Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4

A compound of formula IA or IIA:

• wherein
• R1 has the formula:
• wherein
• R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, amino, cyano, halo and nitro;
• and
• Z is CH or N;
• R2 is selected from the group consisting of alkylene having from 2 to 4 carbon atoms in the alkylene chain, substituted alkylene having from 2 to 4 carbon atoms in the alkylene chain, heteroalkylene containing from 1 to 3 carbon atoms and from 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur and having from 2 to 4 atoms in the heteroalkylene chain, and substituted heteroalkylene containing, in the heteroalkylene chain, from 1 to 3 carbon atoms and from 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur and having from 2 to 4 atoms in the heteroalkylene chain;
• R3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic;
• or R3 can be joined to R2 to form a fused cycloalkyl, substititued cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring;
• X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, acylamino, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxyheterocyclic, carboxy-substituted heterocyclic, and hydroxyl with the proviso that, in formula IIA, X is not hydroxyl;
• R5 is selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, —NH-adamantyl, —NHSO2-p-CH3—φ, —NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and —NH(CH2)pCOOY′ where Y′ is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and p is an integer of from 1 to 8, —O-cholest-5-en-3-β-yl, —OCH2—OC(O)C(CH3)3, —O(CH2)zNHC(O)R9 where z is 1 or 2 and R9 is selected from the group consisting of pyrid-3-yl, N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl, —NR″C(O)—R′ where R′ is aryl, heteroaryl or heterocyclic and R″ is hydrogen or —CH2C(O)OCH2CH3;
• W is oxygen or sulfur;
• and pharmaceutically acceptable salts thereof;
• with the provisos that:
• (a) when R1 is benzyl, R2 is —CH2CH2—, R3 is hydrogen, —CH2X is benzyl, then R5 is not ethyl;
• (b) when R1 is 3,4-dichlorobenzyl, R2 is —CH2CH2—, R3 is hydrogen, —CH2X is 4-(phenylcarbonylamino)benzyl, then R5 is not methyl;
• (c) when R1 is benzyl, R2 is —CH2CH2—, R3 is hydrogen, —CH2X is 4-hydroxybenzyl, then R5 is not isopropyl or tert-butyl;
• (d) when R1 is 4-fluorobenzyl, R2 is —CH2CH2—, R3 is hydrogen, R5 is tert-butyl, then —CH2X is not 4-hydroxybenzyl or 4-(4-nitrophenoxy-carbonyloxy)benzyl;
• and
• (e) when R1 is 4-cyanobenzyl, R2 is —CH2CH2—, R3 is hydrogen, —CH2X is 4-hydroxybenzyl, then R5 is not tert-butyl.

A compound selected from the group consisting of:

