selected from the group consisting of hydrogen, alkyl, and aralkyl; and X is selected from the group consisting of alkoxy; aryloxy; aralkyloxy; hydroxyl; amino; alkylamino optionally substituted with hydroxy, aminocarbonyl, N- alkylaminocarbonyl, carboxy or alkoxycarbonyl; dialkylammo; cycloalkylamino; dicycioaikylammo; cycloalkylalkylamino; (alkyl) (aryl)amino; aralkylamino optionally substituted with carboxy; diaralkyiamino; arylamino; heterocycle; and (mono- or bis-carboxylic acid) -substituted alkylamine. 3. The cell adhesion inhibitory compound according to claim 1, wherein A : is selected from the group consisting of cycloalkyl; heterocyclic ring (when A and R are taken together) ; and alkyl optionally substituted with amino, acylamino, amino-substituted acylamino, aryl, carboxy, cycloalkyl, hydroxy, alkoxy, aralkyloxy, alkoxycarbonyl, aralkoxycarbonyl, aminocarbonyl, alkylammocarbonyl, dialkylaminocarbonyl, (alkyl) (aralkyl) aminocarbonyl, aralkylaminocarbonyl, diaralkylaminocarbonyl, alkoxycarbonylamino, mercapto, thioalkoxy or heterocycle. 4. The cell adhesion inhibitory compound according to claim 3, wherein A 1 is selected from the group consisting of aminocarbonylethyl, benzyl, n-butyl, isobutyl, carboxyethyl, cyclohexyl, 1-hydroxyethyl, hydroxymethyl, mercaptomethyl, 1-methylpropyl, methylthioethyl, n-propyl, isopropyl, methoxycarbonylammobutyl, 6-aminohexanoylaminobutyl and (when A : and R : are taken together) azetidine, aziridine, pyrrolidine, and piperidine. 5. The cell adhesion inhibitory compound according to claim 4, wherein A is selected from the group consisting of benzyl, n-butyl, isobutyl, methylthioethyl, cyclohexyl, 1-methylpropyl, n-propyl and isopropyl. 6. The cell adhesion inhibitory compound according to claim 4, wherein A is (when A and R are taken together) pyrrolidine. 7. The cell adhesion inhibitory compound according to claim 1, wherein A 2 is selected from the group consisting of alkyl optionally substituted with ammo, aminocarbonyl, aryl, alkoxycarbonyl, aralkyloxycarbonyl, hydroxylaminocarbonyl, carboxy, NH- containing heterocycle, hydroxy, or mercapto; aralkyl optionally substituted with amino, aminocarbonyl, carboxy, NH-containing heterocycle, hydroxy, or mercapto; and heterocyclic ring (when A 2 and R 1 are taken together) . 8. The cell adhesion inhibitory compound according to claim 7 wherein A 2 is selected from the group consisting of carboxymethyl, 2-carboxyethyl, 1- carboxyethyl, hydroxylaminocarbonylmethyl, hydroxymethyl, mercaptomethyl, imidazolylmethyl, N-Bn-imidazolylmethyl, phenyl, carbomethoxymethyl, carbobenzyloxymethyl, and (when A 2 and R 1 are taken together) azetidine, aziridine, pyrrolidine and piperidine. 9. The cell adhesion inhibitory compound according to claim 8 wherein A is selected from the grour consisting of carboxymethyl, 2-carboxyethyl, 1- carboxyethyl, hydroxylaminocarbonylmethyl, hydroxymethyl, mercaptomethyl and imidazolylmethyl. 10. The cell adhesion inhibitory compound according to claim 1, wherein A' is independently selectee from the group consisting of ammo acid side chains ana corresponding protected derivatives; cycloalkyl; and alkyl optionally substituted w th aryl, cycloalkyl, carboxy, hydroxylaminocarbonyl, alkoxy, aralkyloxy, mercapto, N-contammg heterocycle, carboxyalkylaminocarbonyl or ammo-substituted acylamm: . 11. The cell adhesion inhibitory compound according to claim 10, wherein A is independently selected from the group consisting of ammo acid side chains and corresponding protected derivatives; cyclohexyl; and alkyl optionally substituted with pheny., cyclohexyl, carboxy, hydroxylaminocarbonyl, methoxy, benzyloxy, mercapto, N-benzylimidazolyl, biotinyl, tetrazolyl, valinyl-N-carbonyl or 6-aminohexanoylamino. 12. The cell adhesion inhibitory compound according to claim 1, wherein each Y 3 is independently selected from the group consisting of amino acids and corresponding protected derivatives. 13. The cell adhesion inhibitory compound according to claim 1, wherein: n is 2; Y 1 is leucinyl; Y 2 is aspartyl; and Y : ' s valinylprol yl. 14. The cell adhesion inhibitory compound according to claim 1, wherein X is selected from the group consisting of alkoxy; aryloxy; aralkyloxy; hydroxyl; amino; mono- and dialkylammo optionally substituted w th hydroxy, aminocarbonyl, N- alkylaminocarconyl, carboxy cr alkoxycarbonyl; dialkylammo; cycloalkylammc; cycloalkyialkylam o; dicycioaikylammo; (alkyl) (aryl) ammo; aralkylammc optionally substituted with carboxy; diaralkyiamino; arylamino; N-containing heterocycle; bis-carboxylic aciα- substituted alkylamme and (mono- or bis- carboxy)methy aminocarbonyl-substituted-N-contaming heterocycle. 15. The cell adhesion inhibitory compound according to claim 14, wherein X is selected from the group consisting of amino, methylamino, isopropylamino, isobutylamino, n-butylamino, t-butylamino, isoamyl, isopentylaminc, hexylamino, cyclohexylamino, cyclohexylmethylamino, methylphenylamino, phenylmethylamino, phenylamino, 4- methoxyphenylmethylam o, dimethylam o, diisopropylam o, diisobutylam o, hydroxy, methoxy, n- butoxy, t-butoxy, benzyloxy, 2-pιperιdmecarboxylιc acid, N'- ( ,α'-bιs-carboxymethyl) -2-pιperιdmecarboxamιde, N'- carboxymethyl-2-pιperιdmecarboxamιde, l-hydroxymethyl-2- methylpropylammo, 1-N'-methylamιdo-1-methylethylammo, 3,3-dιmethylbutylammo, l-N'-methylamidobutylammo, 1- amιdo-2-methylbutylammo, l-carbomethoxy-2- methylbutylammo, 1-N'-methylamιαo-2-methylbutylammo, 1- carboxy-I-phenylmethylammo, morpnolmo, piperidinyl, N- phenylpiperazmyl, pipecolmyl, and piperazmyl. 16. The cell adhesion inhibitory compound according to claim 1, wherein Z is selected from the group consisting of aliphatic acyl, aroyl, aralkylcarbonyl, heterocycloyl, alkoxycarbonyl, aralkylcxycarbonyl and heterocycloalkylcarbonyl. 17. The cell adhesion inhibitory compound according to claim 16, wherein Z s a (N-Ar'-urea)-para- suostituted aralkylcarbonyl group. 18. The cell adhesion inhibitory compound according to claim 17, wherein Z is a (N-Ar'-urea) -para- substituted phenylmethylcarbonyl group. 19. The cell adhesion inhibitory compound according to claim 2 selected from the group consisting of compound numbers 1, 2, 4, 144, 145, 146, 147, 148, 206, 315, 316, 317, 337, 338, 345, 346, 347, 357, 358 and 359. - I l l - 20. The cell adhesion inhibitory compound according to claim 19 selected from the group consisting of compound numbers 1, 206, 316, 358 and 359. 21. The cell adhesion inhibitory compound according to claim 20 selected from the group consisting of compound numbers 358 and 359. 22. A pharmaceutical composition comprising a compound according to any one cf claims 1 to 21 in an amount effective for prevention, lr.h cition or suppression of cell adhesion a a a pharmaceutically acceptable carrier. 23. The pharmaceutical composition according to claim 22, further comprismg an agent selected fror the group consisting of corticosteroiαs, bronchodilators, antiasthmatics, antnnflammatories, artirheumatics, immunosuppressants, antimetabolites, immunomodulators, antipsoriatics and antidiabetics. 24. A method of preventing, inhibiting cr suppressing cell adhesion in a mamma, comprising tne stet cf aaministenng to said mammal tne pharmaceutical composition according to claim 22 cr 23. 25. The method according to claim 24, wherein saiα method is used for preventing, inhibiting or suppressing inflammation. 26. The method according to claim 25, wherein said inflammation is cell-adhesion associated inflammation. 27. The method according to claim 24, wherein said method is used for preventing, inhibiting or suppressing an immune or autoimmune response. 28. The method according to claim 27, wherein said immune or autoimmune response is cell-adhesion associated immune or autoimmune response. 29. The method according to claim 24, wherein said method is used to treat or prevent a disease selected from the group consisting of asthma, arthritis, psoriasis, transplantation rejection, multiple sclerosis, diabetes and inflammatory bowel disease.

Inventors: ADAMS STEVEN P, ALMQUIST RONALD G, CARTER MARY BETH, CASTRO ALFREDO C, CUERVO JULIO HERNAN, ENSINGER CAROL LEE, HAMMOND CHARLES E, LEE WEN-CHERNG, LIN KO-CHUNG, ZIMMERMAN CRAIG N, ADAMS, STEVEN, P., ALMQUIST, RONALD, G., CARTER, MARY, BETH, CASTRO, ALFREDO, C., CUERVO, JULIO, HERNAN, ENSINGER, CAROL, LEE, HAMMOND, CHARLES, E., LEE, WEN-CHERNG, LIN, KO-CHUNG, ZIMMERMAN, CRAIG, N.
Applicants: ADAMS STEVEN P, ALMQUIST RONALD G, BIOGEN INC, CARTER MARY BETH, CASTRO ALFREDO C, CUERVO JULIO HERNAN, ENSINGER CAROL LEE, HAMMOND CHARLES E, LEE WEN CHERNG, LIN KO CHUNG, ZIMMERMAN CRAIG N, ADAMS, STEVEN, P., ALMQUIST, RONALD, G., BIOGEN, INC., CARTER, MARY, BETH, CASTRO, ALFREDO, C., CUERVO, JULIO, HERNAN, ENSINGER, CAROL, LEE, HAMMOND, CHARLES, E., LEE, WEN-CHERNG, LIN, KO-CHUNG, ZIMMERMAN, CRAIG, N.
Application year: 1996
Main classification: C07K14
IPC codes: A61K31, A61K38, A61P1, A61P3, A61P11, A61P17, A61P19, A61P29, A61P37, A61P43, C07K5, C07K7, C07K14