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

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I or II.

wherein:

R 1 has the formula:

where R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, amino, cyano, halo and nitro;

Z is CH or N;

R 2 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;

R 3 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 R 3 can be joined to R 2 to form a fused cycloalkyl, substituted 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 akyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, and hydroxyl with the proviso that in formula II, X is not hydroxyl;

W is oxygen or sulfur;

and pharmaceutically acceptable salts thereof.

2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula IA or IIA

wherein:

R 1 has the formula:

where R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, amino, cyano, halo and nitro;

Z is CH or N;

R 2 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;

R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cylcloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic; or R 3 can be joined to R 2 to form a fused cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring;

R 5 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, —NHSO 2 -p-CH 3 -φ, —NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, and —NH(CH 2 ) p COOY′ 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, —OCH 2 OC(O)CH 3 , —O(CH 2 ) z NHC(O)R 9 where z is 1 or 2 and R 9 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 —CH 2 C(O)OCH 2 CH 3 ;

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, carboxylheterocyclic, carboxyl-substituted heterocyclic, and hydroxyl with the proviso that in formula II, X is not hydroxyl;

W is oxygen or sulfur;

and pharmaceutically acceptable salts thereof

with the provisos that when:

(a) R 1 is benzyl, R 2 is —CH 2 CH 2 —, R 3 is hydrogen, R 4 is benzyl, then R 5 is not ethoxy;

(b) R 1 is 3,4-dichlorobenzyl, R 2 is —CH 2 CH 2 —, R 3 is hydrogen, R 4 is 4-(phenyl-carbonylamino)benzyl, then R 5 is not methoxy;

(c) R 1 is benzyl, R 2 is —CH 2 CH 2 —, R 3 is hydrogen, R 4 is 4-hydroxy-benzyl, then R 5 is not isopropyloxy or tert-butyloxy;

(d) R 1 is 4-fluorobenzyl, R 2 is —CH 2 CH 2 —, R 3 is hydrogen, R 5 is tert-butyloxy, then R 4 is not 4-hydroxybenzyl or 4-(4-nitrophenoxycarbonyl-oxy)benzyl;

(e) R 1 is 4-cyanobenzyl, R 2 is —CH 2 CH 2 —, R 3 is hydrogen, R 4 is 4-hydroxy-benzyl, then R 5 is not tert-butyloxy; and

(f) R 1 is benzyloxycarbonyl, R 2 is —NHCH 2 —, R 3 is hydrogen, R 5 is tert-butyloxy, then R 4 is not 4-hydroxybenzyl or 4-(N,N-dimethylcarbamyl-oxy)benzyl.

3. The pharmaceutical composition according to claim 1 or claim 2 wherein Z is CH.

4. The pharmaceutical composition according to claim 3 wherein one of R 6 and R 7 is hydrogen and the other is selected from the group consisting of hydrogen, methyl, methoxy, amino, chloro, fluoro, cyano or nitro; or both R 6 and R 7 are chloro.

5. The pharmaceutical composition according to claim 1 or claim 2 wherein R 1 is selected from the group consisting of benzyl, 4-aminobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, 4-cyanobenzyl, 4-fluorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, and (pyrdin-3-yl)methyl.

6. The pharmaceutical composition according to claim 1 or claim 2 wherein R 2 is selected from the group consisting of alkylene having 2 or 3 carbon atoms in the alkylene chain, substituted alkylene having 2 or 3 carbon atoms in the alkylene chain, heteroalkylene containing 1 or 2 carbon atoms and 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and having 2 or 3 atoms in the heteroalkylene chain, and substituted heteroalkylene containing, in the heteroalkylene chain, 1 or 2 carbon atoms and 1 heteroatom selected from the group consisting of nitrogen, oxygen and sulfur and having 2 or 3 atoms in the heteroalkylene chain.

7. The pharmaceutical composition according to claim 6 wherein R 2 is selected from the group consisting of —CH 2 CH 2 —, —CH 2 —S—CH 2 —, —CH 2 —O—CH 2 — and —NHCH 2 —.

8. The pharmaceutical composition according to claim 1 or claim 2 wherein R 3 is hydrogen.

9. The pharmaceutical composition according to claim 1 or claim 2 wherein R 3 is joined to R 2 to form a fused and/or bridged cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic or substituted heterocyclic ring.

10. The pharmaceutical composition according to claim 9 wherein R 2 and R 3 , together with the other atoms of the nitrogen-containing ring form a 5-oxo-4-azatri-cyclo[4.2.1.0(3,7)]nonane ring.