• N-(benzyl)-L-pyroglutamyl-L-phenylalanine
• N-(benzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine
• N-(3,4-dichlorobenzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine
• N-(3-chlorobenzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine
• N-(3-chlorobenzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine
• methyl ester
• N-(4-chlorobenzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine
• N-(4-chlorobenzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine methyl ester
• N-(4-methylbenzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine
• N-(4-methylbenzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine methyl ester
• N-(4-methoxybenzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine
• N-(4-methoxybenzyl)-L-pyroglutamyl-L-4-(phenylcarbonylamino)phenylalanine methyl ester
• N-(3-chlorobenzyl)-L-pyroglutamyl-L-(N′-benzyl)histidine
• N-(4-methylbenzyl)-L-pyroglutamyl-L-(N′-benzyl)histidine methyl ester
• N-(4-methylbenzyl)-L-pyroglutamyl-L-(N′-benzyl)histidine
• N-(benzyl)-D-pyroglutamyl-L-phenylalanine
• N-(4-benzyl-3-oxothiomorpholin-5-carbonyl)-L-phenylalanine
• N-(4-benzyl-3-oxothiomorpholin-5-carbonyl)-L-phenylalanine ethyl ester
• N-(4-benzyl-3-oxomorpholin-5-carbonyl)-L-phenylalanine
• N-(4-benzyl-3-oxothiomorpholin-5-carbonyl)-L-4-nitrophenylalanine methyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-(pyridin-4-ylcarbonylamino)phenylalanine methyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-(1′-benzyloxycarbonylpiperidin-4′-ylcarbonylamino)phenylalanine methyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-(pyridin-4-ylcarbonylamino)phenylalanine
• N-(benzyl)-L-pyroglutamyl-L-4-(1′-benzyloxycarbonylpiperidin-4′-ylcarbonylamino)phenylalanine
• N-(benzyl)-L-pyroglutamyl-L-tyrosine ethyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-(piperidin-4′-ylcarbonylamino)phenylalanine
• N-(benzyl)-L-pyroglutamyl-L-4-nitrophenylalanine ethyl ester
• N-(benzyl)-L-pyroglutamyl-L-tyrosine
• N-(benzyl)-L-pyroglutamyl-L-4-(1′-methylpiperidin-4′-yloxy)phenylalanine ethyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-nitrophenylalanine
• N-(benzyl)-L-pyroglutamyl-L-4-[(4′-methylpiperazin-1′-yl)carbonyloxy]phenylalanine ethyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-(1′-methylpiperidin-4′-yloxy)phenylalanine
• -(benzyl)-L-pyroglutamyl-L-4-[(4′-methylpiperazin-1′-yl)carbonyloxy]phenylalanine
• N-(benzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine ethyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-aminophenylalanine ethyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine
• N-(benzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-[(4′-methylpiperazin-1′-yl)carbonyloxy]phenylalanine tert-butyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-[(thiomorpholin-4′-yl)carbonyloxy]phenylalanine tert-butyl ester
• N-(4-fluorobenzyl)-L-pyroglutamyl-L-4-[(thiomorpholin-4′-yl)carbonyloxy]phenylalanine tert-butyl ester
• N-(benzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine isopropyl ester
• N-(4-fluorobenzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester
• N-(benzyl)-L-pyroglutamyl-L-3-chloro-4-hydroxyphenylalanine
• N-(4-cyanobenzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester
• N-(benzyl)-L-pyroglutamyl-L-3-chloro-4-(N,N-dimethylcarbamyloxy)phenylalanine methyl ester
• N-(4-fluorobenzyl)-L-pyroglutamyl-L-4-[(thiomorpholin-4′-yl)carbonyloxy]phenylalanine
• N-(4-cyanobenzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine
• N-(4-nitrobenzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester
• N-(benzyl)-L-pyroglutamyl-L-3-chloro-4-(N,N-dimethylcarbamyloxy)phenylalanine
• N-(4-fluorobenzyl)-L-pyroglutamyl-L-4-[(4′-(pyridin-2-yl)piperazin-1′-yl)carbonyloxy]phenylalanine
• N-(4-fluorobenzyl)-L-pyroglutamyl-L-4-[(4′-(pyridin-2-yl)piperazin-1′-yl)carbonyloxy]phenylalanine tert-butyl ester
• N-(4-aminobenzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester
• N-(pyridin-3-ylmethyl)-L-pyroglutamyl-L-tyrosine tert-butyl ester
• N-(pyridin-3-ylmethyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine
• N-(pyridin-3-ylmethyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester
• N-(pyridin-3-ylmethyl)-L-pyroglutamyl-L-4-[(4′-(pyridin-2-yl)piperazin-1′-yl)carbonyloxy]phenylalanine tert-butyl ester
• N-(pyridin-3-ylmethyl)-L-pyroglutamyl-L-4-[(4′-(pyridin-2-yl)piperazin-1′-yl)carbonyloxy]phenylalanine
• N-(4-benzyl-5-oxo-4-azatricyclo[4.2.1.0(3,7)]nonane-3-carbonyl)-L-tyrosine tert-butyl ester
• N-(4-benzyl-5-oxo-4-azatricyclo[4.2.1.0(3,7)]nonane-3-carbonyl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine tert-butyl ester
• N-(4-benzyl-5-oxo-4-azatricyclo[4.2.1.0(3,7)]nonane-3-carbonyl)-L-4-(N,N-dimethylcarbamyloxy)phenylalanine
• N-(4-fluorobenzyl)-L-pyroglutamyl-L-4-(N,N-dimethylcarbamyloxy)phenylalanine
• and pharmaceutically acceptable salts thereof, as well as any of the ester compounds recited above wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester.