Cell adhesion inhibitors

A cell adhesion inhibitory compound selected from a compound of the formula (I):

• or a pharmaceutically acceptable salt thereof, wherein;
• X is —CO2H;
• Y is selected from the group consisting of —CO—;
• R1 is a (N-Ar-urea) wherein the urea is substituted at the para position of the arylalkyl;
• R2 is selected from the group consisting of hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and aryl-substituted alkyl;
• R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, aralkoxy-substituted alkyl, amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino)-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio)-substituted alkyl, thioalkoxy-substituted alkyl, acylamino substituted alkyl, alkylsulfonylamino-substituted alkyl, arylsulfonylamino-substituted alkyl, (N-(alkyl, alkenyl or alkynyl)-amino) carbonyl-substituted alkyl, N,N-(dialkyl, dialkenyl, dialkynyl or (alkyl, alkenyl)-amino)carbonyl-substituted alkyl, carboxyl-substituted alkyl, and amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, alloisoleucine, tert-leucine, norleucine, phenylalanine, tyrosine, proline, alanine, ornithine, glutamine, valine, threonine, serine, aspartic acid, betacyanoalanine, and allothreonine;
• R4 is selected from the group consisting of aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl;
• and n is 0, 1 or 2;
• and wherein
• alkyl represents a C1-10 alkyl radical;
• alkenyl represents a C2-10 alkenyl radical;
• alkynyl represents a C2-10 alkynyl radical;
• cycloalkyl represents a C3-8 cyclic alkyl radical;
• cycloalkenyl represents a C4-8 cyclic carbocycle containing one or more double bonds;
• aryl represents a carbocyclic selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, and anthracenyl;
• and may contain up to four substituents independently selected from the group consisting of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, cyano, carboxy, carboalkoxy, Ar′-substituted alkyl, Ar′-substituted alkenyl or alkynyl, alkoxy, alkenoxy or alkynoxy, Ar′-substituted alkoxy, Ar′-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, Ar′-substituted alkylamino, Ar′-substituted alkenylamino 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′-substituted oxycarbonylamino, alkylsulfonylamino, mono- or bis-(Ar′-sulfonyl)amino, Ar′-substituted alkyl-sulfonylamino, N-alkyl guanidino, N-Ar′ guanidino, N-N-(Ar′,alkyl), 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;
• acylcarbonylamino;
• Ar′-substituted aryl;
• aromatic acyl-substituted aromatic or aliphatic acyl;
• Ar′-substituted cycloalkyl or cycloalkenyl;
• N,N-(Ar′, hydroxyl)urea;
• Ar′-substituted cycloalkyl and cycloalkenyl;
• Ar′-substituted biaryl;
• Ar′-substituted aminocarbonylamino;
• Ar′-mercapto-substituted alkyl;
• Ar′ amino-substituted aryl;
• Ar-oxysubstituted alkyl;
• Ar′-substituted aminocycloalkyl and cycloalkenyl;
• aralkylaminosulfonyl;
• aralkoxyalkyl;
• N-Ar′-substituted thiourea;
• N-aralkoxyurea;
• N-hydroxylurea;
• N-alkenylurea;
• N,N-(alkyl, hydroxyl)urea;
• thioaryloxy-substituted aryl;
• N,N-(aryl, alkyl) hydrazine;
• cycloalkyl-fused aryl;
• aryloxy-substituted alkyl;
• Ar′-substituted arylaminosulfonyl;
• thioaryl-substituted thioxy;
• and Ar′-substituted alkenoyl;
• aliphatic or aromatic acylaminocarbonyl;
• aliphatic or aromatic acyl-substituted alkenyl;
• Ar′-substituted aminocarbonyloxy;
• Ar′, Ar′-disubstituted aryl;
• aliphatic or aromatic acyl-substituted acyl;
• Ar′-substituted hydrazine;
• Ar′-substituted aminosulfonyl;
• Ar′-substituted alkylimino;
• Ar′,Ar′-disubstituted acylamino;
• Ar′-substituted cycloalkenonylamino;
• N,N-Ar′,hydroxylurea;
• N,N′-Ar′, hydroxylurea;
• Ar′-substituted aminocarbonyl;
• Ar′-substituted carbonylamino;
• Ar′-substituted aminosulfonylamino;
• Ar′-substituted mercaptoalkyl;
• Ar′-amino substituted biaryl;
• aralkylaminoalkoxy;
• alkyl- and aryloxy-substituted alkoxy;
• Ar′-substituted sulfonylalkyl;
• Ar′-amino carbocyclyl;
• aralkylsulfonyl;
• aryl-substituted alkenyl;
• Ar′-substituted sulfonylaminoalkyl;
• Ar′-substituted cycloalkyl;
• thioaryloxyalkyl;
• thioaryloxymercapto;
• cycloalkylcarbonylalkyl;
• cycloalkyl-substituted amino;
• Ar′-substituted arylamino;
• aryloxycarbonylalkyl;
• phosphorodiamidyl acid or ester;
• aryloxydimethylsiloxy;
• 1,3-indandionylcarbonylalkyl;
• 1,3-indandionylcarbonyl;
• arylsulfonylurea;
• Ar′-carbamoyloxy and alkyl- and aryloxy-substituted urea;
• in which each Ar′, independently, is aryl containing up to three substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethyoxy, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino or alkynylamino, alkylcarbonyloxy, aliphatic or aromatic acyl, alkylcarbonylamino, alkoxylcarbonylamino, alkylsulfonylamino, and N-alkyl or N,N-dialkyl urea;
• alkoxy represents an alkyl ether radical, wherein alkyl has been defined above;
• alkenoxy represents an alkenyl ether radical, wherein alkenyl has been defined above;
• alkynyloxy represents an alkynyl ether radical, wherein alkynyl has been defined above;
• thioalkyoxy represents an alkyl thioether radical, wherein alkyl has been defined above;
• alkylamino represents a mono- or di-alkyl-substituted amino radical, wherein alkyl has been defined above;
• alkenylamino represents a mono- or di-alkenyl-substituted amino radical, wherein alkenyl has been defined above;
• alkynylamino represents a mono- or di-alkynyl-substituted amino radical, wherein alkynyl has been defined above;
• aryloxy represents an aryl ether radical, wherein aryl has been defined above;
• arylamino represents a radical of the formula aryl-NH—, wherein aryl has been defined above;
• biaryl represents a radical of the formula aryl-aryl-, wherein aryl has been defined above;
• thioaryl represents an aryl thioether radical, wherein aryl has been defined above;
• aryl-fused cycloalkyl represents a cycloalkyl radical which shares two adjacent atoms with an aryl radical, wherein cycloalkyl and aryl have been defined above;
• aliphatic acyl represents radicals of the formula alkyl-CO—, alkenyl-CO—, or alkynyl-CO—, wherein alkyl, alkenyl, and alkynyl have been defined above;
• aromatic acyl or aroyl represents a radical of the formula aryl-CO—, wherein aryl has been defined above;
• alkylcarbonylamino represents a radical of the formula alkyl-CONH, wherein alkyl has been defined above;
• alkoxycarbonylamino represents a radical of the formula alkyl-OCONH, wherein alkyl has been defined above;
• alkylsulfonylamino represents a radical of the formula alkyl-SO2NH, wherein alkyl has been defined above;
• arylsulfonylamino represents a radical of the formula aryl-SO2NH, wherein aryl has been defined above;
• N-alkylurea represents a radical of the formula alkyl-NH—CO—NH—, wherein alkyl has been defined above;
• N-arylurea represents a radical of the formula aryl-NH—CO—NH—, wherein aryl has been defined above;
• and
• halogen represents fluorine, chlorine, bromine, or iodine.

A cell adhesion inhibitory compound selected from a compound of the formula (I):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is —CO2H;
• Y is selected from the group consisting of —CO—;
• R1 is selected from the group consisting of alkenyl, alkynyl, cycloalkyl, arylfused cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl (“aralkyl”), aryl-substituted alkenyl or alkynyl, cycloalkyl-substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkenoxy, alkynoxy, aryl-substituted alkoxy (“aralkoxy”), aryl-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, N-alkylurea-substituted alkyl, N-arylurea-substituted alkyl, alkylcarbonylamino-substituted alkyl, aminocarbonyl-substituted alkyl,
• with the proviso that R1 and Y taken together are not acetyl, pivalyl, t-butylacetyl, t-butyloxycarbonyl, benzyloxycarbonyl, benzoyl, a substituted or unsubstituted L- or D-aminoacyl residue, a phenylacyl group meta substituted with a carboxy group, 2,2-dibenzylacetyl, 3-phenylpronanoyl, L-3-phenyllactyl, methyl-3-phenylpropanoyl, (4-hydroxycarbonyl-3,3-dimethyl)butanoyl, or 6-aminohexanoyl;
• R2 is selected from the group consisting of hydrogen, aryl, alkyl, alkenyl or alkynyl, cycloalkyl, cycloalkenyl, and aryl-substituted alkyl;
• R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, aralkoxy-substituted alkyl, amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino)-substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio)-substituted alkyl, thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsufonylamino-substituted alkyl, arylsulfonylamino-substituted alkyl, N-(alkyl, alkenyl or alkynyl)- or N,N-carbonyl-substituted alkyl, carboxyl-substituted alkyl, and amino acid side chains selected from arginine, asparagine, glutamine, S-methyl cysteine, methionine and corresponding sulfoxide and sulfone derivatives thereof, glycine, leucine, isoleucine, all-isoleucine, tert-leucine, norleucine, phenylalanine, tyrosine, alanine, ornithine, glutamine, valine, threonine, serine, aspartic acid, betacyanoalanine, and allothreonine;
• R4 is selected from the group consisting of aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl;
• and n is 0, 1, or 2;
• and wherein
• alkyl represents a C1-10 alkyl radical;
• alkenyl represents a C2-10 alkenyl radical;
• alkynyl represents a C2-10 alkynyl radical;
• cycloalkyl represents a C3-8 cyclic alkyl radical;
• cycloalkenyl represents a C4-8 cyclic carbocycle containing one or more double bonds;
• aryl represents a carbocyclic selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, and anthracenyl;
• and may contain up to four substituents independently selected from the group consisting of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, cyano, carboxy, carboalkoxy, Ar′-substituted alkyl, Ar′-substituted alkenyl or alkynyl, alkoxy, alkenoxy or alkynoxy, Ar′-substituted alkoxy, Ar′-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, Ar′-substituted alkylamino, Ar′-substituted alkenylamino 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′-substituted oxycarbonylamino, alkylsulfonylamino, mono- or bis-(Ar′-sulfonyl)amino, Ar′-substituted alkyl-sulfonylamino, N-alkyl guanidino, N-Ar′ guanidino, N-N-(Ar′,alkyl), 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;
• acylcarbonylamino;
• Ar′-substituted aryl;
• aromatic acyl-substituted aromatic or aliphatic acyl;
• Ar′-substituted cycloalkyl or cycloalkenyl;
• N,N-(Ar′, hydroxyl)urea;
• Ar′-substituted cycloalkyl and cycloalkenyl;
• Ar′-substituted biaryl;
• Ar′-substituted aminocarbonylamino;
• Ar′-mercapto-substituted alkyl;
• Ar′ amino-substituted aryl;
• Ar-oxysubstituted alkyl;
• Ar′-substituted aminocycloalkyl and cycloalkenyl;
• aralkylaminosulfonyl;
• aralkoxyalkyl;
• N-Ar′-substituted thiourea;
• N-aralkoxyurea;
• N-hydroxylurea;
• N-alkenylurea;
• N,N-(alkyl, hydroxyl)urea;
• thioaryloxy-substituted aryl;
• N,N-(aryl, alkyl) hydrazine;
• cycloalkyl-fused aryl;
• aryloxy-substituted alkyl;
• Ar′-substituted arylaminosulfonyl;
• thioaryl-substituted thioxy;
• and Ar′-substituted alkenoyl;
• aliphatic or aromatic acylaminocarbonyl;
• aliphatic or aromatic acyl-substituted alkenyl;
• Ar′-substituted aminocarbonyloxy;
• Ar′, Ar′-disubstituted aryl;
• aliphatic or aromatic acyl-substituted acyl;
• Ar′-substituted hydrazine;
• Ar′-substituted aminosulfonyl;
• Ar′-substituted alkylimino;
• Ar′,Ar′-disubstituted acylamino;
• Ar′-substituted cycloalkenonylamino;
• N,N-Ar′,hydroxylurea;
• N,N′-Ar′, hydroxylurea;
• Ar′-substituted aminocarbonyl;
• Ar′-substituted carbonylamino;
• Ar′-substituted aminosulfonylamino;
• Ar′-substituted mercaptoalkyl;
• Ar′-amino substituted biaryl;
• aralkylaminoalkoxy;
• alkyl- and aryloxy-substituted alkoxy;
• Ar′-substituted sulfonylalkyl;
• Ar′-amino carbocyclyl;
• aralkylsulfonyl;
• aryl-substituted alkenyl;
• Ar′-substituted sulfonylaminoalkyl;
• Ar′-substituted cycloalkyl;
• thioaryloxyalkyl;
• thioaryloxymercapto;
• cycloalkylcarbonylalkyl;
• cycloalkyl-substituted amino;
• Ar′-substituted arylamino;
• aryloxycarbonylalkyl;
• phosphorodiamidyl acid or ester;
• aryloxydimethylsiloxy;
• 1,3-indandionylcarbonylalkyl;
• 1,3-indandionylcarbonyl;
• arylsulfonylurea;
• Ar′-carbamoyloxy and alkyl- and aryloxy-substituted urea;
• in which each Ar′, independently, is aryl containing up to three substituents selected from the group consisting of halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethyoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino or alkynylamino, alkylcarbonyloxy, aliphatic or aromatic acyl, alkylcarbonylamino, alkoxylcarbonylamino, alkylsulfonylamino, and N-alkyl or N,N-dialkyl urea;
• alkoxy represents an alkyl ether radical, wherein alkyl has been defined above;
• alkenoxy represents an alkenyl ether radical, wherein alkenyl has been defined above;
• alkynyloxy represents an alkynyl ether radical, wherein alkynyl has been defined above;
• thioalkyoxy represents an alkyl thioether radical, wherein alkyl has been defined above;
• alkylamino represents a mono- or di-alkyl-substituted amino radical, wherein alkyl has been defined above;
• alkenylamino represents a mono- or di-alkenyl-substituted amino radical, wherein alkenyl has been defined above;
• alkynylamino represents a mono- or di-alkynyl-substituted amino radical, wherein alkynyl has been defined above;
• aryloxy represents an aryl ether radical, wherein aryl has been defined above;
• arylamino represents a radical of the formula aryl-NH—, wherein aryl has been defined above;
• biaryl represents a radical of the formula aryl-aryl-, wherein aryl has been defined above;
• thioaryl represents an aryl thioether radical, wherein aryl has been defined above;
• aryl-fused cycloalkyl represents a cycloalkyl radical which shares two adjacent atoms with an aryl radical, wherein cycloalkyl and aryl have been defined above;
• aliphatic acyl represents radicals of the formula alkyl-CO—, alkenyl-CO—, or alkynyl-CO—, wherein alkyl, alkenyl, and alkynyl have been defined above;
• aromatic acyl or aroyl represents a radical of the formula aryl-CO—, wherein aryl has been defined above;
• alkylcarbonylamino represents a radical of the formula alkyl-CONH, wherein alkyl has been defined above;
• alkoxycarbonylamino represents a radical of the formula alkyl-OCONH, wherein alkyl has been defined above;
• alkylsulfonylamino represents a radical of the formula alkyl-SO2N4H, wherein alkyl has been defined above;
• arylsulfonylamino represents a radical of the formula aryl-SO2NH, wherein aryl has been defined above;
• N-alkylurea represents a radical of the formula alkyl-NH—CO—NH—, wherein alkyl has been defined above;
• N-arylurea represents a radical of the formula aryl-NH—CO—NH—, wherein aryl has been defined above;
• and
• halogen represents fluorine, chlorine, bromine, or iodine.