11. The pharmaceutical composition according to claim 1 or claim 2 wherein W is oxygen.

12. The pharmaceutical composition according to claim 2 wherein R 5 is selected from the group consisting of 2,4- dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-α-iso-propyl-4-β-methyl-cyclohexoxy, 2-β-isopropyl-4-β-methylcyclohexoxy, —NH 2 , benzyloxy, —NHCH 2 COOH, —NHCH 2 CH 2 COOH, —NH-adamantyl, —NHCH 2 CH 2 COOCH 2 CH 3 , —NHSO 2 -p-CH 3 -φ, —NHOR 8 where R 8 is hydrogen, methyl, iso-propyl or benzyl, O—(N-succinimidyl), —O-cholest-5-en-3-β-yl, —OCH 2 —OC(O)C(CH 3 ) 3 , —O(CH 2 ) z NHC(O)R 9 where z is 1 or 2 and R 9 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 —CH 2 C(O)OCH 2 CH 3 .

13. The pharmaceutical composition according to claim 1 or claim 2 wherein —CH 2 X is selected from the group consisting of:

4-methylbenzyl,

4-hydroxybenzyl,

4-methoxybeuzyl,

4-t-butoxybenzyl,

4-benzyloxybenzyl,

4-[φ-CH(CH 3 )O—]benzyl,

4-[φ-CH(COOH)O—]benzyl,

4-[BocNHCH 2 C(O)NH—]benzyl,

4-chlorobenzyl,

4-[NH 2 CH 2 C(O)NH—]benzyl,

4-carboxybenzyl,

4-[CbzNHCH 2 CH 2 NH—]benzyl,

3-hydroxy-4-(φ-OC(O)NH-)benzyl,

4-[HOOCCH 2 CH 2 C(O)NH—]benzyl,

benzyl,

4-[2′-carboxylphenoxy—]benzyl,

4-[φ-C(O)NH—]benzyl,

3-carboxybenzyl,

4-iodobenzyl,

4-hydroxy-3,5-diiodobenzyl,

4-hydroxy-3-iodobenzyl,

4-[2′-carboxyphenyl—]benzyl,

φ-CH 2 CH 2 —,

4-nitrobenzyl,

2-carboxybenzyl,

4-[dibenzylamino]-benzyl,

4-[(1′-cyclopropylpiperidin-4′-yl)C(O)NH-—]benzyl,

4-[—NHC(O)CH 2 NHBoc]benzyl,

4-carboxybenzyl,

4-hydroxy-3-nitrobenzyl,

4-[—NHC(O)CH(CH 3 )NHBoc]benzyl,

4-[—NHC(O)CH(CH 2 φ)NHBoc]benzyl,

isobutyl,

methyl,

4-[CH 3 C(O)NH—]benzyl,

—CH 2 -(3-indolyl),

n-butyl,

t-butyl-OC(O)CH 2 —,

t-butyl-OC(O)CH 2 CH 2 —,

H 2 NC(O)CH 2 —,

H 2 NC(O)CH 2 CH 2 —,

BocNH—(CH 2 ) 4 —,

HOOCCH 2 —,

HOOC(CH 2 ) 2 —,

H 2 N(CH 2 ) 4 —,

isopropyl,

(1-naphthyl)-CH 2 —,

(2-naphthyl)-CH 2 —,

(2-thiophenyl)-CH 2 —,

φ-CH 2 —OC(O)NH—(CH 2 ) 4 —,

cyclohexyl-CH 2 —,

benzyloxy-CH 2 —,

HOCH 2 —,

5-(3-N-benzyl)imidazolyl-CH 2 —,

2-pyridyl-CH 2 —,

3-pyridyl-CH 2 —,

4-pyridyl-CH 2 —,

5-(3-N-methyl)imidazolyl-CH 2 —,

N-benzylpiperid-4-yl-CH 2 —,

N-Boc-piperidin-4-yl-CH 2 —,

N-(phenylcarbonyl)piperidin-4-yl-CH 2 —,

H 3 CSCH 2 CH 2 —,

1 -N-benzylimidazol-4-yl-CH 2 —,

iso-propyl-C(O)NH—(CH 2 ) 4 —,

iso-butyl-C(O)NH—(CH 2 ) 4 —,

phenyl-C(O)NH—(CH 2 ) 4 —,

benzyl-C(O)NH—(CH 2 ) 4 —,

allyl-C(O)NH—(CH 2 ) 4 —,

4-(3-N-methylimidazolyl)-CH 2 —,

4-imidazolyl,

4-[(CH 3 ) 2 NCH 2 CH 2 CH 2 —O—]benzyl,

4-[(benzyl) 2 N—]-benzyl,

4-aminobenzyl,

allyloxy-C(O)NH(CH 2 ) 4 —,

allyloxy-C(O)NH(CH 2 ) 3 —,

allyloxy-C(O)NH(CH 2 ) 2 —,

NH 2 C(O)CH 2 —,

2-pyridyl-C(O)NH—(CH 2 ) 4 —,

4-methylpyrid-3-yl-C(O)NH—(CH 2 ) 4 —,

3-methylthien-2-yl-C(O)NH—(CH 2 )4—,

2-pyrrolyl-C(O)NH—(CH 2 ) 4 —,

2-furanyl-C(O)NH—(CH 2 ) 4 —,

4-methylphenyl-SO 2 —N(CH 3 )CH 2 C(O)NH(CH 2 ) 4 —,

4-[cyclopentylacetylenyl]-benzyl,

4-[—NHC(O)-(N-Boc)-pyrrolidin-2-yl)]-benzyl-,

1-N-methylimidazol-4-yl-CH 2 —,

1-N-methylimidazol-5-yl-CH 2 —,

imidazol-5-yl-CH 2 —,

6-methylpyrid-3-yl-C(O)NH—(CH 2 )4—,

4-[2′-carboxymethylphenyl]-benzyl,

4-[—NHC(O)NHCH 2 CH 2 CH 2 -φ]-benzyl,

4-[—NHC(O)NHCH 2 CH 2 -φ]-benzyl,

—CH 2 C(O)NH(CH 2 ) 4 φ,

4-[φ(CH 2 ) 4 O—]-benzyl,

4-[—C≡C-φ-4′-φ]-benzyl,

4-[—C≡C—CH 2 —O—S(O) 2 -4′-CH 3 -φ]-benzyl,

4-[—C≡C—CH 2 NHC(O)NH 2 ]-benzy,

4-[—C≡C—CH 2 —O-4′-COOCH 2 CH 3 -φ]-benzyl,

4-[—C≡C—CH(NH 2 )-cyclohexyl]-benzyl,

—(CH 2 ) 4 NHC(O)CH 2 -3-indolyl,

—(CH 2 ) 4 NHC(O)CH 2 CH 2 -3-indolyl,

—(CH 2 ) 4 NHC(O)-3-(5-methoxyindolyl),

—(CH 2 ) 4 NHC(O)-3-(1-methylindolyl),

—(CH 2 ) 4 NHC(O)-4-(—SO 2 (CH 3 )-φ),

—(CH 2 ) 4 NHC(O)-4-(C(O)CH 3 )-phenyl,

—(CH 2 ) 4 NHC(O)-4-fluorophenyl,

—(CH 2 ) 4 NHC(O)CH 2 O-4-fluorophenyl,

4-[—C≡C-(2-pyridyl)benzyl,

4-[—C≡C—CH 2 —O-phenyl]benzyl,

4-[—C≡C—CH 2 OCH 3 ]benzyl,

4-[—C≡C-(3-hydroxyphenyl)]benzyl,

4-[—C≡C—CH 2 —O-4′-(—C(O)OC 2 H 5 )phenyl]benzyl,

4-[—C≡C—CH 2 CH(C(O)OCH 3 ) 2 ]benzyl,

4-[—C≡C—CH 2 NH-(4,5-dihydro-4-oxo-5-phenyl-oxazol-2-yl),

3-aminobenzyl,

4-[—C≡C—CH 2 CH(NHC(O)CH 3 )C(O)OH]-benzyl,

—CH 2 C(O)NHCH(CH 3 )φ,

—CH 2 C(O)NHCH 2 -(4-dimethylamino)-φ,

—CH 2 C(O)NHCH 2 -4-nitrophenyl,

—CH 2 CH 2 C(O)N(CH 3 )CH 2 -φ,

—CH 2 CH 2 C(O)NHCH 2 CH 2 -(N-methyl)-2-pyrrolyl,

—CH 2 CH 2 C(O)NHCH 2 CH 2 CH 2 CH 3 ,

—CH 2 CH 2 C(O)NHCH 2 CH 2 -3-indolyl,

—CH 2 C(O)N(CH 3 )CH 2 phenyl,

—CH 2 C(O)NH(CH 2 ) 2 -(N-methyl)-2-pyrrolyl,

—CH 2 C(O)NHCH 2 CH 2 CH 2 CH 3 ,

—CH 2 C(O)NHCH 2 CH 2 -3-indolyl,

—(CH 2 ) 2 C(O)NHCH(CH 3 )φ,

—(CH 2 ) 2 C(O)NHCH 2 -4-dimethylaminophenyl,

—(CH 2 ) 2 C(O)NHCH 2 -4-nitrophenyl,

—CH 2 C(O)NH-4-[—NHC(O)CH 3 -phenyl],

—CH 2 C(O)NH-4-pyridyl,

—CH 2 C(O)NH-4-[dimethylaminophenyl],

—CH 2 C(O)NH-3-methoxyphenyl,

—CH 2 CH 2 C(O)NH-4-chlorophenyl,

—CH2CH 2 C(O)NH-2-pyridyl,

—CH 2 CH 2 C(O)NH-4-methoxyphenyl,

—CH 2 CH 2 C(O)NH-3-pyridyl,

4-[(CH 3 ) 2 NCH 2 CH 2 O—]benzyl,

—(CH 2 ) 3 NHC(NH)NH—SO 2 -4-methylphenyl,

4-[(CH 3 ) 2 NCH 2 CH 2 O—]benzyl,

—(CH 2 ) 4 NHC(O)NHCH 2 CH 3 ,

—(CH 2 ) 4 NHC(O)NH-phenyl,

—(CH 2 ) 4 NHC(O)NH-4-methoxyphenyl,

4-[4′-pyridyl-C(O)NH—]benzyl,

4-[3′-pyridyl-C(O)NH—]benzyl,

4-[—NHC(O)NH-3 ′-methylphenyl]benzyl,

4-[-NHC(O)CH 2 NHC(O)NH-3′-methylphenyl]benzyl,

4-[-NHC(O)-(2′,3′-dihydroindol-2-yl)]benzyl,

4-[-NHC(O)-(2′,3′-dihydro-N-Boc-indol-2-yl)]benzyl,

p-[—OCH 2 CH 2 -1′-(4′pyrimidinyl)-piperazinyl]benzyl,

4-[—OCH 2 CH 2 -(1′-piperidinyl)benzyl,

4-[—OCH 2 CH 2 -(1′-pyrrolidinyl)]benzyl,

4-[—OCH 2 CH 2 CH 2 -(1′-piperidinyl)]benzyl,

—CH 2 -3-(1,2,4-triazolyl),

4-[—OCH 2 CH 2 CH 2 -4-(3′-chlorophenyl)-piperazin-1-yl—]benzyl,

4-[—OCH 2 CH 2 N(φ)CH 2 CH 3 ]benzyl,

4-[—OCH 2 -3′-(N-Boc)-piperidinyl]benzyl,

4-[di-n-pentylamino]benzyl,

4-[n-pentylamino]benzyl,

4-[di-iso-propylamino-CH 2 CH 2 O—]benzyl,

4-[—OCH 2 CH 2 -(N-morpholinyl)]benzyl,

4-[—O-(3′-(N-Boc)-piperidinyl]benzyl,

4-[—OCH 2 CH(NHBoc)CH 2 cyclohexyl]benzyl,

p-[OCH 2 CH 2 -(N-piperidinyl]benzyl,

4-[—OCH 2 CH 2 CH 2 -(4-m-chlorophenyl)-piperazin-1-yl—]benzyl,

4-[—OCH 2 CH 2 -(N-homopiperidinyl)benzyl,

4-[—NHC(O)-3′-(N-Boc)-piperidinyl]benzyl,

4-[—OCH 2 CH 2 N(benzyl) 2 ]benzyl,

—CH 2 -2-thiazolyl,

3-hydroxybenzyl,

4-[—OCH 2 CH 2 CH 2 N(CH 3 ) 2 ]benzyl,

4-[—NHC(S)NHCH 2 CH 2 -(N-morpholino)]benzyl,

4-[—OCH 2 CH 2 N(C 2 H 5 ) 2 ]benzyl,

4-[—OCH 2 CH 2 CH 2 N(C 2 H 5 ) 2 ]benzyl,

4-[CH 3 (CH 2 ) 4 NH—]benzyl,

4-[N-n-butyl,N-n-pentylamino—]benzyl,

4-[—NHC(O)-4′-piperidinyl]benzyl,

4-[—NHC(O)CH(NHBoc)(CH 2 ) 4 NHCbz]benzyl,

4-[—NHC(O)-(1′,2′,3′,4′-tetrahydro-N-Boc-isoquinolin-1′-yl]benzyl,

p-[—OCH 2 CH 2 CH 2 -1′-(4′-methyl)-piperazinyl]benzyl,

—(CH 2 ) 4 NH-Boc,

3-[—OCH 2 CH 2 CH 2 N(CH 3 ) 2 ]benzyl,

4-[—OCH 2 CH 2 CH 2 N(CH 3 ) 2 ]benzyl,

3-[—OCH 2 CH 2 -(1′-pyrrolidinyl)]benzyl,

4-[—OCH 2 CH 2 CH 2 N(CH 3 )benzyl]benzyl,

4-[—NHC(S)NHCH 2 CH 2 CH 2 -(N-morpholino)]benzyl,

4-[—OCH 2 CH 2 -(N-morpholino)]benzyl,

4-[—NHCH 2 -(4′-chlorophenyl)]benzyl,

4-[—NHC(O)NH-(4′-cyanophenyl)]benzyl,

4-[—OCH 2 COOH]benzyl,

4-[—OCH 2 COO-t-butyl]benzyl,

4-[—NHC(O)-5′-fluoroindol-2-yl]benzyl,

4-[—NHC(S)NH(CH 2 ) 2 -1-piperidinyl]benzyl,

4-[—N(SO 2 CH 3 )(CH 2 ) 3 -N(CH 3 ) 2 ]benzyl,

4-[—NHC(O)CH 2 CH(C(O)OCH 2 φ)-NHCbz]benzyl,

4-[—NHS(O) 2 CF 3 ]benzyl,

3-[—O—(N-methylpiperidin-4′-yl]benzyl,

4-[—C(═NH)NH 2 ]benzyl,

4-[—NHSO 2 —CH 2 Cl]benzyl,

4-[—NHC(O)-(1′,2′,3′,4′-tetrahydroisoquinolin-2′-yl]benzyl,

4-[—NHC(S)NH(CH 2 ) 3 -N-morpholino]benzyl,

4-[—NHC(O)CH(CH 2 CH 2 CH 2 CH 2 NH 2 )NHBoc]benzyl,

4-[—C(O)NH 2 ]benzyl,

4-[—NHC(O)NH-3′-methoxyphenyl]benzyl,

4-[—OCH 2 CH 2 -indol-3′-yl]benzyl,

4-[—OCH 2 C(O)NH-benzyl]benzyl,

4-[—OCH 2 C(O)O-benzyl]benzyl,

4-[—OCH 2 C(O)OH]benzyl,

4-[—OCH 2 -2′-(4′,5′-dihydro)imidazolyl]benzyl,

—CH 2 C(O)NHCH 2 -(4-dimethylamino)phenyl,

4-[—NHC(O)-L-2′-pyrrolidinyl-N-SO 2 -4′-methylphenyl]benzyl,

4-[—NHC(O)NHCH 2 CH 2 CH 3 ]benzyl,

4-[aminobenzyl]benzyl,

4-[—OCH 2 CH 2 -1-(4-hydroxy-4-(3-methoxypyrrol-2-yl)-piperazinyl]benzyl,

4-[—O—(N-methylpiperidin-4′-yl)]benzyl,

3-methoxybenzyl,

4-[—NHC(O)-piperidin-3′-yl]benzyl,

4-[—NHC(O)-pyridin-2′-yl]benzyl,

4-[—NHCH 2 -(4′-chlorophenyl)]benzyl,

4-[—NHC(O)—(N-(4′-CH 3 -φ-SO 2 )-L-pyrrolidin-2′-yl)]benzyl,

4-[—NHC(O)NHCH 2 CH 2 -φ]benzyl,

4-[—OCH 2 C(O)NH 2 ]benzyl,

4-[—OCH 2 C(O)NH-t-butyl]benzyl,

4-[—OCH 2 CH 2 -1-(4-hydroxy-4-phenyl)-piperidinyl]benzyl,

4-[—NHSO2—CH═CH 2 ]benzyl,

4-[—NHSO2—CH 2 CH 2 Cl]benzyl,

—CH 2 C(O)NHCH 2 CH 2 N(CH 3 ) 2 ,

4-[(1′-Cbz-piperidin-4′-yl)C(O)NH—]benzyl,

4-[(1′-Boc-piperidin-4′-yl)C(O)NH—]benzyl,

4-[(2′-bromophenyl)C(O)NH—]benzyl,

4-[—NHC(O)-pyridin-4′-yl]benzyl,

4-[(4′-(CH 3 ) 2 NC(O)O-)phenyl)-C(O)NH—]benzyl,

4-[—NHC(O)-1′-methylpiperidin-4′-yl—]benzyl,

4-(dimethylamino)benzyl,

4-[—NHC(O)-(1′-N-Boc)-piperidin-2′-yl]benzyl,

3-[—NHC(O)-pyridin-4′-yl]benzyl,

4-[(tert-butyl-O(O)CCH 2 -O-benzyl)-NH—]benzyl,

[BocNHCH 2 C(O)NH—]butyl,

4-benzylbenzyl,

2-hydroxyethyl,

4-[(Et) 2 NCH 2 CH 2 CH 2 NHC(S)NH—]benzyl,

4-[(1′-Boc-4′-hydroxypyrrolidin-2′-yl)C(O)NH—]benzyl,

4-[φCH 2 CH 2 CH 2 NHC(S)NH—]benzyl,

4-[(perhydroindolin-2′-yl)C(O)NH—]benzyl,

2-[4-hydroxy-4-(3 -methoxythien-2-yl)piperidin-1-yl]ethyl,

4-[1′-Boc-perhydroindolin-2′-yl)-C(O)NH—]benzyl,

4-[N-3-methylbutyl-N-trifluoromethanesulfonyl)amino]benzyl,

4-[N-vinylsulfonyl)amino]benzyl,

4-[2-(2-azabicyclo[3.2.2]octan-2-yl)ethyl-O—]benzyl,

4-[4′-hydroxypyrrolidin-2N-yl)C(O)NH—]benzyl,

4-(φNHC(S)NH)benzyl,

4-(EtNHC(S)NH)benzyl,

4-(φCH 2 NHC(S)NH)benzyl,

3-[(1′-Boc-piperidin-2′-yl)C(O)NH—]benzyl,

3-[piperidin-2′-yl-C(O)NH—]benzyl,

4-[(3′-Boc-thiazolidin-4′-yl)C(O)NH—]benzyl,

4-(pyridin-3′-yl-NHC(S)NH)benzyl,

4-(CH 3 —NHC(S)NH)benzyl,

4-(H 2 NCH 2 CH 2 CH 2 C(O)NH)benzyl,

4-(BocHNCH 2 CH 2 CH 2 C(O)NH)benzyl,

4-(pyridin-4′-yl-CH 2 NH)benzyl,

4-[(N,N-di(4-N,N-dimethylamino)benzyl)amino]benzyl,

4-[(1-Cbz-piperidin-4-yl)C(O)NH—]butyl,

4-[φCH 2 OCH 2 (BocHN)CHC(O)NH]benzyl,

4-[(piperidin-4′-yl)C(O)NH—]benzyl,

4-[(pyrrolidin-2′-yl)C(O)NH—]benzyl,

4-(pyridin-3′-yl-C(O)NH)butyl,

4-(pyridin-4′-yl-C(O)NH)butyl,

4-(pyridin-3′-yl-C(O)NH)benzyl,

4-[CH 3 NHCH 2 CH 2 CH 2 C(O)NH—]benzyl,

4-[CH 3 N(Boc)CH 2 CH 2 CH 2 C(O)NH—]benzyl,

4-(aminomethyl)benzyl,

4-[φCH 2 OCH 2 (H 2 N)CHC(O)NH]benzyl,

4-[(1′,4′-di(Boc)piperazin-2N-yl)-C(O)NH—]benzyl,

4-[(piperazin-2′-yl)-C(O)NH—]benzyl,

4-[(N-toluenesulfonylpyrrolidin-2′-yl)C(O)NH—]butyl,

4-[—NHC(O)-4′-piperidinyl]butyl,

4-[—NHC(O)-1′-N-Boc-piperidin-2′-yl]benzyl,

4-[—NHC(O)-piperidin-2′-yl]benzyl,

4-[(1′-N-Boc-2′,3′-dihydroindolin-2′-yl)-C(O)NH]benzyl,

4-(pyridin-3′-yl-CH 2 NH)benzyl,

4-[(piperidin-1′-yl)C(O)CH 2 —O—]benzyl,

4-[((CH 3 ) 2 CH) 2 NC(O)CH 2 —O—]benzyl,

4-[HO(O)C(Cbz-NH)CHCH 2 CH 2 —C(O)NH—]benzyl,

4-[φCH 2 O(O)C(Cbz-NH)CHCH 2 CH 2 —C(O)NH—]benzyl,

4-[—NHC(O)-2′-methoxyphenyl]benzyl,

4-[(pyrazin-2′-yl)C(O)NH—]benzyl,

4-[HO(O)C(NH 2 )CHCH 2 CH 2 —C(O)NH—]benzyl,

4-(2′-formyl-1′,2′,3′,4′-tetrahydroisoquinolin-3′-yl-CH 2 NH—)benzyl,

N-Cbz-NHCH 2 —,

4-[(4′-methylpiperazin-1′-yl)C(O)O—]benzyl,

4-[CH 3 (N-Boc)NCH 2 C(O)NH—]benzyl,

4-[-NHC(O)-(1′,2′,3′,4′-tetrahydro-N-Boc-isoquinolin-3′-yl]-benzyl,

4-[CH 3 NHCH 2 C(O)NH—]benzyl,

(CH 3 ) 2 NC(O)CH 2 —,

4-(N-methylacetamido)benzyl,

4-(1′,2′,3′,4′-tetrahydroisoquinolin-3′-yl-CH 2 NH—)benzyl,

4-[(CH 3 ) 2 NHCH 2 C(O)NH—]benzyl,

(1-toluenesulfonylimidizol-4-yl)methyl,

4-[(1′-Boc-piperidin-4′-yl)C(O)NH—]benzyl,

4-trifluoromethylbenzyl,

4-[(2′-bromophenyl)C(O)NH—]benzyl,

4-[(CH 3 ) 2 NC(O)NH—]benzyl,

4-[CH 3 OC(O)NH—]benzyl,

4-[(CH 3 ) 2 NC(O)O—]benzyl,

4-[(CH 3 ) 2 NC(O)N(CH 3 )—]benzyl,

4-[CH 3 OC(O)N(CH 3 )—]benzyl,

4-(N-methyltrifluoroacetamido)benzyl,

4-[(1′-methoxycarbonylpiperidin-4′-yl)C(O)NH—]benzyl,

4-[(4′-phenylpiperidin-4′-yl)C(O)NH—]benzyl,

4-[(4′-phenyl-1 ′-Boc-piperidin-4′-yl)-C(O)NH—]benzyl,

4-[(piperidin-4′-yl)C(O)O—]benzyl,

4-[(1′-methylpiperidin-4′-yl)-O-—]benzyl,

4-[(1′-methylpiperidin-4′-yl)C(O)O—]benzyl,

4-[(4′-methylpiperazin-1′-yl)C(O)NH—]benzyl,

3-[(CH 3 ) 2 NC(O)O—]benzyl,

4-[(4′-phenyl-1′-Boc-piperdin-4′-yl)-C(O)O—]benzyl,

4-(N-toluenesulfonylamino)benzyl,

4-[(CH 3 ) 3 CC(O)NH—]benzyl,

4-[(morpholin-4′-yl)C(O)NH—]benzyl,

4-[(CH 3 CH 2 ) 2 NC(O)NH—]benzyl,

4-[—C(O)NH-(4′-piperidinyl)]benzyl,

4-[(2′-trifluoromethylphenyl)C(O)NH—]benzyl,

4-[(2′-methylphenyl)C(O)NH—]benzyl,

4-[(CH 3 ) 2 NS(O) 2 O—]benzyl,

4-[(pyrrolidin-2′-yl)C(O)NH—]benzyl,

4-[—NHC(O)-piperidin-1′-yl]benzyl,

4-[(thiomorpholin-4′-yl)C(O)NH—]benzyl,

4-[(thiomorpholin-4′-yl sulfone)-C(O)NH—]benzyl,

4-[(morpholin-4′-yl)C(O)O—]benzyl,

3-nitro-4-(CH 3 OC(O)CH 2 O—)benzyl,

(2-benzoxazolinon-6-yl)methyl-,

(2H-1,4-benzoxazin-3(4H)-one-7-yl)methyl-,

4-[(CH 3 ) 2 NS(O) 2 NH—]benzyl,

4-[(CH 3 ) 2 NS(O) 2 N(CH 3 )—]benzyl,

4-[(thiomorpholin-4′-yl)C(O)O—]benzyl,

4-[(thiomorpholin-4′-yl sulfone)-C(O)O—]benzyl,

4-[(piperidin-1′-yl)C(O)O—]benzyl,

4-[(pyrrolidin-1′-yl)C(O)O—]benzyl,

4-[(4′-methylpiperazin-1′-yl)C(O)O—]benzyl,

4(2′-methylpyrrolidin-1′-yl)-,

(pyridin-4-yl)methyl-,

4-[(piperazin-4′-yl)-C(O)O—]benzyl,

4-[(1′-Boc-piperazin-4′-yl)-C(O)O—]benzyl,

4-[(4′-acetylpiperazin-1′-yl)C(O)O—]benzyl,

p-[(4′-methanesulfonylpiperazin-1′-yl)-benzyl,

3nitro-4-[(morpholin-4′-yl)-C(O)O—]benzyl,

4-{[(CH 3 ) 2 NC(S)] 2 N—}benzyl,

N-Boc-2-aminoethyl-,

4-[(1,1-dioxothiomorpholin-4-yl)-C(O)O—]benzyl,

4-[(CH 3 ) 2 NS(O) 2 —]benzyl,

4-(imidazolid-2′-one-1′-yl)benzyl,

4-[(piperidin-1′-yl)C(O)O—]benzyl,

1-N-benzyl-imidazol-4-yl-CH 2 —,

3,4-dioxyethylenebenzyl,

3,4-dioxymethylenebenzyl,

4-[—N(SO 2 )(CH 3 )CH 2 CH 2 CH 2 N(CH 3 ) 2 ]benzyl,

4-(3′-formylimidazolid-2′-one-1′-yl)benzyl,

4-[NHC(O)CH(CH 2 CH 2 CH 2 CH 2 NH 2 )NHBoc]benzyl,

[2′-[4″-hydroxy-4″-(3″′-methoxythien-2″′-yl)piperidin-2″-yl]ethoxy]benzyl, and

p-[(CH 3 ) 2 NCH 2 CH 2 N(CH 3 )C(O)O—]benzyl.

14. The pharmaceutical composition according to claim 1 or 2 wherein —CH 2 X is selected from the group consisting of benzyl, 4-aminobenzyl, 4-hydroxy-benzyl, 4-nitrobenzyl, 3-chloro-4-hydroxybenzyl, 4(phenylC(O)—NH—)benzyl, 4-(pyridin-4-ylC(O)NH—)benzyl, 4-[(CH 3 ) 2 NC(O)O—]benzyl, 4-[(1′-Cbz-piperidin-4′-yl)C(O)NH—]benzyl, 4-[(piperidin-4′-yl)C(O)—NH—]benzyl, 4-[—O—(N-methylpiperidin-4′-yl)]benzyl, 4-[(4′-methylpiperazin-1′-yl)C(O)O—]benzyl, 4-[(4′-(pyridin-2-yl)piperazin-1′-yl)C(O)O—]benzyl, 4-[(thiomorpholin-4′-yl)C(O)O—]benzyl, 3-chloro-4-[(CH 3 ) 2 NC(O)O—]benzyl, and 5-(3-N-benzyl)imidazolyl-CH 2 —.

15. The pharmaceutical composition according to claim 1 or claim 2 wherein ═CHX is CH═- φ.

16. The pharmaceutical composition according to claim 1 or 2 wherein said compound of formula IA, IB, IIA or IIB is 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-(phenylcarbonyl-amino)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—oxomorpholin-5-carbonyl)-L-phenylalanine;

N-(4-benzyl-3-oxothiomorpholin-5-carbonyl)-L-4-nitrophenylalanine methyl ester;

N-(benzyl)-L-pyroglutanamyl-L-4-(pyridin-4-ylcarbonylamino)-phenylalanine methyl ester;

N-(benzyl)-L-pyroglutamyl-L-4-(1′-benzyloxycarbonylpiperidin-4′-ylcarbonyl -amino)phenylalanine methyl ester;

N-(benzyl)-L-pyroglutamyl-L-4-(pyridin-4-ylcarbonylamino)-phenylalanine;

N-(benzyl)-L-pyroglutamyl-L-4-(1′-benzyloxycarbonylpiperidin-4′-ylcarbonyl -amino)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]phenyl alanine ethyl ester;

N-(benzyl)-L-pyroglutamyl-L-4-(1′-methylpiperidin-4′-yloxy)phenylalanine,

N-(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)carbonyl-oxy]phenyl-alanine 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 exter;

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-dimethylcarbamyl-oxy)phenylalanine tert-butyl ester;

N-(benzyl)-L-pyroglutamyl-L-3-chloro-4-(N,N-dimethylcarbamyl-oxy)phenylalanine methyl ester;

N-(4-fluorobenzyl)-L-pyroglutamyl-L-4-[(thiomorpholin-4′-yl)carbonyloxy]phenylalanine;

N-(4-cyanobenzyl)-L-pyroglutamyl-L-4-(N,N-diemthylcarbamyloxy)-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.

17. A method for treating an inflammatory condition in a mammalian patient which condition is mediated by VLA-4, wherein said inflammatory condition is selected from the group consisting of asthma, rheumatoid arthritis, multiple sclerosis, viral meningitis, encephalitis, nephritis, diabetes, atopic dermatitis and ulcerative colitis and wherein said which method comprises administering to said patient a therapeutically effective amount of a pharmaceutical composition of claim 1 or claim 2 .